Pedro Gines

Richard E Bodmer

Manel Lopez Bejar

P G Mayor

M L Bejar

R E Bodmer Durrell

Reproductive performance of the wild collared peccary (Tayassu tajacu) female in the Peruvian Amazon

Keywords: Tayassu tayassu, Collared peccary, Reproductive production, Amazon

Based on the gross anatomic examination of 218 adult female reproductive tracts, we characterised the reproductive biology of the wild collared peccary in the Northeastern Peruvian Amazon. Collared peccary apparently breed year round in the Northeastern Peruvian Amazon and the number of pregnant females was 92 (42.2%). Estimations suggest 1.12 births/year and a yearly reproductive production of 1.98 piglets per pregnant female. Collared peccary females presented a mean ovulation rate of 2.25±0.58 CLs, a litter size of 1.77±0.48 embryos or foetuses and a reproductive wastage of 0.45±0.65 (21.3%) oocytes or embryos per pregnant female. A phenomenon of embryo migration was observed in 31.8% of pregnant females. This study provides reproductive information that should be taken into account in management plans.

Introduction

In the Amazon region, the collared peccary (Tayassu tajacu) is one of the most frequently hunted species and represents an important source of food and animal skins.

The reproductive biology determines the ability to support high hunting pressures and is fundamental to understand the dynamics of wild populations. Nevertheless, most information on the collared peccary reproduction in the Amazon region is based on outstanding long-term studies conducted in captivity in recent years [START_REF] Mayor | Integrating ultrasonography within the reproductive management of the collared peccary (Tayassu tajacu)[END_REF][START_REF] Mayor | Ovarian features of the wild collared peccary (Tayassu tajacu) from Peruvian Northeastern Amazon[END_REF].

In the Amazon, the collared peccary female is considered to be aseasonally polyoestrous [START_REF] Mayor | Ovarian features of the wild collared peccary (Tayassu tajacu) from Peruvian Northeastern Amazon[END_REF], with an oestrous cycle length of 27.8±1.5 days [START_REF] Mauget | Hormonal and behavioural monitoring of ovarian cycles in peccaries, Proceedings of the First International Symposium on Physiology and Ethology of Wild and Zoo Animals, 18-21 September 1996[END_REF], a mean gestation period of 138 days [START_REF] Mayor | Integrating ultrasonography within the reproductive management of the collared peccary (Tayassu tajacu)[END_REF]) and a litter size of 1.7-1.9 foetuses or newborns [START_REF] Gottdenker | Reproduction and productivity of white-lipped and collared peccaries in the Peruvian Amazon[END_REF]. Reproductive production of the species in the wild was estimated at 1.4-1.8 [START_REF] Gottdenker | Reproduction and productivity of white-lipped and collared peccaries in the Peruvian Amazon[END_REF].

Models used to determine the sustainability of bush meat hunting in the Amazon are paramount for conservation and community-based management [START_REF] Bodmer | Evaluating the sustainability of hunting in the Neotropics[END_REF]. The commonly used production and unified harvest models rely on accurate estimations of reproductive productivity for specific sites. Conservation programmes aimed at sustainable use must therefore collect specific data on the reproduction of species, in this case the collared peccary. The objective of the present study was to examine the reproductive performance of the wild collared peccary in the Northeastern Peruvian Amazon.

Materials and methods

Study area

This study was conducted in the Tamshiyacu-Tahuayo Communal Reserve, in the Northeastern Peruvian Amazon. The reserve spans 322,500 ha of continuous forest, predominantly non-flooded terra firme forest, with a harvest per square kilometre and year between 1.1 and 2.7 mammals. The climate in that region is typically equatorial with an annual temperature of 22-36°C, a relative humidity of 80-100% and an annual rainfall of 1,500-3,000 mm. Seasons are defined as dry (January-February and July-September) and wet (March-June and October-December).

Animal collection and sample analysis

From 1996 to 2007, hunters in the study area, as part of an ongoing participatory conservation programme, collected genital organs of 218 adult collared peccary females. Genital organs were maintained in buffered 4% formaldehyde solution (v/v) until analysis. Ovaries were dehydrated, embedded in paraffin wax, cut into 3-µm sections and stained with haematoxylin and eosin. Females with at least one embryo or foetus were considered to be pregnant. Non-pregnant adult animals with ovaries bearing large antral follicles and lacking corpora lutea (CL) were considered to be in the follicular phase of the oestrous cycle, while those with ovaries containing active luteal tissue were described to be in the luteal phase of the oestrous cycle. Corpora lutea were considered active in the presence of a pregnancy or as indicated by luteal cell morphology [START_REF] Jori | Functional anatomy of the ovaries of the wild brush-tailed porcupine (Atherurus africanus, Gray 1842) from Gabon[END_REF]. Since [START_REF] Mayor | Integrating ultrasonography within the reproductive management of the collared peccary (Tayassu tajacu)[END_REF] determined first anatomical signs of pregnancy around the 15th day of gestation in the collared peccary, we considered a possible underestimation of 10% of pregnancies with respect to non-pregnant females in the luteal phase.

Monthly conceptions were determined by back-dating embryos or foetuses from the estimated age on the date when collared peccary females were collected. Gestation length used to back-date foetuses was 138 days [START_REF] Mayor | Integrating ultrasonography within the reproductive management of the collared peccary (Tayassu tajacu)[END_REF]. The determination of embryo/foetal age was based primarily on the description given by [START_REF] Mayor | Integrating ultrasonography within the reproductive management of the collared peccary (Tayassu tajacu)[END_REF], who used developmental characteristics of the collared peccary in the Amazon. Litter size and foetal sex of each pregnancy were recorded.

Reproduction performance of the wild collared peccary was estimated as follows [START_REF] Mayor | Reproductive performance of the white-lipped peccary (Tayassu pecari) female in the Peruvian Amazon[END_REF]

Statistical analysis

To test the hypothesis of seasonal reproduction, we used the number of parturitions by season and applied the chi-square test. Comparison between weight of pregnant and nonpregnant females, and number of CL in right and left ovary was calculated using analysis of variance.

Hunting vulnerability of pregnant females according to its pregnancy stage or adult sex was analysed using chisquare test. Statistical analyses were performed using GraphPad Instat (GraphPad Software Inc., San Diego, CA, USA). Differences with a probability value of 0.05 or less were considered significant. All values are expressed as the mean±standard deviation (SD).

Results

Among the 218 studied adult females, 92 (42.2%) were pregnant and 126 (57.8%) were non-pregnant females (Fig. 1). Table 1 shows the estimated reproductive performance of the collared peccary in the study area. Non-pregnant females included 20 (15.9%) females in the follicular phase and 106 (84.1%) females in the luteal phase. Considering a possible underestimation of 10% of pregnancies with respect to nonpregnant females in the luteal phase, ten females in the luteal phase could be considered as pregnant females in the earliest pregnancy stage. Therefore, the pregnancy rate could be as high as 46.8% (102 pregnant females). Pregnant females showed a higher weight of carcasses compared to non-pregnant females (21.8±3.3 and 19.8±4.3 kg, respectively; P=0.01).

Females conceived in every month of the year (P=0.69), and there was no significant difference between the number of estimated conceptions during the wet and the dry season (43 and 30, respectively; P=0.86). Number and percentages of pregnant females were similar in every month.

Ovulation rate did not show differences between pregnant and non-pregnant females in the luteal stage (2.25±0.58 vs. 2.03±0.72 follicles per ovulating female, respectively; P=0.09). There was no significant difference in the number of CL in the left and right ovaries (1.03±0.69 vs. 1.10±0.75, respectively; P=0.44).

The average litter size was 1.77±0.48 embryos or foetuses per pregnant female, with a foetal sex ratio of 52.2% females and 47.8% males, which did not differ from a 1:1 sex ratio (P=0.35). Among all pregnancies studied, 23 (25.0%) were single, 67 (72.8%) double and two (2.2%) triple. Collared peccary females presented a fertilisation rate of 79.7%, and a reproductive wastage of 0.45± 0.65 (21.3%) oocytes or embryos per pregnancy.

Right and left uterine horns presented a similar number of embryo or foetuses (49.6% and 51.4%, respectively). In 63 (68.5%) pregnancies, there was a correspondence between the occurrence of embryos or foetuses and CL in the ipsilateral ovary. On the contrary, in 29 (31.5%) females, the number of embryos or foetuses exceeded the number of CL in the ipsilateral ovary. Among females with embryo migration, four (13.8%) and 25 (86.2%) females presented a litter size of one and two foetuses, respectively.

There was no significant differences in hunted pregnant females according to the pregnancy stage (P=0.12) or adult sex (P=0.20).

Discussion

The presence of pregnant females in all months-year shows that pregnancies are evenly distributed year round. In agreement with the findings of [START_REF] Gottdenker | Reproduction and productivity of white-lipped and collared peccaries in the Peruvian Amazon[END_REF], this study suggests that the collared peccary breeds year round in the Northeastern Peruvian Amazon, probably due to the lack of huge seasonal differences in resources in the tropical environment and resulting in a sufficient food supply for peccaries to sustain a pregnancy regardless of the month of year.

Similarly to other studies conducted in the wild [START_REF] Mayor | Ovarian features of the wild collared peccary (Tayassu tajacu) from Peruvian Northeastern Amazon[END_REF], mean ovulation rate of the collared peccary in the wild was 2.25 follicles per female, with a low rate of reproductive wastage of 0.45 oocytes or embryo per pregnancy. In this study, the collared peccary female in the wild presented a pregnancy rate of 42.5% and presented an estimated yearly reproductive production of 1.98 piglets per pregnant female. This value was slightly higher than that reported by [START_REF] Gottdenker | Reproduction and productivity of white-lipped and collared peccaries in the Peruvian Amazon[END_REF]. The increase in reproductive productivity reported in this study corresponds well with the likely Lotka-Volterra interactions between collared and white-lipped peccary. White-lipped peccary have gone through a natural decrease in the study site and collared peccary have increased accordingly, presumably because of decreased competition from the former species [START_REF] Fang | Certificación de pieles de pecaries (Tayassu tajacu y T. pecari) en la Amazonía peruana: una estrategia de conservación y manejo de fauna silvestre en la Amazonía peruana[END_REF]. The increase in the rate of population growth of the collared peccary at the site corresponds well with the observed increase in reproductive potential observed in this study. In turn, this increase makes for more sustainable hunting of collared peccary by local people. A phenomenon of embryo migration was observed in 31.5% of pregnant females in the wild collared peccary. Moreover, 86.2% of females showing embryo migration were pregnant females with one embryo or foetus in each uterine horn and two CLs only in one ovary, suggesting the inability of each uterine horn to support the development of more than one foetus. This embryo migration has also been observed in its conspecific white-lipped peccary [START_REF] Mayor | Reproductive performance of the white-lipped peccary (Tayassu pecari) female in the Peruvian Amazon[END_REF]).

In the Amazon region, the collared peccary is one of the most hunted species, making necessary a consideration directed to a management priority based primarily in the establishment of sustainable harvest rates. The present reproductive evaluation of the collared peccary in the Northeastern Peruvian Amazon provides important information that should be taken into account in management plans, and the results of this study are being used to determine the sustainability of hunting using the production model.

Fig. 1

 1 Fig. 1 Monthly pregnancy rate and estimated number of collared peccary females (n=73) conceiving in each month in the Northeastern Peruvian Amazon. Percentage of pregnant females per month is shown in brackets

Table 1

 1 Reproductive performance of wild collared peccary females (n=218) in the Northeastern Peruvian Amazon from1996 to 2007

	Reproductive parameters	Value
	Number of females	218
	Number of non-pregnant females	126
	Number of pregnant females	92
	Number of foetuses	163
	Pregnancy rate (%)	42.2
	Pregnant days/year (days)	154
	Non-pregnant days/year (days)	211
	Parturitions/year/female	1.12
	Farrowing interval (days)	327
	Parturition-conception interval (days)	189
	Litter size (piglets/parturition)	1.77
	Foetal sexual ratio (F/M)	78:85
	Yearly reproductive production	1.98
	(piglets/year/pregnant female)
	Gross productivity (piglets/year/adult female)	0.61
	Gross fecundity (female piglets/year/female)	0.306

Acknowledgements We sincerely thank P. Puertas, E. Puertas, M. Antúnez and P. Pérez and all the people from the Tamshiyacu-Tahuayo Communal Reserve who actively participated in data collection. We are especially thankful for the institutional support provided by the Universidad Nacional de la Amazonía Peruana and the Dirección General Forestal y de Fauna of Perú.


Björn Hackanson

MD Cornelius F Waller
email: cornelius.waller@uniklinik-freiburg.de

Long-term follow-up of patients with chronic myeloid leukemia having received autologous stem cell transplantation

Keywords: CML, autologous transplantation, long-term follow up

Prior to introduction of imatinib mesylate, the median survival of chronic myeloid leukemia (CML) patients was approximately 60 months and the standard treatment with interferonalpha (IFN-α) resulted in major cytogenetic responses of 20-25 %. As an alternative treatment approach besides allogeneic transplantation intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) was investigated at that time with the rationale of debulking disease burden and mobilisation and transplantation of Philadelphia chromosome-negative (Ph-) stem cells.

In the era of tyrosine kinase inhibitors (TKIs) as state-of-the-art therapy for CML, the concept of autoHSCT has attracted only little interest and long-term follow-up and outcome data after autoHSCT in CML patients is scarce. In this long-term analysis, we report on 21 CML patients, mobilized in early chronic phase (ECP) and transplanted with largely Ph-grafts, who received IFNα as maintenance therapy. Imatinib mesylate was administered upon cytogenetic relapse or disease progression while on IFN-α. The 10-year survival was 61% and 11 patients (52%) were alive at a median follow-up of 12.5 years (range 0.3 -13.8) with 8 patients in complete hematologic remission (CHR) and 3 of 8 in major molecular remission (MMR). While all patients in MMR and 2 of 5 patients in CHR received imatinib, it is noteworthy that three patients remaining in CHR only received IFN-α maintenance after autoHSCT.

With the limitations of a small patient population, this is the longest follow-up analysis demonstrating that autoHSCT in CML is very efficient to debulk the disease, restore Phnegative hematopoiesis and is able to induce major and sustained molecular responses in the majority of patients with substantial long-term survival rates.

Introduction

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, a reciprocal translocation that results in the BCR-ABL fusion gene [START_REF] Koeffler | Chronic myelogenous leukemia--new concepts[END_REF][START_REF] Daley | Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome[END_REF][START_REF] Sawyers | Chronic myeloid leukemia[END_REF].

Deciphering of the BCR-ABL protein as a tyrosine kinase (TK) and the development of several substances, which are able to block BCR-ABL´s increased tyrosine kinase activity, have revolutionized the treatment of CML [START_REF] Druker | Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells[END_REF][START_REF] Baccarani | Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet[END_REF]. Currently, Imatinib mesylate is considered standard of care for first-line treatment of chronic phase CML [START_REF] Peggs | Imatinib mesylate--the new gold standard for treatment of chronic myeloid leukemia[END_REF][START_REF] Hochhaus | Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia[END_REF].

However, in the 1990´s, before the introduction of TKIs, treatment intensification of CML patients in early chronic phase (ECP) with high-dose chemotherapy (e.g. busulfan, melphalan and cyclophosphamide combined with total body irradiation in some studies) followed by autoHSCT and IFNα maintenance was a promising and intensively investigated treatment regimen [START_REF] Mcglave | Autologous transplants for chronic myelogenous leukaemia: results from eight transplant groups[END_REF][START_REF] Bhatia | Autologous Transplantation Therapy for Chronic Myelogenous Leukemia[END_REF][START_REF] Waller | Mobilization and transplantation of Philadelphia chromosome-negative peripheral blood progenitor cells in patients with CML[END_REF][START_REF] Heinzinger | Quality of IL-3 and G-CSF-mobilized peripheral blood stem cells in patients with early chronic phase CML[END_REF][START_REF] Bergamaschi | Restoration of normal polyclonal haemopoiesis in patients with chronic myeloid leukaemia autografted with Ph-negative peripheral stem cells[END_REF][START_REF] Carella | Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells early in chronic myelogenous leukemia[END_REF][START_REF] Carella | Autografting in chronic myeloid leukemia[END_REF]. The strong rationale behind this treatment approach was the concept of debulking the disease burden, mobilization of Ph-hematopoietic stem cells and consecutive transplantation of a largely Ph-autograft.

While some observations pointed to increased remission rates and prolonged survival when autografting was performed in ECP, a meta-analysis of six randomized studies was unable to show a benefit for autoHSCT compared to IFNα-based therapy with regard to event free survival and overall survival [START_REF]Autologous stem cell transplantation in chronic myeloid leukaemia: a meta-analysis of six randomized trials[END_REF]. Whether there still exists a role for autoHSCT in the current management of CML, e.g. to reverse imatinib resistance or to eliminate clones harbouring BCR-ABL kinase domain mutations remains to be determined [START_REF]Autologous stem cell transplantation in chronic myeloid leukaemia: a meta-analysis of six randomized trials[END_REF][START_REF] Olavarria | Autologous stem cell transplantation in chronic myeloid leukemia[END_REF].

Interestingly, only few long-term data on autografted patients are available [START_REF]Autologous stem cell transplantation in chronic myeloid leukaemia: a meta-analysis of six randomized trials[END_REF][START_REF] Simonsson | Intensive treatment and stem cell transplantation in chronic myelogenous leukemia: long-term follow-up[END_REF]. Therefore, we report our long-term follow-up analysis on 21 CML patients who were autografted in ECP between 1995 and 1999.

Patients and Methods

Patient selection, mobilization of CD 34 + stem cells and high-dose chemotherapy with autologous transplantation have been described in detail previously [START_REF] Waller | Mobilization and transplantation of Philadelphia chromosome-negative peripheral blood progenitor cells in patients with CML[END_REF][START_REF] Heinzinger | Quality of IL-3 and G-CSF-mobilized peripheral blood stem cells in patients with early chronic phase CML[END_REF]. Briefly, after priming with rhG-CSF (5 μg/kg s.c.; Filgrastim, Amgen, Germany), mobilization chemotherapy consisted of idarubicin (8 mg/m 2 , day 1-3), cytosine arabinoside (400 mg/m 2 , day 1-3) and etoposide (150 mg/m 2 , day 1-4). On day 7 after chemotherapy, administration of rhG-CSF (10 μg/kg s.c. daily) in all patients and rhIL-3 (5 μg/kg s.c, Novartis, Germany) in 12 patients was started until stem cell harvest. After apheresis, positive selection for CD 34 + cells was performed using avidin-immunoaffinity columns (CellPro, Washington, USA) or Isolex magnetic cell separation (Baxter, Unterschleissheim, Germany). High-dose chemotherapy contained busulphan (4 mg/kg day -7 to -4) and cyclophosphamide (60 mg/kg day -1 to -2). After autologous transplantation of a minimum of 1.5 x 10 6 CD 34 + cells, intravenous rhG-CSF treatment was started on day +3 until neutrophil recovery (> 1.5 x 10 9 /l). 20 patients were transplanted in first chronic phase and one patient in accelerated phase with a median time from initial diagnosis of 12 months (Table 1). Following platelet regeneration, patients were treated with IFN-α (initially 3 x 3x10 6 units/week; dose reduction to 3 x 1.5x10 6 units/week or less if side effects occurred) until complete cytogenetic/molecular remission, onset of intolerance or progressive disease. If imatinib was started, the inital dose was 400 mg daily. One patient received Nilotinib 2 x 400 mg daily and Dasatinib 2 x 70 mg daily after imatinib failure and one patient received Nilotinib 2 x 400 mg daily upon imatinib failure. Patient's characteristics are provided in Table 1.

Overall survival and median follow-up were estimated using the Kaplan-Meier method.

Results

Of 21 CML patients transplanted with an autograft between 1995 and 1999 at our institution, 11 patients were alive at follow-up analysis in 2009. Three patients (one receiving imatinib, one nilotinib and one dasatinib) were in complete hematologic remission (CHR) but without complete regeneration. Five patients (two on imatinib, three on IFNα) were in CHR and three patients were in major molecular remission (MMR) (Table 2). It is noteworthy that three patients remaining in CHR only received IFNα maintenance after autoHSCT, while all patients in MMR and 2/5 patients in CHR received imatinib.

Five patients had died after a median of 36 months (range 20-150) due to progressive disease with only one patient having received imatinib (Table 2). Three patients had received allogeneic stem cell transplantation (alloHSCT) in complete hematologic remission, chronic or accelerated phase, three, four and nine years after autoHSCT, respectively.

Unfortunately, all three died due to infectious complications or graft-versus-host disease following alloHSCT. One patient died two months after autoHSCT in CP due to toxic alveolitis and lung bleeding and one patient died seven years after autoHSCT of undetermined cause.

In our patient cohort, the 10-year survival rate after autologous transplantation was 61% (13/21) and overall survival after a median follow-up of 12.5 years was 52 % (11/21) (Figure 1).

Discussion

Due to the impact of TKI in the first-line therapy of CP-CML only few data are available on long-term outcome after autoHSCT in CML patients. However, as some patients have primary or develop secondary resistance to imatinib and other TKIs and are not eligible for alloHSCT, autoHSCT might still be a treatment option in a defined subset of CML patients.

Simonsson et al. showed a median survival of 7.5 years after autoHSCT in the pre-imatinib era [START_REF] Olavarria | Autologous stem cell transplantation in chronic myeloid leukemia[END_REF]. However, in a meta-analysis of this and other trials from several groups, a benefit of autoHSCT in the initial treatment of CML as compared to interferon-α (alone or in combination) could not be demonstrated [START_REF]Autologous stem cell transplantation in chronic myeloid leukaemia: a meta-analysis of six randomized trials[END_REF]. Furthermore, it has to be mentioned that all trials involved in that analysis closed early because of the introduction of imatinib. Of those trials, the German CML III A trial is still ongoing for analysis.

However, intensive chemotherapy for HSC-mobilization followed by autoHSCT of Phnegative grafts has been shown to be effective in debulking leukemia burden and to induce good cytogenetic and molecular responses maintained by low-dose IFN-a in some patients as demonstrated by our data and others' [START_REF] Waller | Mobilization and transplantation of Philadelphia chromosome-negative peripheral blood progenitor cells in patients with CML[END_REF][START_REF] Heinzinger | Quality of IL-3 and G-CSF-mobilized peripheral blood stem cells in patients with early chronic phase CML[END_REF][START_REF] Bergamaschi | Restoration of normal polyclonal haemopoiesis in patients with chronic myeloid leukaemia autografted with Ph-negative peripheral stem cells[END_REF][START_REF] Carella | Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells early in chronic myelogenous leukemia[END_REF][START_REF] Carella | Autografting in chronic myeloid leukemia[END_REF]. Recently, some very promising studies have shown that mobilization of Ph-negative peripheral blood progenitor cells by G-CSF alone while patients are being treated with imatinib is feasible [START_REF] Kreuzer | Filgrastiminduced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy: safety, feasibility and evidence for an efficient in vivo purging[END_REF][START_REF] Hui | Successful peripheral blood stem cell mobilisation with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR[END_REF]. However, data on successful transplantation of such cells has not been investigated thoroughly, yet [START_REF] Le Coutre | Autologous peripheral blood stem cell transplantation of stem cells harvested in imatinib-induced complete cytogenetic remission: an example of in vivo purging in CML[END_REF].

In our study all patients had received mobilization chemotherapy plus filgrastim in order to collect CD34 + stem cells. While in this study CML patients were treated with TKIs several years after autoHSCT, in the era of imatinib and 2nd and 3rd generation TKIs a potential treatment concept would rather consist of initial treatment with TKIs and a stem cell harvest in CCR and/or MMR. In case of TKI-resistance later on in the course of CML, autoHSCT could be one possible treatment option for patients who are ineligible for alloHSCT.

Compared to the median survival in CP-CML of 60 months prior to introduction of imatinib our data on a small cohort of selected patients show substantial overall survival after treatment with intensive chemotherapy and autologous stem cell transplantation, followed by TKI therapy in the majority of patients. However, the significance of maintenance therapy with IFN-α and that of subsequent therapy with imatinib or another TKI is difficult to interpret [START_REF] Fischer | Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT)[END_REF]. The initial debulking by chemotherapy might be of primary importance in this setting.

As the precise role of transplantation of autologous Ph-negative PBPC in the management of CML patients resistant to current first-line therapy with TKIs is still unknown further evaluation in suitably designed clinical trials is warranted.

□Figure 1 .

 1 Figure legendsFigure 1. Overall survival of CML patients from time of transplantation using the Kaplan-Meier method.

Figure 1

 1 Figure 1.

Table 2 .

 2 Time course of 21 CML patients with remission status (where available) from transplantation to last follow-up or death.

		1995 96	97	98	99	2000	01	02	03	04	05	06	07	08	09
	1	Tx	▲•			▲			▲	▲	▲	▲		▲	▲	▲ a
	2		Tx	BC BC ж
	3	Tx	▲◙ ▲◙		CP	CP	CP		▲□		▲	▲	▲□♠ ▲□	▲□ a
	4	Tx	CP			CP	CP	CP AC♠	▲ ▲al.Tx	ж
	5		Tx	▲•	AC	CP	al.Tx	ж
															BC
	6		Tx	▲◙			▲		▲	•	▲◙	▲	▲	BC♠	ж
	7		Tx	AC		2.Tx	BC ж
	8		Tx	▲•	▲○		▲○	▲◙		▲◙		▲	▲		▲	▲ a
	9		Tx			CP	♠	CP	▲◙ ▲□	▲		▲■	▲	▲	▲□ a
	10		Tx		CP AC al.Tx	ж
	11		Tx	▲	▲◙	▲◙	▲■	▲■	▲■ ▲■						▲ a
	12		Tx	▲	▲•	▲	▲•	▲	▲	▲	▲•	▲	▲	▲	▲○	▲♠ a
	13		Tx	CP	CP	CP	CP	CP CP♠			CP• CP•			▲x a
	14		Tx	CP	CP	CP	CP	CP♠ CP	CP	CP	CP	CP CP ♦♣ CP	▲x a
	15		Tx	▲	▲	▲	CP	CP	CP	CP	▲♠	▲	▲		CP	▲x♦ a
	16		Tx	CP	CP	CP	CP	CP	▲	▲♠	▲	▲	▲	▲	▲□	▲ a
	17			Tx	ж
	18				Tx	CP	BC ж
	19				Tx	CP	CP	CP	CP	CP	CP	CP	CP	CP	CP	BC ж
	20					Tx	CP	▲	CP	CP	CP♠	▲	ж
	21					Tx	▲	▲	▲	▲	▲	▲	▲	▲	▲□♠	▲□ a

Tx = transplantation; ж = death; a = alive


B Al T -E P P I N G

G Wu

Dear editor,

despite signi fi cant t herap eutic advances in the last decades, more than half of all adult p atients with h ematological malignancies (I CD 10: C81 -C95) will event ually di e from th ei r di sease (53,6% in Germany; Robert Koch Instit ute 2010). Speciali zed p alliati ve care (PC) instit utions , that are chara ct erized by a multidisciplin ary team app roach in order t o improve the qualit y of life of patients with advan ced and progressive disease, have gained broad acceptance in th e care for patient s with solid t umors . How ever, patient s with hemat ological malignanc i es are considered t o be underrepresent ed in specialized PC services (M addocks 1994(M addocks , M cGrath 2002) ) .

Patient s wit h hemat ol ogic al mali gnancies had significantly later access t o PC services, defin ed as th e interval from first PC consultation until death (13 v ersus 46 days) (Fadul 2008) , an d a n eed of explicit PC concept s for patient s with hemat ological mali gn anc ies undergoing stem cell t ransplantation ha s been claimed (Ch un g 2009).

We therefore revi ewed all patient s wit h hemat ological malignancies at our specialized PC in stituti on i n order t o define underlying clin ical and disease specific ch aract eri stics, t he subjective needs of these patients, t he environment of care and di fferent mode s of PC support , and t ried t o outline a specific PC app roach t hat could se rve as a first fundament and framew ork for closer PC / hematol ogy coop eration s. supp orti ng i ndivi dual di sease coping strategies by psychological interventi on s . Thi s proved especially helpful in sit uations where disease traject ories and p rogn osti cation were uncertain .

advan ce care pl anni ng of precaut ionary and preparative measures for inpati ent consultati ve PC services : n umerous patients have bee n cared for b y hemat ol ogy servi ces for years , and antineoplastic and supportive measures may p rove useful thr oughout the disease; therefore, an "asneeded" consultati ve approach will permit continuous hemat ological care.

stren gthenin g medi cal h ome care and outpatient nursing: facilit ating home care in cl uded day and night contact options, early involveme nt of soci al services, and a flexible readmission policy that offers inpatient service if h ome care fail ed.

- Both approach es t o p atient care, PC and hematolo gy, can be expected t o benefit mut uall y from inten sified communication that meets the specific needs of our pati ent s.

Female

  entit y: Aggressi ve l ymp h oma with all o PBSCT Aggressi ve l y mp h oma w/o all o PBSCT -subgroup T-cell origi n Acut e leukemi a with all o PB SCT Acut e leukemi a w /o all o PB SCT M ultiple myel oma / pl asmocyt oma with allo PBSCT M ultiple myel oma / pl asmocyt oma w /probl em for PC in vol vement : General supp ort n eeds / n ursi ng / family / final phase -subgroup en compassi ng w ound car oma an d acut e leukemia, as well as myeloma, were the most frequent entities.Pain w as p reval ent in 29.1% of cases (23 pts), 43 .4% of t hose suffered from myeloma. In stead, t he req uest for PC w as predominantly (56.9%) motivated by psychosocial or n ursi ng relat ed demands or general support needs for the patient and hi s / her famil y .For the referred p atient s , th e PC approach encompassed coun sellin g and p harmacotherapy for pain, dyspnea, fatigue, loss of app etite, an d oth er measures of sympt om control tailored th erap eutic int erventions like sympt om guided blood product substit uti on , ant i-in fecti ve therapy or antineoplastic therapy, as w ell as w oun d care or i ndi vi dual modifications of nut rition and infusional therap y. Asp ect s of b l ood product substit ution, the event ual changes in tran sfusi on req ui rement s, t he indications t o modify or even restrict previ ous t ran sfusi on concept s with regard t o end of life care aspect s were addressed in 31 pt s / 39,2% of cases.

  possi ble emergenci es: b l eeding, dyspn ea, pain and other end of life crises were antici pat ed by open communication. Inst ructions and medi cati on s (l i ke on -demand medication for dyspnea, restlessness or pain ) w ere gi ven in order t o facilit ate home care and t o avoid invol vement of emergency medical services at the end of life.

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  K re bs i n De ut sch l an d 2005/ 2006 . Häu fi gkei ten un d Tr en ds , 7 th e d . Ro b ert K och I nsti tu te , Ge se ll sch af t d er e pi de mi o l o gi schen Kre b sre gi s ter i n Deu tsch la nd (e d s . ) . B erli n 20 10 -M a d d ocks I , Ben t le y L , S hee d y J . Q ua li ty of li fe i s sue s i n p a ti en ts d yi n g fr o m h ae ma t o lo gi c al di sea se s . An n Ar c Me d Si n gap or e 1994 , 23 (2 ): 244 -8 Mc Gr a th P . Ar e w e m a ki n g pr o gre ss ? No t i n h ae ma to lo gy! O me ga ( We s tp o r t) 2002 ; 45 (4 ): 331 -48 -F a d ul N A, E l O s t a B , D a la l S , Pou l ter V A, B ruer a E . C o mp ari s on o f s y mp to m b ur den a mo n g p a tien t s referr ed to pal li a ti ve car e wi th he ma to lo gi c ma l i gn anci es vers us t ho se wi th s oli d tu mor s . J Pal li a t Me d 2008 ; 11 (3 ) : 422 -7 -C hun g H M , L yck ho l m L J , S mi th TJ . Pa l li a ti ve C are i n B M T. B one M arr ow Tr an s pl an t a ti on 2009 ; 43 : 265 -273 -R a dbruc h L , Nauck F , e t a l . Wh a t a re the pro b le ms i n p al li a ti ve c are ? Re su lts fr o m a re pre sen t a ti ve sur ve y . Sup p or t C are Ca ncer 2003 ; 1 1 : 442 -451 -S o l an o J P, G o me s B , Hi ggi n son I J . A c o mp a ri s on of s y mp to m p re va lence i n p a ti en t s wi th fa r a d vanc ed c ancer , AI D S , he ar t di se ase , c hro ni c o b s truc ti ve p ul mo n ary di se as e an d r en al di s ea se . J Pai n Sy mp t M an a ge 2006 ; 31 : 58 -69

Manuscript Click here to download Manuscript: Letter -PM in Hematology.doc Click here to view linked References

	Within 31 month s (01.10.2006 -21.04.2009), 79 patient s with underlying
	hemat ological malign ancies w ere t reated at the Department of Palliative
	M edicine i n G oettingen / German y (5.1% of 1555 PC patient s t otal). M ost
	patients (34 pt s; 43.0%) w ere t reated on an outpatient basis / PC home care
	service, whil e 33 pt s (41.1%) al so required inpatient palliative care. Ten patient
	contact s (12.7%) w ere limited t o PC consultation service , and t w o patients
	(and relati ves) w ere solel y supported by PC volunteer services, at home and
	on a hemat ol ogy ward , resp ectively . In further 15 document ed cases, PC
	services were contact ed b y th e hemat ology department , but PC support was
	not initialized as care con cept s were modified before t ransfer (6/15 = 40.0%) or
	due t o shortage of a free PC unit bed (9/15 = 60.0%). Six of th e waiting patients
	died while b ein g on th e waiti ng list for a PC unit transfer (6/15 = 40%), one of
	them on th e same day PC servi ces were cont acted.

Table 1: Demographic and clini cal charact eristics (n = 79 ) Demographi c ch aracteri stics: Mean age (years) Male

  Our case seri es ill ust rat es th e n eed for a specific PC concept for patients with hemat ological mal ign an cies. From a PC perspective, traditional thinking in PC that suggest s a "common p athway" for all disease entities at the end of li fe (Solano 2006) have t o b e abandoned befor ehand. The h emat ological perspective ought t o con sider that PC is more than pain th erapy: it provides numerous multi professi on al competencies in the medical, nursing, social, psychologi cal , sp iritual and ethical field that can (and should) be utilized within contin uous h emat ol ogical care.

	invol vement of relati ves, friends and other non -professionals like
	commun ity health care providers into home care . As general support
	needs w ere hi gh (e.g. due t o general weakness) but focal sympt oms
	requirin g special i zed care not always present , non -professional support
	proved help ful for conti n uing car e at home.
	In our case seri es , th e major therapeutic challenges w ere relat ed t o social
	problems (di sch arge p lan nin g, organisational tasks , home care , family support )
	Eleven pati ent s (13.9%) came from an allogenic st em cell transplantation
	backgroun d. For thi s p arti cular group of patients, the transition fr om curative
	intervention t o a PC app roach is considered t o be especially difficult ,
	regarding th e maximum efforts for cure f rom an otherwise fatal disease,
	accepting a hi gh treat ment relat ed morbidit y and mortalit y. Transplanters w ho
	are about t o decide t o seek PC support might ask whether they had given up
	t oo soon, or i f they sh ould h ave bett er given up their curative efforts a long
	time ago. Several observati onal st udies with st em cell transplantation patients
	show ed that th e introducti on of a hospice t e am earlier in the disease process
	did not sh orten survival or di smiss hope, but appeared t o improve symptoms
	and allowed bett er pl anni ng (Chung 2009 ).

or psychical probl ems . Psych ological consultations oft en aimed to provide relief for th e p atient s´ (or th e families´) ambivalence t owards realistically understandi ng th e narrow p rognostic limitations but still hoping for disease stabilisation or even cl ini cal improvement . Reassessment of transfusion requirements w ith regard t o altered t reatme nt goals proved t o be a major medical an d eth ical controversy in almost half of our patient s.

We found a coh ort of pati ent s that did not necessarily suffer from focal sympt oms, as describ ed in epidemiological surveys of general PC patient population s , w here, for in stance, pain is reported t o be a major clinical problem in 81 .7%, and dyspn ea i n 20 .2%

(Radbruch 2003)

.