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Radiation Oncology/Liver/Treatment

EBRT Whole Liver
Given the low whole-liver tolerance (~30 Gy), whole liver RT has been used historically (prior to development of conformal therapy) for palliation of painful primary and metastatic liver disease. Up to 90% of patients may report improvement in pain control. Overall survival is short (~6 months), and not improved with RT. Several RTOG attempts at improving whole-liver RT efficacy have not shown much benefit (hyperfractionation, misonidazole radiosensitization, radiolabelled antiferritin and CEA antibodies).

Please see the Whole Liver RT section for literature review.

EBRT Conformal

 * Guangxi China 1999-03 PMID 15812834 -- Hypofractionated three-dimensional conformal radiation therapy for primary liver carcinoma. (2005 Liang SX, Cancer. 2005 May 15;103(10):2181-8.)
 * Retrospective. 128 patients with inoperable primary liver CA; mean GTV 459 cm3, mean dose 53.6 Gy at average 4.9 Gy/fx
 * Response: 55%, median survival 20 months
 * Toxicity: RILD 15%, GI 8/125 patients
 * Conclusion : "Hypofractionated 3DCRT is effective in carefully selected patients with PLC. Gastrointestinal complications and RILD were the most distinct complications."

 * Changhua Taiwan 1999-03 PMID 15466827 -- Three-dimensional conformal radiation therapy for unresectable hepatocellular carcinoma patients who had failed with or were unsuited for transcatheter arterial chemoembolization. (2004 Liu MT, Jpn J Clin Oncol. 2004 Sep;34(9):532-9.)
 * Retrospective. 44 patients treated with 3D-CRT after failed/unsuitable for TACE
 * Response: 61%, median survival 15.2 months
 * Conclusion : "Although we do not know whether there is a survival benefit through the use of this treatment, 3DCRT seems to be a practical method of salvage for this subset of patients."

 * Yonsei Korea
 * 1994-00 PMID 12957204 -- Clinical results of 3-dimensional conformal radiotherapy combined with transarterial chemoembolization for hepatocellular carcinoma in the cirrhotic patients. (2003 Seong J, Hepatol Res. 2003 Sep;27(1):30-35.
 * Retrospective. 50 HCC with liver cirrhosis (38 Child A, 12 Child B). Mean tumor size 8.3cm. Treated with TACE + 3D-CRT (mean 50.1 Gy) determined by fraction liver getting 50% dose
 * Toxicity: 26% LFTs (no Grade 4), 12% RILD, 14% GI toxicity
 * Partial response 66%; 3-year survival 43%
 * Conclusion : "Radiotherapy using 3-DCRT combined with TACE can achieve a substantial tumor response and survival rate for HCC in the cirrhotic patients.

 * 1992-00 PMID 12527045 -- Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: a retrospective study of 158 patients. (2003 Seong J, Int J Radiat Oncol Biol Phys. 2003 Feb 1;55(2):329-36.)
 * Retrospective. 158 unresectable HCC treated with RT (67 Stage III, 91 Stage IVA). Mean tumor 9.0cm, liver cirrhosis in 142. RT + transarterial chemo (107 patients) or salvage (51 patients). Mean RT dose 48.2 Gy
 * 2-year (5-year) OS: 30% (9%). Response rate 67%. RT dose only predictor of survival
 * Conclusion : "Local RT achieved substantial tumor regression and survival. The radiation dose was found to be a significant prognostic factor in the RT of hepatocellular carcinoma."

 * 1992-00 PMID 12182985 -- Dose-response relationship in local radiotherapy for hepatocellular carcinoma. (2002 Park HC, Int J Radiat Oncol Biol Phys. 2002 Sep 1;54(1):150-5.)
 * Retrospective. 158 patients, no mets, no cirrhosis Class C, or tumor >2/3 volume
 * 2-year survival (response): 20% (67%)
 * Dose-response: <40 Gy 29%, 40-50 Gy 69%, >50 Gy 77%
 * Toxicity: liver <40 Gy 4.2%, 40-50 Gy 5.9%, >50 Gy 8.4%; GI 4.2%, 9.9%, 13.2%
 * Conclusion : "The present study showed the existence of a dose-response relationship in local radiotherapy for primary HCC. Only the radiation dose was a significant factor for predicting an objective response."

 * Taipei Taiwan Paper link -- Hyperfractionated Three-dimensional Conformal Radiotherapy for Small Hepatocellular Carcinoma: A Pilot Study (2002 Wang PM, Chin J Radiol 2002; 27: 281-287)
 * Retrospective. 39 patients with HCC (<5 cm) treated with 3D-CRT (45-75 Gy at 1.5 Gy/fx BID)
 * Median survival: 16.5 months
 * Toxicity: acute leukopenia 26%, LFTs 23%, GI toxicity 33%
 * Conclusion : "hyperfractionated 3-D conformal RT may be a safe, effective treatment modality in small HCC patients with preserved liver function even if they have already been treated with other therapies."

 * Tsuchiura Japan PMID 11422619 -- Radiation therapy in combination with transcatheter arterial chemoembolization for hepatocellular carcinoma with extensive portal vein involvement. (2001 Tazawa J, J Gastroenterol Hepatol. 2001 Jun;16(6):660-5.)
 * Prospective. 24 patients with HCC and extensive portal vein thrombosis treated with RT + TACE
 * PVTT response: 50% CR/PR; Child's class only factor associated with local response
 * Conclusion : "The combined therapy is feasible and may be useful to reverse PVTT in patients with good hepatic function reserve."

 * Michigan
 * 2000 PMID 10829040 -- Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. (Dawson LA, J Clin Oncol. 2000 Jun;18(11):2210-8.)
 * Prospective, phase I. 43 patients with unresectable intrahepatic hepatobiliary cancer (27 patients) and colorectal liver mets (16 patients). Large tumors (10x10x8). Median dose 58.5 Gy (1.5 BID) with concurrent FUdR.
 * Escalated RT dose associated with improved OS and PFS.
 * Conclusion : "The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies."
 * 1995 PMID 7751185 -- The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy. (Robertson JM, Int J Radiat Oncol Biol Phys. 1995 May 15;32(2):445-50.)
 * Phase I/II. 22 patients with CRC mets, RT dose escalation + IAH FdUrd. RT given as 1.5-1.65 Gy/fx BID split-course to 48-72.6 Gy, depending on liver volume treated
 * Response: 50% CR/PR; median survival 20 months. PR - 2 in-field failures, SD/PD - 5 in-field failures
 * Toxicity: no clinical RILS
 * Conclusion : "Combined conformal radiation therapy and IAH FdUrd can produce an objective response in 50% of patients with hepatic metastases from colorectal cancer. However, response was not durable, and hepatic progression was frequent. Improvements in hepatic tumor control for patients with metastatic colorectal cancer may require higher doses of conformal radiation and/or improved radiosensitization. In an effort to increase radiosensitization, we have recently initiated a clinical trial combining IAH bromode-oxyuridine, a thymidine analog radiosensitizer, with conformal high dose radiation therapy."
 * 1993 PMID 8391066 -- Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. (Robertson JM, J Clin Oncol. 1993 Jul;11(7):1286-93.)
 * 26 patients with non-met primary HB cancer (6 diffuse HCC, 11 localized HCC, 9 CCA) treated with conformal RT (48-72.6 Gy @ 1.5/1.65 Gy/fx BID) + intraarterial FdUrd (see 1991 Lawrence below)
 * Toxicity: 2 patient radiation hepatitis, 7 patients >= Grade III toxicity (5/7 whole liver RT)
 * Conclusion : "These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer."
 * 1991 PMID 1847363 -- Treatment of cancers involving the liver and porta hepatis with external beam irradiation and intraarterial hepatic fluorodeoxyuridine. (Lawrence TS, Int J Radiat Oncol Biol Phys. 1991 Mar;20(3):555-61.)
 * Phase I/II trial of RT (30 Gy total liver @ 1.5 Gy/fx BID + 15/30 Gy boost depending on DVH) + intraarterial FdUrd as radiosensitizer; 33 patients reported
 * 20 patients whole liver only, 6 patients 15 Gy boost, 7 patients 30 Gy boost
 * Toxicity: GI but <=Grade 2, 2 radiation hepatitis
 * Response: 48% (14/29) had objective CT-scan response
 * Conclusion : "These data suggest that the treatment of intrahepatic malignancies can be guided by the concept of DVH analysis of the normal liver to allow the safe administration of doses of radiation that are potentially tumoricidal and are well above those that would be predicted to be tolerable for the whole liver."

 * Yonsei Korea 1993-97 PMID 10889387 -- Local radiotherapy for unresectable hepatocellular carcinoma patients who failed with transcatheter arterial chemoembolization. (2000 Seong J, Int J Radiat Oncol Biol Phys. 2000 Jul 15;47(5):1331-5.)
 * Prospective. 27 patients with unresectable HCC who failed TACE; mean tumor 7.2 cm, treated with conformal RT mean 51.8 Gy in 1.8 Gy/fx
 * Response: 67% PR/CR, median survival 14 months from RT
 * Toxicity: acute LFTs, thrombocytopenia, gastroduodenal ulcer/duodenitis
 * Conclusion : "In unresectable HCC patients who failed with TACE, local RT induced a substantial tumor response of 66.7%, with a 3-year survival rate of 21.4% and a median survival time of 14 months. Toxicity was significant but manageable. Although we do not know if there is survival benefit through this treatment, local RT in these patients seems to be valuable as a salvage for TACE-failed HCC."

 * Taiwan 1993-96 PMID 10530500 -- A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma. (1999 Cheng SH, J Gastroenterol Hepatol. 1999 Oct;14(10):1025-33.)
 * Prospective. 13 patients (9 3D-CRT alone, 4 3D-CRT + TACE)
 * Tumor median 15 cm (6-25cm); dose 40-60 Gy; PR 58%
 * Conclusion : "Our experience indicates that HCC is more radiosensitive than it was traditionally expected. Three-dimensional reconstruction of tumour and surrounding organs helps to avoid excessive exposure of the liver and adjacent organs to RT and makes it a safer treatment modality for unresectable HCC."

 * Yonsei Korea 1992-94 PMID 10030267 -- Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma. (1999 Seong J, Int J Radiat Oncol Biol Phys. 1999 Jan 15;43(2):393-7.)
 * Prospective. 30 patients with unresectable HCC. TACE + RT (mean 44 Gy)
 * 2-year survival (response): 33% (63%)
 * Toxicity: transient LFTs, fever 67%, thrombocytopenia 13%
 * Conclusion : "Combined TACE and local RT is feasible and tolerable. It gives a 63.3% response rate with median survival of 17 months. We feel that this regimen would be a new promising modality in unresectable HCC."

 * Yonsei Korea
 * 1988-91 PMID 7975734 -- Combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma. (1994 Seong J, Yonsei Med J. 1994 Sep;35(3):252-9.)
 * Prospective. 84 patients treated with hyperthermia ~40C + EBRT 30.6 Gy
 * Response: 40% regression >50% tumor volume; symptomatic improvement in 79%
 * Median survival (2-year OS): 6 months (20%)
 * Conclusion : "In view of acceptable toxicities and the current rate of survival, further evaluation of combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma is warranted."

 * 1988 PMID 1281042 -- Phase II trial for combined external radiotherapy and hyperthermia for unresectable hepatoma. (1992 Kim BS, Cancer Chemother Pharmacol. 1992;31 Suppl:S119-27.)
 * Phase II. Hyperthermia + EBRT 30.6 Gy
 * Median survival: 34% (50% for partial response). Partial response 40%, relief in abdominal pain 79%.
 * Conclusion : "although this study is being continued, the results obtained thus for indicate that combined radiotherapy and hyperthermia seem to be effective in providing local tumor control and pain palliation in unresectable hepatocellular carcinoma while producing an acceptable level of toxicity."

 * Michigan PMID 2211241 -- An application of dose volume histograms to the treatment of intrahepatic malignancies with radiation therapy. (1990 Lawrence TS, Int J Radiat Oncol Biol Phys. 1990 Oct;19(4):1041-7.)
 * Protocol using DVH to determine dose to be delivered (45 Gy if >50% liver could be excluded, 60 Gy if >75% liver could be excluded)
 * Conclusion : "These results show that intrahepatic tumors can be safely treated with high doses of radiation when dose prescription is guided by the dose volume histogram of the normal liver."

EBRT Treatment Planning

 * Michigan PMID 16095848 -- Evaluating the influence of setup uncertainties on treatment planning for focal liver tumors. (2005 Balter JM, Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):610-4.)
 * 8 patients on protocol with online setup measurement/adjustment. Ventilatory immobilization.
 * L-R variation: individual 2.5-5.7 mm, group 4.2 mm
 * A-P variation: individual 2.1-8.3 mm, group 4.1 mm
 * C-C variation: individual 4.1-10.8 mm, group 7.0 mm
 * Initial static plan overestimated volume of liver treated to high dose, shifting some areas to lower doses due to setup uncertainties

 * Duke PMID 16317267 -- Retrospective clinicopathologic correlation of gross tumor size of hepatocellular carcinoma: implications for stereotactic body radiotherapy. (2005 Kelsey CR, Am J Clin Oncol. 2005 Dec;28(6):576-80.)
 * Retrospective. 18 patients with 27 tumors. Pre-op CT or MRI imaging compared to gross path
 * Median radiographic size 2.9cm, median pathologic size 2.5cm. Radiographic size greater in 81% tumors
 * Conclusion : "Our study shows that in most instances (81%), imaging by CT or MRI overestimates true gross pathologic size of HCC. Nineteen percent of tumors appeared smaller on preoperative imaging than on the final pathologic specimen. Radiation therapy utilizing a 0.5 or 1.0 cm margin around the radiographic tumor would have encompassed the gross pathologic tumor in 93% and 100% of cases, respectively."

 * Michigan PMID 15890602 -- Benefit of using biologic parameters (EUD and NTCP) in IMRT optimization for treatment of intrahepatic tumors. (2005 Thomas E, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):571-8.)
 * 15 patients initially planned with 3D-CRT, replanned with IMRT to maximize generalized equivalent uniform dose (gEUD) and NTCP
 * IMRT significantly increased max gEUD by 11 Gy (high grade), 18 Gy (low grade), and 10 Gy (nonoverlap)
 * Conclusion : "We have successfully used mathematical/biologic models directly as cost functions within the optimizing process to produce IMRT plans that maximize the gEUD while maintaining compliance with a well-defined protocol for the treatment of intrahepatic cancer. For both PTV-organ-at-risk overlap and nonoverlap situations, IMRT has the capacity to improve the maximal dose achievable across the PTV, expressed in terms of the gEUD. The use of multiple noncoplanar beams appears to confer an advantage over fewer beams in cases with PTV-organ-at-risk overlap. When liver toxicity is the dose-limiting factor, high gEUD values are obtained most frequently when the field arrangement is chosen to provide the shortest possible transhepatic path length."

 * Princess Margaret ASTRO Abstract A Prospective Comparison Study of Liver Tumour Target Definition Based on Triphasic CT and Gadolinium MR (2005 Voroney JJ, ASTRO 2005 #2088)
 * 23 patients (CCA 4, HCC 10, liver mets 9) on protocol; liver immobilized using ABC/voluntary breath hold. Best CT (arterial phase for HCA, venous phase for CCA and mets), best MRI T1 gado
 * Average GTV difference 11cc (1-263); CT GTV larger in 3/7 mets, 4/4 CCA, 6/11 HCA
 * Conclusion : "MR defined GTVs can be significantly different than CT defined GTVs and this should be considered for high precision liver cancer radiotherapy."

 * Princess Margaret PMID 14752735 -- Interventions to reduce organ motion effects in radiation delivery. (2004 Dawson LA, Semin Radiat Oncol. 2004 Jan;14(1):76-80.)
 * Review of 1) altering breathing patterns and 2) breath holding techniques

 * Michigan PMID 14630287 -- Alterations in normal liver doses due to organ motion. (2003 Rosu M, Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1472-9.)
 * Recalculation of 40 patients to include effect of setup undertainties and liver motion due to patient breathing
 * Actual minimum CTV dose met or exceeded PTV dose from static plan in 39/40 cases (=>adquate PTV)
 * However, clinically and statistically significan change in NTCP for tumors at top and bottom of liver (range from +12% to -12%); corresponding to dose adjustment -4 Gy to +8 Gy for original NTCP
 * Conclusion : "Although the PTV concept can ensure adequate CTV coverage, the doses to normal liver are incorrectly modeled without including patient-related geometric uncertainties."

 * Memorial PMID 12573753 -- Respiratory gating for liver tumors: use in dose escalation. (2003 Wagman R, Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):659-68.)
 * Prospective. 10 patients, 177 treatments. Evaluation of Varian Real-Time Positioning Monitor
 * Reproducible decrease in organ motion with gating enabled reduction in GTV-to-PTV margin from 2 to 1 cm. Calculated dose increased 7%-27% (median 21%)
 * Conclusion : "Gating of radiotherapy for liver tumors enables safe margin reduction on tumor volume, which, in turn, may allow for dose escalation."

 * Taiwan PMID 12694843 -- Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease. (2003 Cheng JC, Int J Radiat Oncol Biol Phys. 2003 May 1;56(1):229-34.)
 * Retrospective. 12/68 HCC patients developed RILD, and replanned with IMRT 5F step-shoot
 * Comparable target coverage, IMRT better with SC, similar kidney, stomach. IMRT significant reduction in NTCP (24% vs. 37%, p=0.009) but significant increase in mean dose (29.2 vs. 25.0 Gy, p=0.009)
 * Conclusion : "IMRT is capable of preserving acceptable target coverage and improving or at least maintaining the nonhepatic organ sparing for patients with HCC and previously diagnosed RILD after 3D-CRT. The true impact of this technique on the liver remains unsettled and may depend on the exact volume effect of this organ."

 * Michigan PMID 11728702 -- The reproducibility of organ position using active breathing control (ABC) during liver radiotherapy. (2001 Dawson LA, Int J Radiat Oncol Biol Phys. 2001 Dec 1;51(5):1410-21.)
 * Conclusion : "Radiotherapy using ABC for patients with intrahepatic cancer is feasible, with good intrafraction reproducibility of liver position using ABC. However, the interfraction reproducibility of organ position with ABC suggests the need for daily on-line imaging and repositioning if treatment margins smaller than those required for free breathing are a goal."

 * PMID 2998178 -- Computed tomography assisted volumetric analysis of primary liver tumor as a measure of response to therapy. (1985 Ettinger DS, Am J Clin Oncol. 1985 Oct;8(5):413-8.)
 * Volumetric CT analysis in 33 patients.
 * Conclusion : "In spite of small changes in total liver volume, there may be concomitantly substantial changes in tumor volume.

Stereotactic Radiotherapy

 * Ongoing: RTOG 04-38 (2005-ongoing)
 * Dose escalation. 35 Gy to 50 Gy in 10 fractions.

 * Colorado; 2009 PMID 19255321 -- "Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases." (Rusthoven KR; J Clin Oncol 2009 April 1; 27(10):1572-1578)
 * Prospective phase I/II trial of 47 patients with 63 liver metastases.
 * Required to (1) have 3 or fewer lesions and (2) largest lesion be <6cm in greatest dimension.
 * Dose escalated from 36Gy/3fx to 60Gy/3fx in phase I w/o DLT
 * Phase II dose 60Gy/3fx
 * Local control at 1yr and 2yr was 95% and 92%, respectively
 * Local control for lesions <3cm was 100%
 * Median survival 20.5mo
 * Conclusion: SBRT results in excellent LC for liver metastases. May be able to acheive long term DFS in well selected patients with favorable histology

 * Rotterdam (The Netherlands)
 * 2006 PMID 16982547 -- "Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study." (Mendez Romero A, Acta Oncol. 2006;45(7):831-7.)
 * Phase I/II. 25 patients with 45 liver tumors (34 mets, 11 HCC). Median F/U 13 months. RT 25/5 or 30/3 or 37.5/3. Median lesion 3.2cm (0.5-7.2)
 * Outcome: 2-year local control: 82%
 * Toxicity: 3 mets patients Grade 3, 1 HCC patient Grade 5 (liver failure), 1 late toxicity (portal HTN)
 * 2007 PMID 17996394 -- "Quality of Life After Stereotactic Body Radiation Therapy for Primary and Metastatic Liver Tumors." (Romero AM, Int J Radiat Oncol Biol Phys. 2007 Nov 7 [Epub ahead of print])
 * QoL secondary end point. 28 patients. Evaluated with EQ-5D, EQ-5D VAS, and QLQ C-30 quality of life instruments
 * Outcome: No change after SBRT, tendency toward improvement
 * Conclusion: SBRT high local control with no significant change in quality of life

 * Rochester, 2006 PMID 17197128 -- "Hypofractionated stereotactic body radiation therapy (SBRT) for limited hepatic metastases." (Katz AW, Int J Radiat Oncol Biol Phys. 2006 Dec 28)
 * Prospective. 69 patients, 174 liver mets from colon (20), breast (16), pancreas (9), lung (5). Median F/U 14 months
 * Median lesion 2.7 cm (0.6-12.2). SRT median dose 48 Gy in 2-6 Gy/fx.
 * 20-month LC: 57% tumor-based. Median OS 14 months
 * Toxicity: no Grade 3+

 * Multi-institutional US
 * 2006 PMID 16982549 -- "Interim analysis of a prospective phase I/II trial of SBRT for liver metastases." (Kavanagh BD, Acta Oncol. 2006;45(7):848-55.)
 * Phase I/II. 7 institutions. 36 patients, mets from lung (10), CRC (9), breast (4), other (13)
 * Criteria: diameter <6 cm, <=3 lesions, 700 cm3 liver <=15 Gy. PTV = GTV + 5-10 mm. RT 20Gy x3
 * Toxicity: No Grade 4, 1 Grade 3
 * 18-month local control: 93%
 * 2005 PMID 16029795 -- "A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases." (Schefter TE, Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1371-8.)
 * Phase I. RT 12Gy x3 escalation to 20Gy x3. Criteria as above.
 * No dose-limiting toxicity. Basis for Phase II of 20Gy x3

 * Princess Margaret, 2006 PMID 16982550 -- "Individualized image guided iso-NTCP based liver cancer SBRT." (Dawson LA, Acta Oncol. 2006;45(7):856-64.)
 * Phase I/II. 79 patients with HCC (33), IHC (12) or liver mets (34).
 * RT: prescription based on NTCP to maintain given risk of RILD to max 60/6 (median dose 36.6/6)

 * Wuerzburg (Germany)
 * 2006 PMID 16982548 -- "Stereotactic radiotherapy of primary liver cancer and hepatic metastases." (Wulf J, Acta Oncol. 2006;45(7):838-47.)
 * Prospective. 39 patients with 51 liver mets and 5 patients with HCC. RT "low dose" (30/3, 28/4) or "high dose" (36/3, 37.5/3, 26/1). Median F/U 15 months
 * Local control: 1-year 92% (low dose 86% vs. high dose 100%), 2-year 66% (low dose 58% vs. high dose 82%)
 * OS: 1-year 72%, 2-year 32%
 * Toxicity: None severe
 * 2001 PMID 11789403 -- "Stereotactic radiotherapy of targets in the lung and liver" (Wulf J, Strahlenther Onkol. 2001 Dec;177(12):645-55.)
 * Phase I. 51 patients (27 lung, 24 liver). Median F/U 9 months
 * Crude local control: 85% pulmonary and 83% hepatic targets
 * 1-year OS: 48%
 * Toxicity: no acute Grade 3-5; 2 late toxicities (Grade 3 esophageal ulceration, Grade 5 pulmonary artery bleeding)

 * Aarhus, 2006 (Denmark) PMID 16982546 -- "Phase II study on stereotactic body radiotherapy of colorectal metastases." (Hoyer M, Acta Oncol. 2006;45(7):823-30.)
 * Phase II. 64 patients with 141 CRC mets in liver (44), lung (12), LNs (3) or other (5). RT: 15 Gy x3. Median F/U 4.3 years
 * 2-year LC: 86% tumor-based, 63% patient-based. 19/64 patients without progression
 * OS: 2-year 38%; 5-year 13%
 * Side effects: 1 death from hepatic failure, 1 colonic perforation, 2 duodenal ulcerations

 * Stanford, 2005 ASTRO Abstract "Phase I Dose Escalation Study of CyberKnife Stereotactic Radiosurgery for Liver Malignancies" (Lieskovsky YC, ASTRO 2005 #2089)
 * Phase I. 6 patients/7 tumors (1 IH-CCA, 7 mets). Tumors <5cm. Treatment delivered with motion tracking of implanted fiducials
 * Dose escalation: 3 tumors with 18 Gy, 4 tumors with 22 Gy. MTD not reached. Toxicity: 1 GI Grade 1
 * Response: 4 PR
 * Conclusion : "Results thus far indicate that single fractions of 18 and 22 Gy are safe to administer to liver tumors with the CyberKnife. We have not yet reached the MTD at 22 Gy. We plan to dose-escalate to 30 Gy."

 * Heidelberg (Germany)
 * 2004 PMID 15458194 -- "Stereotactic radiation therapy of liver metastases: update of the initial phase-I/II trial." (Herfarth KK, Front Radiat Ther Oncol. 2004;38:100-5.)
 * No abstract
 * 2003 PMID 12957256 -- "Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors." (Herfarth KK, Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):444-51.)
 * 131 CT scans in 36 patients
 * Response: 74% of posttherapeutic scans showed sharply demarcated hypodense area surrounding treated tumor, at median 1.8 months. Reaction volume decreased with longer follow-up
 * Conclusion : "A focal radiation reaction occurs after stereotactic single-dose therapy in the liver. The volume of the reaction decreases and changes its radiologic appearance during follow-up. This reaction has to be differentiated from recurrent tumor."
 * 2001 PMID 11134209 -- "Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial." (Herfarth KK, J Clin Oncol. 2001 Jan 1;19(1):164-70.)
 * Phase I/II. 37 patients, 60 tumors (4 primary, 56 mets). Dose escalation 14 to 26 Gy.
 * Toxicity: no major side effects
 * Tumor control: 81% at 18 months (max 16 months); 4 CR, 28 PR, 22 SD at 6 weeks
 * Conclusion : "Stereotactic single-dose radiation therapy is a feasible method for the treatment of singular inoperable liver metastases with the potential of a high local tumor control rate and low morbidity."
 * 2000 PMID 10661339 -- "Extracranial stereotactic radiation therapy: set-up accuracy of patients treated for liver metastases." (Herfarth KK, Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):329-35.)
 * Phase I/II. 24 patients with liver mets. Liver movement reduced by abdominal pressure
 * Movement: diaphragm 7 mm (3-13), lateral 1.8 mm (0.3-5.0), AP 2.0 mm (0.8-3.8), CC <5mm. Repositioning necessary in 16/26 occasions
 * Conclusion : "In patients with liver metastases, a high set-up accuracy of the body and the target can be achieved. This allows a high-dose focal radiotherapy of these lesions. However, a control CT scan should be performed directly before therapy to confirm set-up accuracy and possibly prompt necessary corrections.

 * Karolinska (Sweden)
 * 2003 PMID 14571698 -- "Radiosurgery for recurring liver metastases after hepatectomy." (Gunven P, Hepatogastroenterology. 2003 Sep-Oct;50(53):1201-4.)
 * Retrospective. 14/18 liver recurrences after resection suitable for RS (20 Gy x2 or 15 Gy x3)
 * 100% local control, 2 CR. Only 1 recurrence in liver.
 * Conclusion : "Radiosurgery of liver tumors merits further study, and may offer a less demanding alternative to resection for selected liver tumors with the prospect of long-term survival."
 * 1995 PMID 7576756 -- "Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients." (Blomgren H, Acta Oncol. 1995;34(6):861-70.)
 * Initial report. 42 tumors in 31 patients (liver, lung, retroperitoneal)
 * CTV mean 78 cm3 (2-622), PTV dose mean 41 Gy (6-66)
 * No progression in 80% during follow-up (1.5-38)

SBRT Treatment Planning

 * Michigan; 2008 PMID 17855011 -- "Liver function after irradiation based on computed tomographic portal vein perfusion imaging." (Cao Y, Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):154-60. Epub 2007 Sep 12.)
 * Dynamic CT-based portal vein flow evaluation, after RT. Dose 45-84 Gy
 * Outcome: Volume of liver with no flow ranged 0-39% at 1 month; significant correlation with indocyanine green clearance
 * Conclusion: Substantial individual variability in liver sensitivity to radiation. Hepatic perfusion imaging may be a marker useful for individualizing therapy

 * Charite, 2006 (Germany) PMID 16982554 -- "Image guided respiratory gated hypofractionated Stereotactic Body Radiation Therapy (H-SBRT) for liver and lung tumors: Initial experience." (Wurm RE, Acta Oncol. 2006;45(7):881-9.)
 * Novalis. Patients with liver and lung.
 * RT 8-11 fractions, dose 74.8-79.2 Gy. Average daily marker deviation 4mm from plan.
 * Conclusion: Novalis is accurate and feasible for real-time respiratory gating

 * Virginia
 * 2006 PMID 16904845 -- "Dose as a function of liver volume and planning target volume in helical tomotherapy, intensity-modulated radiation therapy-based stereotactic body radiation therapy for hepatic metastasis." (Baisden JM, Int J Radiat Oncol Biol Phys. 2006 Oct 1;66(2):620-5.)
 * Dosimetry analysis for HiArt TomoTherapy up to 20 Gy x3.
 * Development of predictive equation for maximum tolerated dose
 * 2005 ASTRO Abstract Helical Tomotherapy SBRT for Liver Metastases: Recommendations for Potential Candidates Based on Tumor Size and Location. (Baisden JM, ASTRO 2005, Abstract 2095)
 * Inverse treatment stimulation in several liver locations to determine size and location treatable. Liver divided into L lobe, RU lobe, RL lobe; 5mm radial expansion of GTV to create PTV. Minimum dose 60 Gy in 3fxs.
 * Conclusion : "The HiArt Helical Tomotherapy system is capable of performing high dose liver SBRT that meets the specified target and normal organ constraints. This study provides broad initial screening eligibility criteria for patients with hepatic metastases who may be suitable for TomoTherapy-based liver SBRT. These guidelines are: for left lobe tumors; a GTV of 3 cm in diameter and a GTV that is at least 13 mm from the heart and 8 mm from the stomach; for right upper lobe tumors; a GTV of 5 cm in diameter that is at least 13 mm from the heart; for right lower lobe tumors; a GTV of 5 cm in diameter that is at least 8 mm from small bowel."

 * Aarhus, 2005 PMID 16246744 -- Comparison of two dose calculation methods applied to extracranial stereotactic radiotherapy treatment planning. (Traberg Hansen A, Radiother Oncol. 2005 Oct;77(1):96-8.)
 * Retrospective. 18 patients with single lung tumor, 8 patients with single liver tumor
 * Comparison of pencil beam convolution vs. collapsed cone convolution
 * Liver: CTV dose almost identical
 * Lung: Mean CTV dose different by up to 20%

Interstitial brachytherapy

 * Ohio State 1989-02 ASTRO Abstract Long Term Follow-Up of Patients of Intrahepatic Malignancies Treated with Iodine-125 Brachytherapy (2005 Nag S, ASTRO 2005 #2086)
 * Retrospective. 64 patients (54 mets CRC, 2 mets non-CRC, 4 CCA) treated with permanent BT 160 Gy; R1 59%, R2 41%; median follow-up 13.2 years
 * Median survival (5-year OS): 20 months (5%). Higher for small implants and without prior resection
 * Local control (5-year): median 9 months (22%)
 * Conclusion : "Permanent I-125 brachytherapy is a safe and effective adjuvant treatment for unresectable intrahepatic malignancies. It is a simple technique with morbidity and mortality rates comparable to liver resection alone. Patients considered good candidates for I-125 brachytherapy include those with small volume implants, those without prior liver resection, and those with solitary liver metastases.

 * Berlin Germany
 * PMID 15050329 -- CT-guided interstitial brachytherapy of liver malignancies alone or in combination with thermal ablation: phase I-II results of a novel technique. (2004 Ricke J, Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1496-505.)
 * Phase II. 37 patients. 21 patients treated with CT-guided HDR alone, 16 patients BT after MRI-guided LITT (laser-induced thermotherapy). BT alone if tumor >5cm, adjacent to CBD or adjacent to major vessels, technical failure of LITT.
 * Mean tumor size 4.6cm (2.5-11cm); severe complications in 2 patients (liver failure, obstructive jaundice)
 * Local control: 73% LITT+BT, 87% BT alone
 * Conclusion : "CT-guided brachytherapy using three-dimensional CT data for dosimetry is safe and effective alone or in combination with LITT. Brachytherapy as a stand-alone treatment displayed genuine advantages over thermal tumor ablation."

 * PMID 15525748 -- Liver malignancies: CT-guided interstitial brachytherapy in patients with unfavorable lesions for thermal ablation. (2004 Ricke J, J Vasc Interv Radiol. 2004 Nov;15(11):1279-86.)
 * Phase II. 20 patients (19 liver mets, 1 cholangiocarcinoma) treated with CT-guided HDR. Group A (n=11, liver tumors >5cm), Group B (n=9, liver tumors <5cm adjacent to hilum). Average dose 17 Gy (12-25 Gy). Median follow-up 13 months
 * Severe side effects 2 patients (10%): obstructive jaundice from tumor edema, intra-abdominal hemorrhage. Frequent LFT elevation without clinical symptoms
 * 1-year local tumor control: Group A 40%, Group B 71%. After CT-guided HDR retreatment 93% overall control
 * Conclusion : "CT-guided brachytherapy based on individual dose plans and 3D CT data sets generated encouraging results in large liver malignancies as well as in tumors located adjacent to the liver hilum."

Microsphere therapy
Two products utilizing 90yttrium microspheres:
 * TheraSpheres (Wikipedia entry; MDS Nordion) - glass beads bound with Y-90
 * SIR-Spheres (Sirtex) - resin with Y-90 in matrix

Y-90 characteristics: pure beta emitter, average energy 0.94 MeV, tissue penetration 2.5 mm, maximum range 1.1 cm. Half life 64.2 hrs.

 * REBOC Recommendations (Radioembolization Brachytherapy Oncology Consortium)
 * 2007 - PMID 17448867 — Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. (Kennedy A, Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):13-23.)

 * SIRFLOX Trial (2006-2013) -- mFOLFOX6 vs mFOLFOX6 + SIRT
 * Randomized. 530 patients. Chemotherapy naïve metastatic colorectal cancer, with liver mets plus/minus limited extrahepatic mets.
 * PMID 26903575 -- "SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer." (van Hazel GA, J Clin Oncol. 2016 Feb 22. pii: JCO661181. [Epub ahead of print])
 * Outcome: Median PFS at any site control 10.2 vs SIRT 10.7 (NS). Median PFS in liver 12.6 vs 20.5 months (SS)
 * Toxicity: Grade 3+ in 73% vs 85%
 * Conclusion: Addition of SIRT to FOLFOX did not improve PFS at any site, but significantly delayed disease progression in the liver

title: Radiation Oncology/Liver/Treatment


text:
X86 Assembly/X86 Interrupts

Interrupts are special routines that are defined on a per-system basis. This means that the interrupts on one system might be different from the interrupts on another system. Therefore, it is usually a bad idea to rely heavily on interrupts when you are writing code that needs to be portable.

What is an Interrupt?
In modern operating systems, the programmer often doesn't need to use interrupts. In Windows, for example, the programmer conducts business with the Win32 API. However, these API calls interface with the kernel, and the kernel will often trigger interrupts to perform different tasks. In older operating systems (specifically DOS), the programmer didn't have an API to use, and so they had to do all their work through interrupts.

Interrupt Instruction
This instruction issues the specified interrupt. For instance:

Calls interrupt 10 (0x0A (hex) = 10 (decimal)).

Types of Interrupts
There are 3 types of interrupts: Hardware Interrupts, Software Interrupts and Exceptions.

Hardware Interrupts
Hardware interrupts are triggered by hardware devices. For instance, when you type on your keyboard, the keyboard triggers a hardware interrupt. The processor stops what it is doing, and executes the code that handles keyboard input (typically reading the key you pressed into a buffer in memory). Hardware interrupts are typically asynchronous - their occurrence is unrelated to the instructions being executed at the time they are raised.

Software Interrupts
There are also a series of software interrupts that are usually used to transfer control to a function in the operating system kernel. Software interrupts are triggered by the instruction int. For example, the instruction "int 14h" triggers interrupt 0x14. The processor then stops the current program, and jumps to the code to handle interrupt 14. When interrupt handling is complete, the processor returns flow to the original program.

Exceptions
Exceptions are caused by exceptional conditions in the code which is executing, for example an attempt to divide by zero or access a protected memory area. The processor will detect this problem, and transfer control to a handler to service the exception. This handler may re-execute the offending code after changing some value (for example, the zero dividend), or if this cannot be done, the program causing the exception may be terminated.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: X86 Assembly/X86 Interrupts


text:
Radiation Oncology/Liver/Treatment/Whole Liver RT

External Beam
Given the low whole-liver tolerance (~30 Gy), whole liver RT has been used historically (prior to development of conformal therapy) for palliation of painful primary and metastatic liver disease. Up to 90% of patients may report improvement in pain control. Overall survival is short (~6 months), and not improved with RT. Several RTOG attempts at improving whole-liver RT efficacy have not shown much benefit (hyperfractionation, misonidazole radiosensitization, radiolabelled antiferritin antibody).

 * Meta-RTOG PMID 9612600 -- Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center. (1998 Abrams RA, Cancer J Sci Am. 1998 May-Jun;4(3):178-84.)
 * Meta-analysis of 1) RTOG 83-19, 2) Hopkins pilot study, 3) RTOG 88-23 during 1983-1991
 * Induction (EBRT 21.0 Gy at 3.0 Gy/fx) + radiosensitizing chemo, followed by 1) doxorubicin + 5-FU +/- 131-I-antiferritin, 2) intrahepatic artery cisplatin, or 3) intrahepatic artery cisplatin +/- 131-I-antiferritin, respectively.
 * 131-I-antiferritin: no improvement on survival, dramatic increase in hematologic toxicity
 * Intrahepatic artery cisplatin: significantly better than doxorubicin/5-FU
 * Conclusion : "Patients with unresectable alpha-fetoprotein-positive hepatocellular carcinoma experienced improved survival and decreased toxicity when managed with post-induction cycles of intra-arterial cisplatin as compared with intravenous doxorubicin and 5-FU. Intravenous 131I-polyclonal antiferritin did not improve survival when added to either post-induction regimen but dramatically increased hematologic toxicities."

 * RTOG 84-05 PMID 8365932 -- Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol. (1993 Russell AH, Int J Radiat Oncol Biol Phys. 1993 Sep 1;27(1):117-23.)
 * Phase I/II. Dose escalation 27 -> 33 Gy in 1.5 Gy BID
 * No patients at 30 Gy showed RILD, 10% patients at 33 Gy showed RILD (study closed)
 * No impact on OS
 * Conclusion : "The study design could not credibly establish a safe dose for hepatic irradiation, however, it did succeed in determining that 33 Gy in fractions of 1.5 Gy is unsafe, carrying a substantial risk of delayed radiation injury. The absence of apparent late liver injury at the 27 Gy and 30 Gy dose levels suggests that a prior clinical trial of adjuvant hepatic irradiation in patients with resected colon cancer may have employed an insufficient radiation dose (21 Gy) to fully test the question."

 * RTOG PMID 2180867 -- Accelerated fractionation radiation therapy for liver metastases: selection of an optimal patient population for the evaluation of late hepatic injury in RTOG studies. (1990 Leibel SA, Int J Radiat Oncol Biol Phys. 1990 Mar;18(3):523-8.
 * Retrospective review of RTOG 76-05 and 80-03 (both liver mets studies). 190 patients selected
 * Favorable characteristics: KPS >=80, CRC primary, no extrahepatic mets

 * RTOG PMID 2557307 -- 194 hepatocellular cancers treated by radiation and chemotherapy combinations: toxicity and response: a Radiation Therapy Oncology Group Study. (1989 Stillwagon GB, Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1223-9.)
 * Prospective. HCC. Arms were 1) 135 patients (70% mets/recurrent) EBRT 21.0 Gy (3.0 Gy/fx) + low dose Adriamycin vs. 2) 59 patients (80% mets/recurrent) hyperfractionated EBRT 24.0 Gy (1.2 Gy/fx BID) + low dose Adriamycin
 * Response: single fraction 22% vs. BID fraction 18% (p=NS)
 * Toxicity: Esophagitis and thrombocytopenia significantly higher in BID arm
 * Conclusion : "Hyperfractionated radiation did not demonstrate a significant benefit over standard daily radiation, but acute toxicity appeared to be higher."

 * RTOG 8003 PMID 3597149 -- A comparison of misonidazole sensitized radiation therapy to radiation therapy alone for the palliation of hepatic metastases: results of a Radiation Therapy Oncology Group randomized prospective trial. (1987 Leibel SA, Int J Radiat Oncol Biol Phys. 1987 Jul;13(7):1057-64.)
 * Phase III. EBRT (whole liver to 21 Gy in 3 Gy/fx) +/- misonidazole. 187 patients
 * Conclusion : "The addition of misonidazole did not significantly improve the therapeutic response to radiation therapy in any of the parameters studied."

 * PMID 2950753 -- Treatment of liver metastases with a combination of chemotherapy and hyperfractionated external radiation therapy. (1987 Raju PI, Am J Clin Oncol. 1987 Feb;10(1):41-3.)
 * Prospective. 12 patients with CRC liver mets treated with intraarterial 5-FUdR + RT (21 Gy in 1.5 Gy/fx BID)
 * Conclusion : "Hyperfractionated external radiotherapy with concomitant 5-FUdR hepatic artery of 5-FU i.v. infusion therapy for liver metastases was well-tolerated, and both subjective and objective response and quality of survival were noted."

 * RTOG 76-05 PMID 6168623 -- The palliation of hepatic metastases: results of the Radiation Therapy Oncology Group pilot study. (1981 Borgelt BB, Int J Radiat Oncol Biol Phys. 1981 May;7(5):587-91.)
 * Prospective, non-randomized. 109 patients with liver mets.
 * RT: Single met: 30.4/19 +/- 20 Gy boost or 30/15 +/- 20 Gy boost; Multiple mets: 30/15 or 25.6/16 or 20/10 or 21/7
 * Toxicity: No RILD.
 * Conclusion: 21/7 best palliative regimen

 * PMID 77184 -- Palliation of hepatic metastasis. (1978 Sherman DM, Cancer. 1978 May;41(5):2013-7.)
 * Retrospective. 55 patients, 24 Gy in 3 Gy/fx; 31 patients concomitant chemotherapy
 * 90% had significant palliation of symptoms
 * Median survival 4.5 months; median survival 9 months of excellent responders (38%) comparable to arterial CT
 * Conclusion : "The median survival of patients having an excellent response to radiation is comparable to that of patients having regional arterial chemotherapy while incuring fewer complications."

 * PMID 66224 -- Irradiation of hepatic metastases. (1977 Prasad, Int J Radiat Oncol Biol Phys. 1977 Jan-Feb;2(1-2):129-32.)
 * No abstract.

 * PMID 47404 -- Palliative irradiation for liver metastases. (1975 Turek-Maischeider M, JAMA. 1975 May 12;232(6):625-8.)
 * Retrospective. 11 patients treated to 25 Gy at 1.5 Gy/fx
 * 8 good response, 2 moderate response, 1 failure
 * Conclusion : "The impression is that radiation therapy is valuable for the treatment of symptomatic liver metastases in the young patient who does not have a terminal condition."

Radiolabeled antibodies
The studies with 131-I Antiferritin and 131-I CEA were done in the 1980's in an effort to improve efficacy of whole liver RT.

131-I-Antiferritin
 * PMID 9612600 -- Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center. (1998 Abrams RA, Cancer J Sci Am. 1998 May-Jun;4(3):178-84.)
 * Meta-analysis of 1) RTOG 83-19, 2) Hopkins pilot study, 3) RTOG 88-23 during 1983-1991
 * Induction (EBRT 21.0 Gy at 3.0 Gy/fx) + radiosensitizing chemo, followed by 1) doxorubicin + 5-FU +/- 131-I-antiferritin, 2) intrahepatic artery cisplatin, or 3) intrahepatic artery cisplatin +/- 131-I-antiferritin, respectively.
 * 131-I-antiferritin: no improvement on survival, dramatic increase in hematologic toxicity
 * Intrahepatic artery cisplatin: significantly better than doxorubicin/5-FU
 * Conclusion : "Patients with unresectable alpha-fetoprotein-positive hepatocellular carcinoma experienced improved survival and decreased toxicity when managed with post-induction cycles of intra-arterial cisplatin as compared with intravenous doxorubicin and 5-FU. Intravenous 131I-polyclonal antiferritin did not improve survival when added to either post-induction regimen but dramatically increased hematologic toxicities."

 * PMID 1850722 -- A randomized prospective trial comparing full dose chemotherapy to 131I antiferritin: an RTOG study. (1991 Order S, Int J Radiat Oncol Biol Phys. 1991 May;20(5):953-63.)
 * Phase I/II (83-01). Non-resectable HCC. EBRT + CRT induction followed by 131-I Antiferritin
 * Response: 48% CR/PR, AFP+ median survival 5 months, AFP- median survival 10.5 months
 * Phase III (83-19). Non-resectable HCC. EBRT + CRT induction followed by randomization to 131-I Antiferritin or doxorubicin/5-FU
 * Response: Comparable in 2 arms (20-30% response; 6 month survival)

 * PMID 1847127 -- Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group Study 83-01. (1991 Stillwagon GB, Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):65-71.)
 * Phase I/II. HCC. 198 patients (74% mets/recurrent). Induction (EBRT + low-dose 5-FU and doxorubicin), followed 1 month later by radiolabelled I-131 antiferritin
 * Median survival: 4.9 months (AFP- 8.5 months vs. AFP+ 4.6 months, p=0.006)
 * Multivariate predictors: KPS, ascites, bilirubin, SGOT, AlkPhos
 * Conclusion : "Our recommendations for structuring future prospective randomized trials are discussed and include stratification by AFP status."

 * PMID 2415692 -- Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study. (1985 Order SE, J Clin Oncol. 1985 Dec;3(12):1573-82.)
 * Phase I/II. 3 sequential protocols. 105 patients total. Induction EBRT + CT followed by 131-I-antiferritin.
 * Conclusion : "These studies have demonstrated the toxicity and therapeutic activity of 131I antiferritin and the emerging role of radiolabelled antibody in cancer therapy."

 * PMID 6085756 -- Comparative tumor dose from 131I-labeled polyclonal anti-ferritin, anti-AFP, and anti-CEA in primary liver cancers. (1984 Leichner PK, Cancer Drug Deliv. 1984 Fall;1(4):321-8.)
 * Dosimetric studies for 30 patients with HCC and 5 patients with hepatic CCA.
 * Hepatoma (30 mCi day 0, 20 mCi day 5): mean dose anti-ferritin 11 Gy, anti-AFP 3.5 Gy, combination anti-ferritin/anti-AFP 9.6 Gy
 * CCA (20 mCi day 0, 10 mCi day 5): mean dose 6.2 Gy
 * Total-body irradiation for these injection schedules ranged from 0.3 to 0.50 Gy

 * PMID 6307515 -- Dosimetry of 131I-labeled antiferritin in hepatoma: specific activities in the tumor and liver. (1983 Leichner PK, Cancer Treat Rep. 1983 Jul-Aug;67(7-8):647-58.)
 * Dosimetric studies for 22 patients with hepatoma
 * Conclusion : "These data, in conjunction with toxicity studies and tumor effective half-life measurements, led to the present treatment regimen of administering 30 mCi of polyclonal antiferritin IgG on Day 0 and 20 mCi on Day 5 following the first injection."

 * PMID 6275989 -- Phase I-II study of isotopic immunoglobulin therapy for primary liver cancer. (1982 Ettinger DS, Cancer Treat Rep. 1982 Feb;66(2):289-97.)
 * 14 patients evaluated for toxicity. Dose-limiting factor hematologic toxicity
 * Conclusion : "Present results suggest that further clinical studies with isotopic immunoglobulin are indicated."

 * PMID 6268576 -- Dosimetry of 131I-labeled anti-ferritin in hepatoma: a model for radioimmunoglobulin dosimetry. (1981 Leichner PK, Int J Radiat Oncol Biol Phys. 1981 Mar;7(3):323-33.)
 * No abstract

131-I-Anti-CEA
 * PMID 3032877 -- Multi-modality treatment of primary nonresectable intrahepatic cholangiocarcinoma with 131I anti-CEA--a Radiation Therapy Oncology Group Study. (1987 Stillwagon GB, Int J Radiat Oncol Biol Phys. 1987 May;13(5):687-95.)
 * Phase I/II. 37 patients. EBRT (21 Gy in 3.0 Gy/fx) + CT (Adriamycin + 5-FU) induction, followed 1 month later by CT (Adriamycin + 5-FU) + 131-I-anti-CEA
 * Toxicity: 3% Grade IV hematologic
 * Response: 27% PR; median survival 6.5 months

 * PMID 6085756 -- Comparative tumor dose from 131I-labeled polyclonal anti-ferritin, anti-AFP, and anti-CEA in primary liver cancers. (1984 Leichner PK, Cancer Drug Deliv. 1984 Fall;1(4):321-8.)
 * Dosimetric studies for 30 patients with HCC and 5 patients with hepatic CCA.
 * Hepatoma (30 mCi day 0, 20 mCi day 5): mean dose anti-ferritin 11 Gy, anti-AFP 3.5 Gy, combination anti-ferritin/anti-AFP 9.6 Gy
 * CCA (20 mCi day 0, 10 mCi day 5): mean dose 6.2 Gy
 * Total-body irradiation for these injection schedules ranged from 0.3 to 0.50 Gy


text:
User:Tiberus~enwikibooks

Dossier

WasabiJesus is a homesite of sorts

title: User:Tiberus~enwikibooks


text:
X86 Assembly/Advanced Interrupts

In the chapter on Interrupts, we mentioned the fact that there are such a thing as software interrupts, and they can be installed by the system. This page will go more in-depth about that process, and will talk about how ISRs are installed, how the system finds the ISR, and how the processor actually performs an interrupt.

Interrupt Service Routines
The actual code that is invoked when an interrupt occurs is called the Interrupt Service Routine (ISR). When an exception occurs, a program invokes an interrupt, or the hardware raises an interrupt, the processor uses one of several methods (to be discussed) to transfer control to the ISR, whilst allowing the ISR to safely return control to whatever it interrupted after execution is complete. At minimum, FLAGS and CS:IP are saved and the ISR's CS:IP loaded; however, some mechanisms cause a full task switch to occur before the ISR begins (and another task switch when it ends).

The Interrupt Vector Table
In the original 8086 processor (and all x86 processors in Real Mode), the Interrupt Vector Table controlled the flow into an ISR. The IVT started at memory address 0x00, and could go as high as 0x3FF, for a maximum number of 256 ISRs (ranging from interrupt 0 to 255). Each entry in the IVT contained 2 words of data: A value for IP and a value for CS (in that order). For example, let's say that we have the following interrupt:

int 14h

When we trigger the interrupt, the processor goes to the 21st location in the IVT (14h = 20, indices start at 0). Since each table entry is 4 bytes (2 bytes IP, 2 bytes CS), the microprocessor goes to location [4*14H]=[50H]. At location 50H is the new IP value, and at location 52H is the new CS value. Hardware and software interrupts are all stored in the IVT, so installing a new ISR is as easy as writing a function pointer into the IVT. In newer x86 models, the IVT was replaced with the Interrupt Descriptor Table.

When interrupts occur in real mode, the FLAGS register is pushed onto the stack, followed by CS, then IP. The iret instruction restores CS:IP and FLAGS, allowing the interrupted program to continue unaffected. For hardware interrupts, all other registers (including the general-purpose registers) must be explicitly preserved (e.g. if an interrupt routine makes use of AX, it should push AX when it begins and pop AX when it ends). It is good practice for software interrupts to preserve all registers except those containing return values. More importantly, any registers that are modified must be documented.

The Interrupt Descriptor Table
Since the 286 (but extended on the 386), interrupts may be managed by a table in memory called the Interrupt Descriptor Table (IDT). The IDT only comes into play when the processor is in protected mode. Much like the IVT, the IDT contains a listing of pointers to the ISR routine; however, there are now three ways to invoke ISRs:

 * Task Gates: These cause a task switch, allowing the ISR to run in its own context (with its own LDT, etc.). Note that IRET may still be used to return from the ISR, since the processor sets a bit in the ISR's task segment that causes IRET to perform a task switch to return to the previous task.
 * Interrupt Gates: These are similar to the original interrupt mechanism, placing EFLAGS, CS and EIP on the stack. The ISR may be located in a segment of equal or higher privilege to the currently executing segment, but not of lower privilege (higher privileges are numerically lower, with level 0 being the highest privilege).
 * Trap Gates: These are identical to interrupt gates, except they do not clear the interrupt flag.

The following NASM structure represents an IDT entry:

struc idt_entry_struct base_low: resb 2 sel:      resb 2 always0:  resb 1 flags:    resb 1 base_high: resb 2 endstruc

where:
 * DPL is the Descriptor Privilege Level (0 to 3, with 0 being highest privilege)
 * The Present bit indicates whether the segment is present in RAM. If this bit is 0, a Segment Not Present fault (Exception 11) will ensue if the interrupt is triggered.

These ISRs are usually installed and managed by the operating system. Only tasks with sufficient privilege to modify the IDT's contents may directly install ISRs.

The ISR itself must be placed in appropriate segments (and, if using task gates, the appropriate TSS must be set up), particularly so that the privilege is never lower than that of executing code. ISRs for unpredictable interrupts (such as hardware interrupts) should be placed in privilege level 0 (which is the highest privilege), so that this rule is not violated while a privilege-0 task is running.

Note that ISRs, particularly hardware-triggered ones, should always be present in memory unless there is a good reason for them not to be. Most hardware interrupts need to be dealt with promptly, and swapping causes significant delay. Also, some hardware ISRs (such as the hard disk ISR) might be required during the swapping process. Since hardware-triggered ISRs interrupt processes at unpredictable times, device driver programmers are encouraged to keep ISRs very short. Often an ISR simply organises for a kernel task to do the necessary work; this kernel task will be run at the next suitable opportunity. As a result of this, hardware-triggered ISRs are generally very small and little is gained by swapping them to the disk.

However, it may be desirable to set the present bit to 0, even though the ISR actually is present in RAM. The OS can use the Segment Not Present handler for some other function, for instance to monitor interrupt calls.

IDT Register
The x86 contains a register whose job is to keep track of the IDT. This register is called the IDT Register, or simply "IDTR". the IDT register is 48 bits long. The lower 16 bits are called the LIMIT section of the IDTR, and the upper 32 bits are called the BASE section of the IDTR:

|LIMIT|BASE|

The BASE is the base address of the IDT in memory. The IDT can be located anywhere in memory, so the BASE needs to point to it. The LIMIT field contains the current length of the IDT.

To load the IDTR, the instruction LIDT is used:

lidt [idtr]

To store the IDTR, the instruction SIDT is used:

sub esp,6 sidt [esp]  ;store the idtr to the stack

Interrupt Instructions
calls the specified interrupt

calls interrupt 4 if the overflow flag is set

returns from an interrupt service routine (ISR).

Default ISR
A good programming practice is to provide a default ISR that can be used as placeholder for unused interrupts. This is to prevent execution of random code if an unrecognized interrupt is raised. The default ISR can be as simple as a single iret instruction.

Note, however, that under DOS (which is in real mode), certain IVT entries contain pointers to important, but not necessarily executable, locations. For instance, entry 0x1D is a far pointer to a video initialisation parameter table for video controllers, entry 0x1F is a pointer to the graphical character bitmap table.

Disabling Interrupts
Sometimes it is important that a routine is not interrupted unexpectedly. For this reason, the x86 allows hardware interrupts to be disabled if necessary. This means the processor will ignore any interrupt signal it receives from the interrupt controller. Usually the controller will simply keep waiting until the processor accepts the interrupt signal, so the interrupts are delayed rather than rejected.

The x86 has an interrupt flag (IF) in the FLAGS register. When this flag is set to 0, hardware interrupts are disabled, otherwise they are enabled. The command cli sets this flag to 0, and sti sets it to 1. Instructions that load values into the FLAGS register (such as popf and iret) may also modify this flag.

Note that this flag does not affect the int instruction or processor exceptions; only hardware-generated interrupts. Also note that in protected mode, code running with less privilege than IOPL will generate an exception if it uses cli or sti. This means that the operating system can disallow "user" programs from disabling interrupts and thus gaining control of the system.

Interrupts are automatically disabled when an interrupt handler begins; this ensures the handler will not be interrupted (unless it issues sti). Software such as device drivers might require precise timing and for this reason should not be interrupted. This can also help avoid problems if the same interrupt occurs twice in a short space of time. Note that the iret instruction restores the state of FLAGS before the interrupt handler began, thus allowing further interrupts to occur after the interrupt handler is complete.

Interrupts should also be disabled when performing certain system tasks, such as when entering protected mode. This consists of performing several steps, and if the processor tried to invoke an interrupt handler before this process was complete, it would be in danger of causing an exception, executing invalid code, trashing memory, or causing some other problem.

title: X86 Assembly/Advanced Interrupts


text:
TI-Basic Z80 Programming/Basic Variables

What are Variables?
Variables are the meat of any programming language as they are used to store and work with data. With variables, the outcomes of programs can differ depending on the user's input or the purpose of the program. Variables in the TI calculators can store different types of data, whether it be numbers, lists of numbers, strings, mathematical functions, etc. However, each data type has its own type of variable that it can be stored in and the rules must be followed fairly strictly.

TI-BASIC is unusual among programming languages in that it does not support actual variables. Instead, all data are treated like files; there is no distinction between an ordinary number and an image, for example. TI refers to all files as "variables." Henceforth, "variable" will refer to a file usable by a program.

Types of Basic Variables
There are many types of variables, but in this chapter, only the most common ones will be dealt with. The Advanced Variables section will deal with the more complex variable types and uses. The following sections will deal with:
 * Number — numbers (e.g.,,  ,  ,  ,  )
 * List — array of numbers (e.g., )
 * String — text (e.g., )

Storing and Recalling Variables
Variables can be stored and recalled at the home screen, or within a program by simply using that variable's name. The method for recalling variables varies depending on the type of variable: To recall the value of, press  [X], then push :
 * To type a number variable, press, then the corresponding key for that letter.
 * To type a list variable, press  [LIST], then select the desired list in the list.
 * To type a string variable, press  7, then select the desired string in the list.

or to recall :

or to recall :

Numbers
Numbers are stored into variables labelled  through   and   and can be real or complex numbers (complex numbers can only be used if the calculator is in a+bi or re^θi modes).

Number variables store both the integer and decimal part of a number. Examples of number variables are,  ,  ,  ,  , or. Number variables are accurate up to eight significant digits and can be in the range of  to   ($$\pm9*10^{99}$$). If an attempt is tried to evaluate or store a value outside of the range, the calculator returns an error.

The calculator can update,  ,  ,  , and   during graphing, so you may want to avoid using these variables to store non-graphing data.

Syntax
To store a number to a number variable, the syntax is as follows:

Variable
In this example, only the value of  is stored to   (i.e., changes to   will not be reflected in   after the assignment).

Equation
In this example, if,  , not the actual equation. Only the result of an equation is stored (the equation is, so  ).

Lists
Lists are essentially an array: they store an array of numbers. The individual numbers of a list are named elements. The maximum number of elements in a list is.

Syntax
To instantiate a list, the following code is used:

It is important to first instantiate a list before attempting to access it so that the size is appropriate for usage. The dim( (  [LIST] OPS 3) command stands for dimension, and in this case, we have set  as the dimension (or size) of the list.

To access a single element in a list, use the format, where N is the N-th element in the list. The index is 1-indexed, so to reference the first element in, use.

Lists can only store numbers.

Equations
In this example,  would consist of   because each element was increased by   then stored to.

Strings
Strings hold text.

Incompatible Types
It should be noted that variables can only contain their respective data type. For example, trying to store a number to a string object will result in an error.

You try it!
Try these examples to practice using the different data types.

Arithmetic
Use variables to store numbers, then perform simple operations on them. Make variables A and B equal to 3 and 7, respectively. Then output $$A/B$$, $$(AB)^A$$, and $$B+(A^{2+4B})$$.

Which outputs:

List Operation
Create a simple list using these numbers:. Now, using Disp, output each value to the screen, then output the average of the values of the list by accessing them from the list. Remember, to type a list, press <tt>2ND</tt> then a number from 1-6.

Which outputs:

String Concatenation
Set  to your first name and set   to your last name. Then, using string concatenation, print your first and last names on two lines, with preceding text  and. For example, your output would appear as follows:


text:
CAT-Tools/DéjàVu X/DOC / RTF format

How to prepare Word files before import
In many cases it is advisable to prepare Word files, in order to avoid a number of well-known problems. The following is a little check-list that can be used as a guideline. (This list is based on material from one of the excellent courses run by Judy Ann Schoen )

 * Accept all changes and switch off track-changes mode.
 * Delete all comments.
 * Remove embedded graphics, logos, icons etc. from headers and footers.
 * Delete graphics and text fields that are located close to the document edge.
 * Remove inline graphics using the macro ImagesOutIn by Miri Ofek (available from the yahoogroups website of the dejavu-l list: )
 * Watch out for spaces with different formatting than the rest of the text. They can lead to excessive codes in the DV project.
 * Switch off the auto-recognition of the language.
 * In severe cases, where the Word document won't import or export or when there is an excessive number of codes, try to save as RTF or open and save using OpenOffice.
 * In hopeless cases, save the Word doc as plain text (*.txt) and apply the formatting manually (and cleanly) after translation.
 * Switch off the syllable division.
 * Remove nested groupings.

title: CAT-Tools/DéjàVu X/DOC / RTF format


text:
X86 Assembly/Bootloaders

When a computer is turned on, there is some beeping, and some flashing lights, and then a loading screen appears. And then magically, the operating system loads into memory. The question is then raised, how does the operating system load up? What gets the ball rolling? The answer is bootloaders.

What is a Bootloader?
Bootloaders are small pieces of software that play a role in getting an operating system loaded and ready for execution when a computer is turned on. The way this happens varies between different computer designs (early computers required a person to manually set the computer up whenever it was turned on), and often there are several stages in the process of boot loading.

It's crucial to understand that the term "bootloader" is simply a classification of software (and sometimes a blurry one). To the processor, a bootloader is just another piece of code that it blindly executes. There are many different kinds of boot loaders. Some are small, others are large; some follow very simple rules while others show fancy screens and give the user a selection to choose from.

On IBM PC compatibles, the first program to load is the Basic Input/Output System (BIOS). The BIOS performs many tests and initialisations, and if everything is OK, the BIOS's boot loader begins. Its purpose is to load another boot loader! It selects a disk (or some other storage media) from which it loads a secondary boot loader.

In some cases, this boot loader loads enough of an operating system to start running it. In other cases, it loads yet another boot loader from somewhere else. This often happens when multiple operating systems are installed on a single computer; each OS may have its own specific bootloader, with a "central" bootloader that loads one of the specific ones according to the user's selection.

Most bootloaders are written exclusively in assembly language (or even machine code), because they need to be compact, they don't have access to OS routines (such as memory allocation) that other languages might require, they need to follow some unusual requirements, and they make frequent use of low-level features. However some bootloaders, particularly those that have many features and allow user input, are quite heavyweight. These are often written in a combination of assembly and C. The GRand Unified Bootloader (GRUB) is an example of such.

Some boot loaders are highly OS-specific, while others are less so - certainly the BIOS boot loader is not OS-specific. The MS-DOS boot loader (which was placed on all MS-DOS formatted floppy disks) simply checks if the files IO.SYS and MSDOS.SYS exist; if they are not present it displays the error "Non-System disk or disk error" otherwise it loads and begins execution of IO.SYS.

The final stage boot loader may be expected (by the OS) to prepare the computer in some way, for instance by placing the processor in protected mode and programming the interrupt controller. While it would be possible to do these things inside the OS's initialisation procedure, moving them into the bootloader can simplify the OS design. Some operating systems require their bootloader to set up a small, basic GDT (Global Descriptor Table) and enter protected mode, in order to remove the need for the OS to have any 16-bit code. However, the OS might replace this with its own sophisticated GDT soon after.

The Bootsector
The first 512 bytes of a disk are known as the bootsector or Master Boot Record. The boot sector is an area of the disk reserved for booting purposes. If the bootsector of a disk contains a valid boot sector (the last word of the sector must contain the signature 0xAA55), then the disk is treated by the BIOS as bootable.

The Boot Process
When switched on or reset, an x86 processor begins executing the instructions it finds at address FFFF:0000 (at this stage it is operating in Real Mode) (Intel Software Developer's Manual Volume 3 Chapter 9 contradicts this information: Execution starts at the physical address 0xFFFFFFF0, among other things). In IBM PC compatible processors, this address is mapped to a ROM chip that contains the computer's Basic Input/Output System (BIOS) code. The BIOS is responsible for many tests and initialisations; for instance the BIOS may perform a memory test, initialise the interrupt controller and system timer, and test that these devices are working.

Eventually the actual boot loading begins. First the BIOS searches for and initialises available storage media (such as floppy drives, hard disks, CD drives), then it decides which of these it will attempt to boot from. It checks each device for availability (e.g. ensuring a floppy drive contains a disk), then the 0xAA55 signature, in some predefined order (often the order is configurable using the BIOS setup tool). It loads the first sector of the first bootable device it comes across into RAM, and initiates execution.

Ideally, this will be another boot loader, and it will continue the job, making a few preparations, then passing control to something else.

While BIOSes remain compatible with 20-year-old software, they have also become more sophisticated over time. Early BIOSes could not boot from CD drives, but now CD and even DVD booting are standard BIOS features. Booting from USB storage devices is also possible, and some systems can boot from over the network. To achieve such advanced functioning, BIOSes sometimes enter protected mode and the like, but then return to real mode in order to be compatible with legacy boot loaders. This creates a chicken-and-egg problem: bootloaders are written to work with the ubiquitous BIOS, and BIOSes are written to support all those bootloaders, preventing much in the way of new boot loading features.

However, a new bootstrap technology, the UEFI, is beginning to gain momentum. It is much more sophisticated and will not be discussed in this article.

Note also that other computer systems - even some that use x86 processors - may boot in different ways. Indeed, some embedded systems whose software is compact enough to be stored on ROM chips may not need bootloaders at all.

Technical Details
A bootloader runs under certain conditions that the programmer must appreciate in order to make a successful bootloader. The following pertains to bootloaders initiated by the PC BIOS:

 * 1) The first sector of a drive contains its boot loader.
 * 2) One sector is 512 bytes — the last two bytes of which must be 0xAA55 (i.e. 0x55 followed by 0xAA), or else the BIOS will treat the drive as unbootable.
 * 3) If everything is in order, said first sector will be placed at RAM address 0000:7C00, and the BIOS's role is over as it transfers control to 0000:7C00 (that is, it JMPs to that address).
 * 4) The DL register will contain the drive number that is being booted from, useful if you want to read more data from elsewhere on the drive.
 * 5) The BIOS leaves behind a lot of code, both to handle hardware interrupts (such as a keypress) and to provide services to the bootloader and OS (such as keyboard input, disk read, and writing to the screen). You must understand the purpose of the Interrupt Vector Table (IVT), and be careful not to interfere with the parts of the BIOS that you depend on. Most operating systems replace the BIOS code with their own code, but the boot loader can't use anything but its own code and what the BIOS provides. Useful BIOS services include  (for displaying text/graphics),   (disk functions) and   (keyboard input).
 * 6) This means that any code or data that the boot loader needs must either be included in the first sector (be careful not to accidentally execute data) or manually loaded from another sector of the disk to somewhere in RAM. Because the OS is not running yet, most of the RAM will be unused. However, you must take care not to interfere with the RAM that is required by the BIOS interrupt handlers and services mentioned above.
 * 7) The OS code itself (or the next bootloader) will need to be loaded into RAM as well.
 * 8) The BIOS places the stack pointer 512 bytes beyond the end of the boot sector, meaning that the stack cannot exceed 512 bytes. It may be necessary to move the stack to a larger area.
 * 9) There are some conventions that need to be respected if the disk is to be readable under mainstream operating systems. For instance you may wish to include a BIOS Parameter Block on a floppy disk to render the disk readable under most PC operating systems.

Most assemblers will have a command or directive similar to  that informs the assembler that the code will be loaded starting at offset 7C00h. The assembler will take this into account when calculating instruction and data addresses. If you leave this out, the assembler assumes the code is loaded at address 0 and this must be compensated for manually in the code.

Usually, the bootloader will load the kernel into memory, and then jump to the kernel. The kernel will then be able to reclaim the memory used by the bootloader (because it has already performed its job). However it is possible to include OS code within the boot sector and keep it resident after the OS begins.

Here is a simple bootloader demo designed for NASM:

To compile the above file, suppose it is called 'floppy.asm', you can use following command: nasm -f bin -o floppy.img floppy.asm While strictly speaking this is not a bootloader, it is bootable, and demonstrates several things:
 * How to include and access data in the boot sector
 * How to skip over included data (this is required for a BIOS Parameter Block)
 * How to place the 0xAA55 signature at the end of the sector (NASM will issue an error if there is too much code to fit in a sector)
 * The use of BIOS interrupts

On Linux, you can issue a command like cat floppy.img > /dev/fd0 to write the image to the floppy disk (the image may be smaller than the size of the disk in which case only as much information as is in the image will be written to the disk). A more sophisticated option is to use the dd utility: dd if=floppy.img of=/dev/fd0 Under Windows you can use software such as RAWRITE.

Hard disks
Hard disks usually add an extra layer to this process, since they may be partitioned. The first sector of a hard disk is known as the Master Boot Record (MBR). Conventionally, the partition information for a hard disk is included at the end of the MBR, just before the 0xAA55 signature.

The role of the BIOS is no different to before: to read the first sector of the disk (that is, the MBR) into RAM, and transfer execution to the first byte of this sector. The BIOS is oblivious to partitioning schemes - all it checks for is the presence of the 0xAA55 signature.

While this means that one can use the MBR in any way one would like (for instance, omit or extend the partition table) this is seldom done. Despite the fact that the partition table design is very old and limited - it is limited to four partitions - virtually all operating systems for IBM PC compatibles assume that the MBR will be formatted like this. Therefore to break with convention is to render your disk inoperable except to operating systems specifically designed to use it.

In practice, the MBR usually contains a boot loader whose purpose is to load another boot loader - to be found at the start of one of the partitions. This is often a very simple program which finds the first partition marked Active, loads its first sector into RAM, and commences its execution. Since by convention the new boot loader is also loaded to address 7C00h, the old loader may need to relocate all or part of itself to a different location before doing this. Also, ES:SI is expected to contain the address in RAM of the partition table, and DL the boot drive number. Breaking such conventions may render a bootloader incompatible with other bootloaders.

However, many boot managers (software that enables the user to select a partition, and sometimes even kernel, to boot from) use custom MBR code which loads the remainder of the boot manager code from somewhere on disk, then provides the user with options on how to continue the bootstrap process. It is also possible for the boot manager to reside within a partition, in which case it must first be loaded by another boot loader.

Most boot managers support chain loading (that is, starting another boot loader via the usual first-sector-of-partition-to-address-7C00 process) and this is often used for systems such as DOS and Windows. However, some boot managers (notably GRUB) support the loading of a user-selected kernel image. This can be used with systems such as GNU/Linux and Solaris, allowing more flexibility in starting the system. The mechanism may differ somewhat from that of chain loading.

Clearly, the partition table presents a chicken-and-egg problem that is placing unreasonable limitations on partitioning schemes. One solution gaining momentum is the GUID Partition Table; it uses a dummy MBR partition table so that legacy operating systems will not interfere with the GPT, while newer operating systems can take advantage of the many improvements offered by the system.

GNU GRUB
The GRand Unified Bootloader supports the flexible multiboot boot protocol. This protocol aims to simplify the boot process by providing a single, flexible protocol for booting a variety of operating systems. Many free operating systems can be booted using multiboot.

GRUB is extremely powerful and is practically a small operating system. It can read various file systems and thus lets you specify a kernel image by filename as well as separate module files that the kernel may make use of. Command-line arguments can be passed to the kernel as well - this is a nice way of starting an OS in maintenance mode, or "safe mode", or with VGA graphics, and so on. GRUB can provide a menu for the user to select from as well as allowing custom loading parameters to be entered.

Obviously this functionality cannot possibly be provided in 512 bytes of code. This is why GRUB is split into two or three "stages":
 * Stage 1 - this is a 512-byte block that has the location of stage 1.5 or stage 2 hardcoded into it. It loads the next stage.
 * Stage 1.5 - an optional stage which understands the filesystem (e.g. FAT32 or ext3) where stage 2 resides. It will find out where stage 2 is located and load it. This stage is quite small and is located in a fixed area, often just after Stage 1.
 * Stage 2 - this is a much larger image that has all the GRUB functionality.

Note that Stage 1 may be installed to the Master Boot Record of a hard disk, or may be installed in one of the partitions and chainloaded by another boot loader.

Windows can not be loaded using multiboot, but the Windows bootloader (like those of other non-multiboot operating systems) can be chainloaded from GRUB, which isn't quite as good, but does let you boot such systems.

Testing the Bootloader
Perhaps the easiest way to test a bootloader is inside a virtual machine, like VirtualBox or VMware.

Sometimes it is useful if the bootloader supports the GDB remote debug protocol.

title: X86 Assembly/Bootloaders


text:
X86 Assembly/Introduction

Why Learn Assembly?
Assembly is among some of the oldest tools in a computer-programmer's toolbox. Nowadays though, entire software projects can be written without ever looking at a single line of assembly code. So this pops up the question: why learn assembly? Assembly language is one of the closest forms of communication that humans can engage in with a computer. With assembly, the programmer can precisely track the flow of data and execution in a program in a mostly human-readable form. Once a program has been compiled, it is difficult (and at times, nearly impossible) to reverse-engineer the code into its original form. As a result, if you wish to examine a program that is already compiled but would rather not stare at hexadecimal or binary, you will need to examine it in assembly language. Since debuggers will frequently only show program code in assembly language, this provides one of many benefits for learning the language.

Assembly language is also the preferred tool, if not the only tool, for implementing some low-level tasks, such as bootloaders and low-level kernel components. Code written in assembly has less overhead than code written in high-level languages, so assembly code frequently will run much faster than equivalent programs written in other languages. Also, code that is written in a high-level language can be compiled into assembly and "hand optimized" to squeeze every last bit of speed out of it. As hardware manufacturers such as Intel and AMD add new features and new instructions to their processors, often times the only way to access those features is to use assembly routines. That is, at least until the major compiler vendors add support for those features.

Developing a program in assembly can be a very time consuming process, however. While it might not be a good idea to write new projects in assembly language, it is certainly valuable to know a little bit about it.

Who is This Book For?
This book will serve as an introduction to assembly language and a good resource for people who already know about the topic, but need some more information on x86 system architecture. It will also describe some of the more advanced uses of x86 assembly language. All readers are encouraged to read (and contribute to) this book, although prior knowledge of programming fundamentals would definitely be beneficial.

How is This Book Organized?
The first section will discuss the x86 family of chips and introduce the basic instruction set. The second section will explain the differences between the syntax of different assemblers. The third section will go over some of the additional instruction sets available, including the floating point, MMX, and SSE operations.

The fourth section will cover some advanced topics in x86 assembly, including some low-level programming tasks such as writing bootloaders. There are many tasks that cannot be easily implemented in a higher-level language such as C or C++. For example, enabling and disabling interrupts, enabling protected mode, accessing the Control Registers, creating a Global Descriptor Table, and other tasks all need to be handled in assembly. The fourth section will also deal with interfacing assembly language with C and other high-level languages. Once a function is written in assembly (a function to enable protected mode, for instance), we can interface that function to a larger, C-based (or even C++ based) kernel. The fifth section will discuss the standard x86 chipset, cover the basic x86 computer architecture, and generally deal with the hardware side of things.

The current layout of the book is designed to give readers as much information as they need without going overboard. Readers who want to learn assembly language on a given assembler only need to read the first section and the chapter in the second section that directly relates to their assembler. Programmers looking to implement the MMX or SSE instructions for different algorithms only really need to read section 3. Programmers looking to implement bootloaders, kernels, or other low-level tasks, can read section 4. People who really want to get to the nitty-gritty of the x86 hardware design can continue reading on through section 5.

Assembler-Programmierung für x86-Prozessoren/ Einleitung Programmation Assembleur x86/Introduction X86アセンブラ/はじめに Programmeren in x86 assembler/Inleiding Assembly x86/Introdução

title: X86 Assembly/Introduction


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User talk:192.114.65.98

Please stop. If you continue to vandalize pages, you will be blocked from editing Wikibooks.

title: User talk:192.114.65.98


text:
Do-It-Yourself/Ionic wind thruster

An ionic wind thruster is a booster based on ionizing air to create thrust. These thrusters work by adding an electron to a particle of air so that the air is forced away from a the negatively charged grid. This produces a level of thrust T=m*(dv/dt), with T being thrust, m being the mass of the air, and v being the velocity of the air.

A common science fair project may be using a charged grid to 'levitate' an object several decimeters above a surface; more interesting applications may include levitating the hull of a car and building something more akin to Luke Skywalker's speeder or a hoverboard as seen in Back to the Future 2.

The basic design involves using a 555 timer to repeatedly and rapidly pulse a high voltage, low current electrical charge through a grid of wire. Typical values would be 30,000V at 0.001A, or 30kV at 1mA. This is typically enough power to levitate a small grid on its own; however, the grid can be combined with a light-weight plastic skirt or cone to better control the thrust angle and create backpressure. The function of such a cone would be to prevent air from going out sideways, which decreases the amount of thrust in the direction we want; however, too much backpressure will also overpower the total thrust of the system and negate the effect.

title: Do-It-Yourself/Ionic wind thruster


text:
Do-It-Yourself/Railgun

A railgun is a form of electromagnetic weaponry that works on Lorentz forces, magnetic fields created by running power through metal rails connected by a metal projectile. Commonly, video games use gauss guns and call them railguns, for example Quake 2 and 3. Wikipedia has an article on railguns.

As stated, railguns utilize an electromagnetic force called the Lorentz force to propel an electrically conductive projectile that is initially part of the current path. The current flowing through the rails sets up a magnetic field between them and through the projectile perpendicularly to the current in the rail. In short, the rails and the projectile push away from each other, and you wind up throwing a hunk of metal away from wherever the battery is connected.

Railguns have an inherent problem with the amount of power driving the projectile; the rails are forced apart, electrical arcing occurs, and the rails are partially vaporized. Because of this, most railguns can only be fired once before the rails need to be replaced. Our model will be a simple, low-power model designed to throw a projectile, but not do anything particularly spectacular like vaporize a car on impact.

title: Do-It-Yourself/Railgun


text:
User talk:Joe Lapinskas

Copyright problem with Image:Max efficiency.gif
--Derbeth talk 19:16, 9 December 2005 (UTC)

title: User talk:Joe Lapinskas


text:
Signals and Systems/Table of Fourier Transforms

Fourier Transform

 * $$F(j\omega) = \mathcal{F} \left\{f(t) \right\} = \int_{-\infty}^\infty f(t) e^{-j\omega t}dt$$

Inverse Fourier Transform

 * $$\mathcal{F}^{-1}\left\{F(j\omega) \right\}

= f(t) = \frac{1}{2\pi}\int_{-\infty}^\infty F(j\omega) e^{j\omega t} d\omega$$

Table of Fourier Transforms
This table contains some of the most commonly encountered Fourier transforms.


text:
Signals and Systems/Table of Laplace Transforms

Laplace Transform

 * $$F(s)

= \mathcal{L} \left\{f(t)\right\} =\int_{0^-}^\infty e^{-st} f(t)\,dt.$$

Inverse Laplace Transform

\mathcal{L}^{-1} \left\{F(s)\right\} = {1 \over {2\pi i}}\int_{c-i\infty}^{c+i\infty} e^{ft} F(s)\,ds = f(t)$$


text:
User talk:72.1.206.172

Please stop adding nonsense to Wikibooks. It is considered vandalism. If you would like to experiment, use the sandbox. Thank you.

title: User talk:72.1.206.172


text: User talk:212.56.128.186

title: User talk:212.56.128.186


text: Signals and Systems/Table of Trigonometric Identities


text:
User talk:147.197.215.16

Please stop adding nonsense to Wikibooks. It is considered vandalism. If you would like to experiment, use the sandbox. Thank you.

title: User talk:147.197.215.16


text:
Talk:Ada Programming/Attributes/'Base

Copyright Notice
Most of the text has been copied from a Newsnet artice with consent of the original author Matthew Heaney .

more on base
We can also add text from [another post of Matthew]. Just have to look what is suitable.

title: Talk:Ada Programming/Attributes/'Base


text: User talk:80.68.2.71

title: User talk:80.68.2.71


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Do-It-Yourself/Gauss guns

Introduction
A Gauss Gun or Coil Gun is a gun that works by using a coil of wire to generate an electromagnetic field used to laterally accelerate a metallic projectile; the projectile becomes the core of a solenoid, but being loose it leaves the barrel after being fired.

Gauss guns come in varied designs, some of which can fire nails or BBs through cardboard; while others make viable hunting rifles suitable for penetrating a deer's skull. Unlike railguns, gauss guns can typically be put to practical use in a hobbyist environment; both should be treated as deadly weapons. Please note that with many of the designs here, you can kill someone; treat these projectile weapons with the care you would give to a store-bought firearm.

Guns

 * /Pskov 1100/ — This gauss gun was featured on Slashdot. homepage

title: Do-It-Yourself/Gauss guns


text:
User talk:24.90.76.199

Please stop adding nonsense to Wikibooks. It is considered vandalism. If you would like to experiment, use the sandbox. Thank you. -- LV (Dark Mark) 20:58, 9 December 2005 (UTC)

title: User talk:24.90.76.199


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Wikijunior talk:Ancient Civilizations/Romans

I have a problem with the text concerning ancient Roman housing: "but normal houses were much smaller and regular-looking," By "normal" houses, do you mean that of the average citizen? What was "normal" in ancient Rome? And what is "regular-looking"? Regular to who? What's regular to me may not be "regular" to someone living in India. I would not consider this text comparable to any high school textbook we have in our schools. The writing is of poor quality. Sorry, but I would definitely discourage my students from using this information.
 * A little better? -- LV (Dark Mark) 21:13, 9 December 2005 (UTC)

What did they believe (Romans in Ancient Civilizations)
There are so many spelling and grammar errors in this section that I am appalled & vow never to let my students use a WikiText for research - ever! This is the problem when anyone can write anything on the web and call it valid information. I don't know if the facts here are correct because the person's writing is incomprehensible. Our students deserve better than this.

 * You are allowed to edit it and change it if it is bad. Anyone can edit! Enjoy. -- LV (Dark Mark) 21:15, 9 December 2005 (UTC)

Correct Latin Pronoucation
Technically, Julius Caesar's name would be pronounced "You-lee-us Ki-sir" The "I" was pronounced as a "y" (later the y became "j" in the middle ages", and all "c" were prononced as hard, i.e. as "k"s, not like "ch" in teh current book.

Please change, or if someone would like to argue. :)

Zidel333 03:03, 8 March 2006 (UTC)

Great job!
This is a great module. It seems complete and is easy to read and follow. Thanks for contributing this module to Wikibooks and Wikijunior. I think kids will find this very fun and interesting. Tannersf 03:20, 5 December 2006 (UTC)

Image replacement
I just replaced the image for the geographic context of the Empire. The previous image was far too detailed (in my opinion) for the book's target audience: 8-12 year olds. It might appear to the reader that the three Prefectures other than Italy were not part the Empire, or cause some other confusion. The new image is a single color, and should be much easier to comprehend. Νεοπτόλεμος 01:19, 5 February 2008 (UTC)


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User talk:204.228.117.202

Welcome to Wikibooks, collection of open-content textbooks! You don't have to log in to read or edit articles on Wikibooks, but creating an account is quick, free and non-intrusive, requires no personal information, and gives you many benefits, including:
 * The use of a username of your choice
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 * Your own talk page which, if you choose, also allows users to send you messages without knowing your e-mail address
 * The use of your own personal watchlist to which you can add articles that interest you
 * The ability to rename pages
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 * The ability to customize the appearance and behavior of the website
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 * The right to be heard in votes and elections
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We hope that you choose to become a Wikibooks and create an account. We hope you enjoy your time here on Wikibooks as a Wikibookian! -- LV (Dark Mark) 21:15, 9 December 2005 (UTC)

title: User talk:204.228.117.202


text:
User talk:128.46.193.209

Please stop. If you continue to blank pages, you will be blocked from editing.

title: User talk:128.46.193.209