What is the impact of neoadjuvant chemoradiation on outcomes in gastro-intestinal cancer?

Multimodal therapeutic strategies combining chemotherapy, radiation therapy and surgery have been shown to be feasible and to have a positive impact on outcomes by decreasing the risk of locoregional recurrence and often by increasing overall survival. The advantages of neoadjuvant chemo(radio)therapy include optimal tumor control combined with better tolerance and compliance to treatment while also increasing the number of candidates for surgery. Whereas indications for neoadjuvant therapy are increasing, its impact on surgical treatment and postoperative outcomes are not well-known. Surgeons frequently believe that chemo(radio)therapy may amplify intraoperative difficulties, thereby increasing postoperative morbidity and mortality. The aim of this review was to report the state of the art regarding: (i) the role of chemo(radio)therapy; (ii) its impact on surgical indications and modalities; and (iii) its impact on postoperative outcomes for the most frequently encountered gastro-intestinal cancers, i.e. esophageal, rectal, pancreatic, and anal canal cancer.

The protein tyrosine phosphatase PTPN22 controls forkhead box protein 3 T regulatory cell induction but is dispensable for T helper type 1 cell polarization.

Protein tyrosine phosphatases (PTPs) regulate T cell receptor (TCR) signalling and thus have a role in T cell differentiation. Here we tested whether the autoimmune predisposing gene PTPN22 encoding for a PTP that inhibits TCR signalling affects the generation of forkhead box protein 3 (FoxP3)(+) T regulatory (Treg ) cells and T helper type 1 (Th1) cells. Murine CD4(+) T cells isolated from Ptpn22 knock-out (Ptpn22(KO) ) mice cultured in Treg cell polarizing conditions showed increased sensitivity to TCR activation compared to wild-type (WT) cells, and subsequently reduced FoxP3 expression at optimal-to-high levels of activation. However, at lower levels of TCR activation, Ptpn22(KO) CD4(+) T cells showed enhanced expression of FoxP3. Similar experiments in humans revealed that at optimal levels of TCR activation PTPN22 knock-down by specific oligonucleotides compromises the differentiation of naive CD4(+) T cells into Treg cells. Notably, in vivo Treg cell conversion experiments in mice showed delayed kinetic but overall increased frequency and number of Treg cells in the absence of Ptpn22. In contrast, the in vitro and in vivo generation of Th1 cells was comparable between WT and Ptpn22(KO) mice, thus suggesting PTPN22 as a FoxP3-specific regulating factor. Together, these results propose PTPN22 as a key factor in setting the proper threshold for FoxP3(+) Treg cell differentiation.

The ALPPS procedure for hepatocellular carcinoma.

BACKGROUND: The main limiting factor to major hepatic resections is the amount of the future liver remnant (FLR). Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy (ALPPS) is a procedure which induces a rapid hypertrophy of the FLR in patients with non-resectable liver tumours. METHODS: ALPPS is a surgical technique of in-situ splitting of the liver along the main portal scissura or the right side of the falciform ligament, in association with portal vein ligation in order to induce a rapid hypertrophy of the left FLR. RESULTS: The median FLR volume increase was 18.7% within one week after the first step and 38.6% after the second step. At the first step the median operating time was 300 min, blood transfusions were not required in any case, median blood loss was 150 cc. At the second step median operating time was 180 min, median blood loss was 50 cc, none of the patients required intra-operative blood. All patients are alive at a median follow up of 9 months. CONCLUSIONS: This novel strategy seems to be feasible even in the context of a cirrhotic liver, and demonstrates the capacity to reach a sufficient FLR within a shorter interval of time.

Downstaging Hepatocellular Carcinoma with Yttrium-90 radioembolization: resection or transplantation?

Trans Arterial Radio Embolization with Yttrium 90 in the treatment of Hepatocellular Carcinoma is becoming a new interesting tool in the treatment of patients that are considered non resectable and non transplantable. A successful downstaging could improve the number of patients that could benefit from a resection or a liver transplantation, but some points still need to be addressed.

Hanging of the hepatic veins septa: a safe control prior and during outflow anastomosis in liver transplantation.

Inferior vena cava (IVC) preservation during orthotopic liver transplantation (OLT) is known as the "piggyback" technique. The end-to-side anastomosis is constructed between the graft's IVC and recipient's hepatic veins using a Satinsky side clamp applied in a transverse position. To stabilize the large Satinsky clamp and preserve a sufficient vascular stump after hepatectomy and before graft implantation, we propose a technical innovation consisting of hanging the septa between the left and middle hepatic vein and between the middle and right hepatic vein using 2 tapes. This technique showed some advantages when performing the caval outflow anastomosis, representing a further technical refinement of the piggyback end-to-side technique for the implantation on the 3 hepatic veins. From November 2001 to September 2012, we performed 272 consecutive OLT at our institution with the piggyback technique using the hanging of the hepatic veins septa in all cases. In conclusion, the hanging of the 3 hepatic veins septa presented in this study represents a simple, safe and reproducible technique for the outflow anastomosis using the piggyback technique.

Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983--93 and 1994--8 at European Group for Blood and Marrow Transplantation centres.

Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983-93 (all with bone marrow) and 356 during 1994-98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with hone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 with the result of a significant reduction in transplant-related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant-related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.

Unrelated donor marrow transplantation for chronic myelogenous leukaemia.

Between January 1989 and July 1995 the search for an unrelated donor (UD) was started for 379 consecutive Italian patients with Philadelphia positive (Ph+) chronic myelogenous leukaemia (CML). 89 (23%) were transplanted. The overall probability of transplant before and after December 1991 was 16% and 49%, respectively (P=0.0001), and average interval between search activation and graft was 23 months and 13 months, respectively (P=0.0001). Disease-free survival (DFS) following 60 consecutive transplants performed before February 1996 was 41.5% at 48 months and was 64% for patients grafted after January 1993. In univariate analysis, five variables had a favourable effect on DFS: year of bone marrow transplantation (BMT) after 1993 (P=0.0002), HLA-DRB1 donor/recipient (D/R) match (P=0.0006), total body irradiation (TBI) containing regimen (P=0.0006), graft-versus-host disease (GvHD) prophylaxis including 'early' cyclosporin before the transplant, and a marrow cell dose > 3 x 10(8)/kg of recipient body weight (P=0.04). Multivariate analysis confirmed that HLA identity (P=0.006), TBI-containing regimen (P=0.0001) and 'early cyclosporin' (P=0.04) were associated with higher DFS. Transplant-related mortality (TRM) was 67% in patients grafted before January 1993 and 30% in patients grafted subsequently (P=0.002). Multivariate analysis confirmed DRB1 identity (P=0.03) and TBI-containing regimen (P=0.0005) to be independent factors predictive of low TRM. This suggests that the outcome of patients transplanted from an HLA DRB1 matched donor, after a TBI-containing preparative regimen, is similar to results recently reported in patients transplanted from geno-identical siblings. These results indicate that the search should be initiated at diagnosis for patients < 45 years of age and UD BMT should be considered early in the disease course for those with an available DRB1-matched unrelated donor.

The effectiveness and tolerability of epoetin alfa in patients with multiple myeloma refractory to chemotherapy.

Anemia is a frequent complication of multiple myeloma, becoming chronic in patients who are resistant to chemotherapy. This randomized, parallel, controlled multicenter study (71 patients receiving concomitant chemotherapy) evaluated the efficacy and safety of epoetin alfa in improving anemia and eliminating the need for transfusions in multiple myeloma patients refractory to conventional first- or second-line chemotherapy. Forty patients were treated with subcutaneous epoetin alfa (150 IU/kg per dose, increasing to 300 IU/kg per dose, every 3 weeks) for 6 months, and 31 entered a control group. The epoetin alfa group had a significantly (P < or = 0.001) greater percentage of patients (75% vs. 21%) with increases in hemoglobin levels and/or reduced transfusion requirements. In 44 non pre-transfused patients (20 controls, 24 in the epoetin alfa group), the mean increase in hemoglobin was significantly (P < or = 0.0001) greater in the epoetin alfa group (+2.1 vs. -0.2 g/dl). Increases in hematocrit and red blood cells were also significantly (P < or = 0.0001) greater in epoetin alfa-treated patients, with corresponding reductions in transfusion requirement. In the 27 pre-transfused patients (11 controls, 16 in the epoetin alfa group), there was a trend towards reduced transfusional need in epoetin alfa-treated patients. Thus, in patients with multiple myeloma refractory to chemotherapy epoetin alfa is a well-tolerated treatment which improves anemia in non pre-transfused patients and appears to reduce transfusion need in those previously transfused.

Constitutive expression of beta-N-acetylhexosaminidase in a microglial cell line: transcriptional modulation by lipopolysaccharide and serum factors.

We investigated the expression of the alpha- and beta-subunits of the lysosomal enzyme beta-N-acetylhexosaminidase in the BV-2 microglial cell line under different culture conditions. Beta-N-acetylhexosaminidase from BV-2 microglia cells was separated into its constituent isoenzymes on diethylaminoethyl (DEAE) cellulose, and its activity was monitored with 4-methylumbelliferyl-beta-N-acetylglucosamine and 4-methylumbelliferyl-beta-N-acetylglucosamine-6-sulphate substrates. Forms corresponding to the mouse isoenzymes A and B were present in the cells incubated in serum-supplemented medium as well as in serum-free medium. Lipopolysaccharide, a well-known activator of microglia in vitro, added to the BV-2 cells in serum-supplemented medium induced a decrease in the specific enzymatic activity determined with the 4-methylumbelliferyl-beta-N-acetylglucosamine substrate. Lipopolysaccharide had no effect on hexosaminidase isoenzyme pattern of BV-2 cells in serum-supplemented medium. The level of alpha-subunit mRNA was increased and the level of beta-subunit mRNA was decreased in BV-2 cells incubated in serum-supplemented medium plus lipopolysaccharide. In the cells incubated in a serum-free medium no significant changes in the hexosaminidase-specific activities towards the above substrates were observed. Interestingly, increased expression of alpha- and beta-subunit mRNA was evident in comparison with cultures in serum-supplemented medium. The present results suggest that the BV-2 cell line may be a useful tool to study the possible role of microglia in the metabolism of brain glycolipids.

[Bone marrow changes in HIV-positive patients (clinical, cytological, histological, and ultrastructural study of 57 cases)]. / Alterazioni osteomidollari in pazienti HIV positivi (studio clinico, citologico, istologico ed ultrastrutturale su 57 casi).

The authors take into consideration clinical, cytological, histological and ultrastructural pattern of 57 HIV+ patients. They want to quantify bone marrow alterations and research their relation with haematological pattern of these patients. They think that peripheral haematological deficit is related with cellular and stromal alterations of the bone marrow. In fact there are many morphological cellular alterations. The most characteristic are that of megakaryocytes. The alterations of these cells are, probably, responsible for bone marrow early sclerosis of these patients. The plasma cells are also numerous and activated. They respect an immunological response.

Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation.

A retrospective case-matched analysis was performed comparing 189 myeloma patients treated with allogeneic bone marrow transplantation (allo-BMT) with an equal number of patients who received autologous stem cell transplantation (ASCT). Matching was performed with respect to gender and number of treatment lines before transplantation. The groups were comparable with the exception of median age (43 years for allo-BMT v 49 years for ASCT, P = .0001) and median posttransplant follow-up (46 months for allo-BMT v 30 months for ASCT, P = .0003). The overall survival was significantly better for ASCT than for allo-BMT, with a median survival of 34 months and 18 months, respectively (P = .001). However, this survival advantage was only observed in men, but not in women. The statistically significant survival advantage for ASCT was seen in most subgroups, ie, chemotherapy-responsive patients, patients who had received two or more treatment lines before transplantation, patients in partial remission, patients with an IgG-subtype, patients older than 46 years of age, patients with stage II disease, and patients with a low or high serum-beta-2-microglobulin at diagnosis. The main reason for the poorer survival in allo-BMT patients was higher transplant-related mortality (41% v 13% for ASCT, P = .0001), which was not compensated for by a lower rate of relapse and progression. However, in patients alive at 1 year posttransplant, there was a trend for better long-term survival (P = .09) and significantly better progression-free survival (P = .02) for allo-BMT as compared with ASCT. We conclude that the median survival is superior for ASCT. However, allo-BMT has a lower relapse rate, which results in a similar long-term outcome for both approaches, but a longer follow-up is needed to assess the final outcome.

Amphotericin B prophylaxis against invasive fungal infections in neutropenic patients: a single center experience from 1980 to 1995.

Fungal infections are a common complication in hematological and oncological patients. In the study the results of a retrospective analysis of the onset of fungal infections among 383 patients admitted at the hematology unit of San Camillo Hospital, Rome, from 1980 to 1995 are reported. In the eleven years prior to 1991 only four cases of fungal infection were detected in high risk patients (1.8% of the high risk patients). From 1991 to 1993 there was a dramatic increase of fungal infections (Candida and Aspergillus). Thirteen cases of infections were observed during this period, eight of which were due to Aspergillus (12% of the high risk patients). For this reason it was decided to introduce a different prophylactic treatment for all high risk patients consisting of combined conventional intravenous (i.v.) amphotericin B, oral amphotericin B and nebulized amphotericin B, starting from the first day of hospitalization. Since the introduction of this new prophylactic regimen no cases of invasive fungal infections were observed in the 48 high risk patients examined. The prophylactic treatment was well tolerated by all patients. The results suggest that the combined use of oral, nebulized and i.v. amphotericin B is very effective in preventing invasive fungal infections in high risk patients.

An update of prognostic factors for allogeneic bone marrow transplantation in multiple myeloma using matched sibling donors. European Group for Blood and Marrow Transplantation.

Analysis of prognostic factors has been made in 369 allogeneic transplants for multiple myeloma reported to the registry of the European Group for Blood and Bone Marrow Transplantation (EBMT). Favorable prognostic factors for obtaining a complete remission (CR) were stage I at diagnosis (CR 77%), one line of treatment before conditioning (CR 52%), CR before conditioning (CR 60%), and Ig A or light chain myeloma (CR 43% and 42%). Factors that predicted significantly for favorable survival in a univariate analysis included having received only one line of treatment, female sex, stage I at diagnosis, stage I at conditioning and a beta 2-Microglobulin less than 4 mg/l. Favorable post-BMT factors consisted of obtaining a CR following BMT and not being in graft-versus-host disease stage III or IV. A multivariate analysis of pre-BMT factors showed that the sex of the patient and the number of lines of treatment pretransplant were independent prognostic factors. Allogeneic BMT is a promising treatment method for patients who have received only one line of treatment, particularly if they are of the female sex. BMT late in the course of the disease is usually unsuccessful.

Recombinant interleukin-2 treatment before and after autologous stem cell transplantation in hematologic malignancies: clinical and immunologic effects.

Autologous bone marrow transplantation (ABMT) for hematologic malignancies is associated with a high relapse rate. Interleukin-2 (IL-2) administration is a therapy that may prevent relapse if used when the tumor burden is minimal. In this study we administered recombinant IL-2 (rIL-2) therapy to 12 patients affected by hematologic malignancies either before or after autologous stem cell transplantation (ASCT). rIL-2 was given by a 6 day continuous intravenous infusion with escalating doses, up to 18 x 10(6)/m2/day, depending on patient tolerance. The functional immune responses of the patients were assessed as natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities and in vitro interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis. During rIL-2 treatment, the expected side effects occurred; only 3 patients, who showed severe cardiovascular toxicity, required suspension of the treatment. All toxicities reversed after the end of the therapy. Immunologic monitoring was carried out the day before starting rIL-2 infusion and then repeated on days 3, 7, and 14 after rIL-2 was discontinued. Following every rIL-2 course, a pronounced increase in CD3+, CD8+, CD56+ cells was found, with a peak value on day 3. The NK and LAK activities showed a significant increase on day 3 (p < 0.001) over pretherapy values; the increase lasted until day 14, although the difference at later time points was not significant. Before transplant the synthesis of both IFN-gamma and TNF-alpha decreased following rIL-2 therapy, whereas higher levels of these lymphokines were found after posttransplant rIL-2 courses.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic factors in autologous stem cell transplantation for multiple myeloma: an EBMT Registry Study. European Group for Bone Marrow Transplantation.

Autologous bone marrow- and blood progenitor cell transplantation was performed in 130 patients with multiple myeloma in 16 European centers between 1986 and 1993. At the time of follow-up, 77 patients were alive and 53 were dead. Complete remission after transplantation was obtained in 47% of all patients. The actuarial survival at 65 months was 28%. The median duration of relapse-free survival among patients who were in complete remission after transplantation was 29 months. The following factors were predictive for longer survival and freedom of progression in a univariate analysis: Male sex, age less than 45 years, a low serum-beta-2-microglobulin value at diagnosis, prior administration of only one treatment regimen, response on conventional chemotherapy immediately pretransplant and the use of a preparative regimen including melphalan. The last factor, in addition to stage I disease at diagnosis, male sex and responsive disease immediately pretransplant, were also demonstrated as independent predictive variables for longer survival in a multivariate analysis. Progression-free survival was significantly better for patients who were in complete remission after transplantation, as compared to those with persisting signs of disease. We conclude that high-dose chemo-radiotherapy with autologous stem cell transplantation can induce long-term responses, primarily in younger, male patients with chemotherapy-responsive early disease. High-dose melphalan, as single drug or in combination, appeared to be superior to other regimens. The chance of being persistently disease-free seemed to be greatest for patients being in complete remission already before the transplantation.

Characterization of a new case of trisomy 8 in acute lymphoblastic leukemia.

Trisomy 8 is a relatively common finding in acute nonlymphoblastic leukemia (ANLL). In childhood acute lymphoblastic leukemia (ALL) it apparently is much more rare. Although Human Gene Mapping 11 included trisomy 8 as a marker for a subgroup of ALL, morphologic and immunologic characteristics of this entity have not been defined. We describe a case of early T-cell ALL (T-ALL) in a pediatric patient in whom this abnormality was the sole chromosome aberration. In situ hybridization with a chromosome 8-specific alpha-satellite DNA probe was performed. Our data are discussed and compared with pertinent literature.

High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with high-grade non-Hodgkin's lymphoma: the EBMT experience. Lymphoma Working Party of the European Group for Bone Marrow Transplantation.

One hundred and eighteen patients presenting with high-grade non-Hodgkin's lymphoma, undergoing autologous bone marrow transplantation (ABMT) in first complete remission (CR), have been reported to the European Group for Bone Marrow Transplantation (EBMT). Of these, 102 were eligible for inclusion in this study following review of registration forms. Patients with lymphoblastic lymphoma were excluded. Remission induction and high-dose regimens varied between contributing centres. A maintained CR was observed in 90% of patients. Early relapse was observed in 6%, and 4% suffered toxic deaths. With a median follow-up of 45 months (3-112 months), the 5-year actuarial overall and progression-free survivals are both 70%. Nineteen (18%) patients relapsed at a median of 3.5 months (0.25-52 months) after ABMT, only 1 achieving a further durable CR. The only factor with prognostic significance was histological subtype, with diffuse small noncleaved-cell lymphoma having a significantly worse outcome. High-dose therapy and ABMT has produced effective consolidation of first remission in this group of patients, even in those with poor prognostic features at presentation.

Haemopoietic reconstitution after autologous blood stem cell transplantation in patients with malignancies: a multicentre retrospective study.

A retrospective study was undertaken to evaluate the efficacy of autologous blood stem cell transplantation (ABSCT) in terms of haemopoietic reconstitution after ablative chemotherapy or chemo-radiotherapy. 55 patients with malignancies, observed in four Italian institutions from January 1987 to June 1991, were eligible for evaluation. This series included 19 non-Hodgkin's lymphoma, 11 multiple myeloma, nine ovarian cancer, seven Hodgkin's disease, seven non-lymphocytic leukaemia, one acute lymphoblastic leukaemia, one neuroblastoma. 522 PBSC collections were performed on 55 patients. Following ABSCT, the rate of engraftment was positively related to the dose of CFU-GM infused and negatively to the presence of bone marrow involvement at conditioning. 48 patients out of 55 transplanted (87%) had rapid, complete and sustained engraftment. Three patients (5%) died of transplant-related complications. Considering that 60% of the patients in this series were in partial remission or in progressive disease at the time of ABSCT, we conclude that ABSCT is a safe approach for the use of ablative conditioning therapy in patients with a wide scope of malignancies, provided that a large number of CFU-GM have been collected after mobilizing treatment.

Progenitor cells purging: negative selection.

Disease relapse after autologous bone marrow transplantation (ABMT) may arise from residual tumor in the recipient and/or from cancer cells that are reinfused. The aim of purging by negative selection is to remove tumor cells from the marrow without adversely affecting the engraftment potential of the normal cell. We report the results of a study on fifty-six patients (pts) with non Hodgkin's lymphoma or acute leukemia submitted to ABMT after immunomagnetobead (IMB) purging (11 pts), Maphosphamide purging (31 pts) and no purging (14 pts). The IBM procedure involved one incubation of 3 monoclonal antibodies (CD10, CD19 and CD22) and two incubations with magnetic beads (Dynabeads M-450). The median recovery of mononuclear cells and CFU-GM was 40% and 45% after IMB purging and 84% and 5% after Maphosphamide purging respectively. The rate of leukocyte, neutrophils and platelets recovery following ABMT was similar in the three groups of pts, although platelet recovery was slow in patients received graft purged with Maphosphamide. Our study confirms the clinical feasibility of the IMB procedure, but only randomized studies will be able to definitely address the question of the clinical utility of purging.

Autologous blood stem cell collection after chemotherapy in patients with sensitive and refractory malignancies: a multicenter retrospective study.

A retrospective study was undertaken to assess the factors affecting the yield of peripheral blood stem cell (PBSC) collections after chemotherapy. Fifty-five patients with malignancies, observed in 4 Italian Institutions from January 1987 to June 1991 were eligible for evaluation. This series included 19 non-Hodgkin lymphoma, 11 multiple myeloma, 9 ovarian cancer, 7 Hodgkin disease, 7 acute non-lymphocytic leukemia, 1 acute lymphoblastic leukemia, 1 neuroblastoma. Five hundred and twenty two PBSC collections were performed on 55 patients after a median of 18 days after the start of chemotherapy. The yields of PBSC collections were related to the dose of cytoreductive chemotherapy exploited for PBSC mobilization and to the number of circulating white blood cells, colony forming unit granulocyte/macrophage (CFU-GM) and the percentage of monocytes at the time of collection. Forty-eight patients out of 55 transplanted (87%) had rapid, complete and sustained engraftment. Three patients (5%) died of transplant related complications.