Haploidentical Stem Cell Transplantation: Half Match but More Hope!-Single Centre Experience from Western India.

With the success of post-transplant cyclophosphamide based platform and improved clinical care, the number of haploidentical stem cell transplants (HaploSCT) have surged over the last decade. However, data from India is scarce. We aimed to evaluate the outcome of haploSCT at our centre. Since the inception of government schemes, many patients at our centre are able to undergo transplantation at subsidized cost. We conducted a retrospective analysis of the haploidentical transplants performed between January 2015 and November 2022. Fifty patients were eligible for this study. Patient details were obtained from case files. The graft versus host disease (GVHD) prophylaxis was post-transplant Cyclophosphamide (PTCy) with Mycophenolate-mofetil and Cyclosporine/tacrolimus/sirolimus. All patients were transfused peripheral blood stem cells from donors. Post-transplant, patients continued regular follow up as per schedule. Supportive care was given as per unit protocol. Overall survival (OS) was calculated using the Kaplan-Meier method. Fifty patients underwent haploSCT. A total of fifty patients with a median age of 20 years (range 3-53 years) underwent haploidentical HSCT from a family donor. Twenty three (46%) patients were > 18 years age and 82% were males. Indications for transplant included both benign and malignant hematological diseases. Most common conditioning regimen used was Fludarabine + Busulphan + Cyclophosphamide (n = 38, 76%). Thirty five patients (70%) engrafted successfully. In the patients who had successful engraftment, the median time to neutrophil engraftment was 16 days (range 10-20 days) and platelet engraftment was 18 days (range 10-32). Fourteen patients developed acute GVHD (28%), and three patients developed chronic GVHD (6%). The median follow-up was 30 months and the two-year OS was 43% with a median OS of 17 months. Twenty-one (adult = 9, pediatric = 12) out of 50 patients (42%) are alive and on regular follow-up. HaploSCT with a PTCy platform is a cost-effective, promising modality of treatment in patients who have no suitable matched donors and are not affording matched unrelated transplants. At our centre, we were able to achieve acceptable results with use of generic medications at affordable cost. Transplant Related Mortality (TRM) rates were comparable to other centres, however, multi-drug resistant bacterial infection remains a challenge in performing haploidentical HSCT in developing countries.

N-Nitrosodimethylamine investigations in Muta™Mouse define point-of-departure values and demonstrate less-than-additive somatic mutant frequency accumulations.

The N-nitrosamine, N-nitrosodimethylamine (NDMA), is an environmental mutagen and rodent carcinogen. Small levels of NDMA have been identified as an impurity in some commonly used drugs, resulting in several product recalls. In this study, NDMA was evaluated in an OECD TG-488 compliant Muta™Mouse gene mutation assay (28-day oral dosing across seven daily doses of 0.02-4 mg/kg/day) using an integrated design that assessed mutation at the transgenic lacZ locus in various tissues and at the endogenous Pig-a gene-locus, along with micronucleus frequencies in peripheral blood. Liver pathology was determined together with NDMA exposure in blood and liver. The additivity of mutation induction was assessed by including two acute single-dose treatment groups (i.e. 5 and 10 mg/kg dose on Day 1), which represented the same total dose as two of the repeat dose treatment groups. NDMA did not induce statistically significant increases in mean lacZ mutant frequency (MF) in bone marrow, spleen, bladder, or stomach, nor in peripheral blood (Pig-a mutation or micronucleus induction) when tested up to 4 mg/kg/day. There were dose-dependent increases in mean lacZ MF in the liver, lung, and kidney following 28-day repeat dosing or in the liver and kidney after a single dose (10 mg/kg). No observed genotoxic effect levels (NOGEL) were determined for the positive repeat dose-response relationships. Mutagenicity did not exhibit simple additivity in the liver since there was a reduction in MF following NDMA repeat dosing compared with acute dosing for the same total dose. Benchmark dose modelling was used to estimate point of departure doses for NDMA mutagenicity in Muta™Mouse and rank order target organ tissue sensitivity (liver > kidney or lung). The BMD50 value for liver was 0.32 mg/kg/day following repeat dosing (confidence interval 0.21-0.46 mg/kg/day). In addition, liver toxicity was observed at doses of ≥ 1.1 mg/kg/day NDMA and correlated with systemic and target organ exposure. The integration of these results and their implications for risk assessment are discussed.

Buccal mucosal application of dissolvable microneedle patch containing photosensitizer provides effective localized delivery and phototherapy against oral carcinoma.

The effectiveness of phototherapy using photosensitizers is limited by the challenges in their delivery at the site of irradiation. Here, we demonstrate the localized application of a photosensitizer-loaded microneedle patch for effective photodynamic and photothermal therapy in oral carcinoma. Indocyanine green (ICG) was studied as a photosensitizer for its effect on oral carcinoma, FaDu cells. Different parameters including concentration, near-infrared (NIR) laser irradiation intensity and irradiation time were optimized while measuring temperature increase and reactive oxygen species (ROS) generation in FaDu cells. A dissolvable microneedle (DMN) patch made of sodium carboxymethyl cellulose and sodium alginate was fabricated by the micromolding technique. DMN showed sufficient mechanical strength for insertion in the excised porcine buccal mucosa. DMN dissolved within 30 s in phosphate buffer and 30 min in the excised buccal mucosa. Confocal microscopy studies revealed DMN penetration up to a depth of 300 µm within the buccal mucosa. ICG-DMN applied on the back of the rat was found to be localized at the application site before and after irradiation using an 808 nm NIR laser. ICG-DMN was applied on the FaDu xenografted tumor model in athymic nude mice. The localized temperature increase and ROS generation significantly (P < 0.05) decreased the tumor volume after ICG-DMN application compared with the control group. In conclusion, DMN can be developed for the localized administration of photosensitizers for phototherapy in oral carcinoma.

Safety and Efficacy of Thalidomide and Hydroxyurea Combination in Beta Thalassemia Patients.

Beta thalassemia results from imbalance in alpha and beta globin chains causing severe anemia, transfusion dependency, and iron overload. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Patients without the option of HSCT may benefit from Hemoglobin F (HbF) inducing agents like thalidomide and hydroxyurea (HU). We conducted a retrospective analysis on 87 beta thalassemia patients who received a combination of low dose thalidomide and HU from January 2017 to December 2020. Patients received combination of HU 500 mg everyday (> 30 kg) or every alternate day (< 30 kg) and thalidomide 100 mg (> 30 kg) or 50 mg (< 30 kg) once daily. Parameters such as transfusion requirement, anthropometry, Hb levels, ferritin, drug side effects etc. were monitored and evaluated at the end of one year of therapy. Sixty-three patients (72%) achieved transfusion independence and were eligible for the study. Median time to transfusion independence was 6 months (range 3-11 months). At the end of 1 year, overall response rate was 72%. There was significant improvement in the Hb levels, ferritin values and height at the end of 1 year of follow up. No grade 3 or 4 toxicities were noted. We document improvement of Hb levels, transfusion independence, reduction in iron overload, and improvement in growth parameters with minimal side effects at the end of 1 year of follow up.

Experience of Nivolumab Prior to Autologous Stem Cell Transplant for Relapsed Refractory Hodgkin Lymphoma.

Purpose Nivolumab is an anti-programmed cell death protein 1 (PD1) monoclonal antibody that is indicated in relapsed/refractory Hodgkin lymphoma (R/R HL) after autologous stem cell transplant (autoSCT). Purpose of our retrospective study was to assess safety and efficacy of Nivolumab in R/R HL as a bridge to autoSCT in patients who are refractory to ≥ 2 lines of chemotherapy. Methods Demographic data, number of chemotherapy regimens given previously, number of Nivolumab doses taken, and disease status on PET/CT were noted. Nivolumab was administered as a 3 mg/kg IV infusion every 2 weeks. The immunotherapy related adverse events (irAEs) were noted if any and documented. Results A total of 16 patients were included in the study. Ten patients were male and 6 were female. Median age was 22 years (range 3-32 years). The median number of treatment lines prior to Nivolumab was 3 (range 2-7). Nine patients had Complete Response (CR), 3 had Partial response (PR), 2 had Stable Disease (SD), 1 patient had pseudo-progression; classified as IR (3) and 1 expired before end of treatment evaluation. The drug was well tolerated, with mild irAEs noted. Twelve patients (75%) successfully underwent autoSCT. At a median follow up of 17.5 months (range 0.5-35 months), the progression- free survival (PFS) was 75% and overall survival (OS) was 87.5%. Conclusion Nivolumab is effective and safe in patients with R/R HL and is a good bridging therapy to autoSCT.

Unmanipulated Stem Cell Boost for Mixed Chimerism in Transfusion Dependent Thalassemia.

Early mixed chimerism (MC) can lead to secondary graft rejection post allogeneic hematopoietic stem cell transplantation in transfusion dependent thalassemia (TDT) patients. Reduction of immunosuppression and donor lymphocyte infusions is the mainstay for treating MC. We report our experience of administering unmanipulated stem cell boost (SCB) in reversing progressive early MC. There were 70 transplants done for 69 TDT patients at our center between September 2005 and January 2020. Mixed chimerism was defined by > 5% recipient cells and the severity was assigned according to the proportion of recipient cells as level 1 = < 10%, level 2 = 10-25%, level 3 = > 25%. For patients developing MC level 2 and 3, we administered unmanipulated SCB and analyzed its safety and efficacy. Out of 70 transplants 7 (10%) had MC level 2 (3/7) and 3 (4/7). These patients received unmanipulated SCB at a median CD34 cell dose of 4.5 × 106/kg (range-3.5 × 106/kg-5.5 × 106/kg). Overall Response (stable MC and/or transfusion independency) to unmanipulated SCB was seen in 5 patients (71.4%). Five patients (71.4%) developed acute graft versus host disease (GVHD) of which 1 patient expired due to severe GVHD. SCB infusion was well tolerated by majority of our patients. The 3 year overall survival and thalassemia free survival was 85.7% (6/7) and 57.1% (4/7) respectively. Timely monitoring of chimerism is important for detecting early MC. Development of acute GVHD is common after administration of unmanipulated SCB and requires vigilance and prompt management. Unmanipulated SCB is a feasible modality for treating progressive MC and salvaging the graft especially in resource-constrained settings.

Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial.

BACKGROUND: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. METHODS: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30. FINDINGS: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients). INTERPRETATION: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials. FUNDING: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.

Post-transplant Hemophagocytic Lymphohistiocytosis in Benign Hematological Disorders: Experience of 4 Cases with Review of Literature.

Post transplant Hemophagocytic lymphohistiocytosis (HLH) is a form of secondary HLH, which can be either early onset or late onset and is associated with significant morbidity and mortality. With the increasing popularity of post transplant cyclophosphamide based haploidentical stem cell transplantation (SCT), post transplant HLH is becoming a significant complication especially in benign hematological disorders. Methods: We present 4 cases of post transplant HLH occurring in 2 cases of severe aplastic anemia (post haploidentical SCT) and 2 cases of thalassemia major (post matched sibling SCT). All 4 cases had early onset variety with dismal prognosis. Conclusion: Post-transplant HLH is an important entity in benign hematological disorders, which needs to be identified early and treated promptly with steroids, monoclonal agents or immunosuppressive therapy. Serum ferritin levels are an important biomarker and help in monitoring response.

Stepwise Description and Outcomes of Bladder Neck Sparing Robot-Assisted Simple Prostatectomy.

Background: To present a stepwise description and outcomes of bladder neck sparing (BNS) robot-assisted simple prostatectomy (RASP). Methods: Between March 2015 and December 2018, 30 consecutive patients with benign prostate hyperplasia underwent BNS RASP. Baseline characteristics, and intraoperative and postoperative variables were retrospectively abstracted. Descriptive statistics were used to report the variables. Results: The median age was 66.5 (59.3-72.3) years, and median body mass index was 27.6 (24.5-72.3) kg/m2. The median preoperative International Prostate Symptoms Score was 23 (17.5-27), and median prostate size was 97 (74-148.75) mL. The mean (standard deviation [SD]) operative time was 107.5 (22.2) minutes, and the mean (SD) estimated blood loss was 132.4 (35.4) mL. All cases were completed robotically without any intraoperative complications, and continuous bladder irrigation was not necessary for any patient postoperatively. All patients were able to void after catheter removal except one patient with a preexisting diagnosis of neurogenic bladder who resumed clean intermittent catheterization. All patients were continent as defined as using 0 pads postoperatively. Of the 19 patients who had antegrade ejaculation before the operation, 8 patients (42%) reported of continued antegrade ejaculation after the operation. Conclusions: In this report, we demonstrate a simplified approach of BNS RASP that is reproducible with a favorable perioperative complication rates and acceptable postoperative functional outcomes. This technique obviates the need for continuous bladder irrigation and intraperitoneal drain.

Aspirin as an adjuvant treatment for cancer: feasibility results from the Add-Aspirin randomised trial.

BACKGROUND: Preclinical, epidemiological, and randomised data indicate that aspirin might prevent tumour development and metastasis, leading to reduced cancer mortality, particularly for gastro-oesophageal and colorectal cancer. Randomised trials evaluating aspirin use after primary radical therapy are ongoing. We present the pre-planned feasibility analysis of the run-in phase of the Add-Aspirin trial to address concerns about toxicity, particularly bleeding after radical treatment for gastro-oesophageal cancer. METHODS: The Add-Aspirin protocol includes four phase 3 randomised controlled trials evaluating the effect of daily aspirin on recurrence and survival after radical cancer therapy in four tumour cohorts: gastro-oesophageal, colorectal, breast, and prostate cancer. An open-label run-in phase (aspirin 100 mg daily for 8 weeks) precedes double-blind randomisation (for participants aged under 75 years, aspirin 300 mg, aspirin 100 mg, or matched placebo in a 1:1:1 ratio; for patients aged 75 years or older, aspirin 100 mg or matched placebo in a 2:1 ratio). A preplanned analysis of feasibility, including recruitment rate, adherence, and toxicity was performed. The trial is registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN74358648) and remains open to recruitment. FINDINGS: After 2 years of recruitment (October, 2015, to October, 2017), 3494 participants were registered (115 in the gastro-oesophageal cancer cohort, 950 in the colorectal cancer cohort, 1675 in the breast cancer cohort, and 754 in the prostate cancer cohort); 2719 (85%) of 3194 participants who had finished the run-in period proceeded to randomisation, with rates consistent across tumour cohorts. End of run-in data were available for 2253 patients; 2148 (95%) of the participants took six or seven tablets per week. 11 (0·5%) of the 2253 participants reported grade 3 toxicity during the run-in period, with no upper gastrointestinal bleeding (any grade) in the gastro-oesophageal cancer cohort. The most frequent grade 1-2 toxicity overall was dyspepsia (246 [11%] of 2253 participants). INTERPRETATION: Aspirin is well-tolerated after radical cancer therapy. Toxicity has been low and there is no evidence of a difference in adherence, acceptance of randomisation, or toxicity between the different cancer cohorts. Trial recruitment continues to determine whether aspirin could offer a potential low cost and well tolerated therapy to improve cancer outcomes. FUNDING: Cancer Research UK, The National Institute for Health Research Health Technology Assessment Programme, The MRC Clinical Trials Unit at UCL.

Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial.

Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear. Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival. Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019. Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine. Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence. Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03). Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection. Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

Impact of Neoadjuvant Chemotherapy on Concordance of PD-L1 Staining Fidelity between the Primary Tumor and Lymph Node Metastases in Bladder Cancer.

OBJECTIVE: To evaluate programmed death ligand 1 (PD-L1) staining fidelity between the primary tumor and associated lymph node metastases in bladder cancer. To secondarily evaluate whether neoadjuvant chemotherapy (NAC) affects this relationship. METHODS: Sixty-seven subjects with residual bladder cancer on cystectomy and associated positive lymph nodes were identified between 2008 and 2015. PD-L1 staining of tumor cells was evaluated using H score and 49 specimens were also evaluated using combined positive score (CPS). Univariable and multivariable logistic regression analysis were used to assess how various clinical variables affected odds of PD-L1 fidelity between primary and metastatic tumors. RESULTS: Tumor PD-L1 staining was concordant in 79.1% of cases and CPS was concordant in 79.6% of cases. NAC did not significantly impact odds of PD-L1 or CPS fidelity (OR 1.974, 95% CI 0.673-5.784, OR 0.500, 95% CI 0.093-2.700). Among clinical variables analyzed on univariable analysis of tumor PD-L1 fidelity, H-score, and PD-L1 staining intensity were associated with significantly increased odds of PD-L1 fidelity and the association with staining intensity was confirmed on multivariable analysis. CONCLUSION: PD-L1 fidelity between primary bladder tumors and nodal metastases was observed in >75% of cases in this study. Additionally, NAC was not shown to diminish this propensity to maintain PD-L1 staining status. Further standardization of immunohistochemistry of tumor and infiltrating imsmune cells in metastatic bladder cancer is needed to improve application of therapeutics.

Immunosuppressive therapy for aplastic anemia: a single-center experience from western India.

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CsA) is the first-line therapy for acquired aplastic anemia (AA) in those not suitable for bone marrow transplant. Horse ATG (hATG) is preferred for this purpose, but its use is often impeded by shortages and costs. Being a rare disease, there is limited data on this therapy. This study aimed to evaluate this therapy in a large cohort of AA patients from western India. We retrospectively analyzed AA patients who received an indigenous preparation of hATG along with CsA as first-line treatment, between 2012 and 2015, at our center and evaluated the response, survival, and occurrence of adverse events. The response was further assessed separately for adults and children. During the period, 91 AA patients (4 non-severe, 57 severe and 30 very severe) were treated with IST. At 2 years, 23.5% adults and 39.1% children showed complete response and an overall of 68.1% cases became transfusion independent. More than half of the patients developed febrile neutropenia while roughly one sixth of the patients developed gum hypertrophy and/or hypertension. Two patients had clonal evolution. Mortality rate was calculated to be 31%; most common causes of death were infection and intracranial hemorrhage. The results of the study substantiate the effectiveness of IST in AA, using an inexpensive indigenous preparation of hATG along with CsA.

Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with National Cancer Institute (NCI) intermediate- or high-risk (HR) ALL is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 67 patients with either BCR-ABL1 (n = 6) or ETV6-RUNX1 (n = 61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted reverse transcription polymerase chain reaction assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%), and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared with non-Ph-like ALL (82.4 ± 3.6% vs 90.7 ± 1.0%, P = .0022), with no difference in overall survival (93.2 ± 2.4% vs 95.8 ± 0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

Improving Outcome of Thalassemia with Hematopoetic Stem Cell Transplantation: An Experience of Gujarat Cancer Research Institute.

Total 26 children of thalassemia underwent hematopoetic stem cell transplantation from September 2006 to December 2014. Out of these 17 were matched sibling transplantation (MST) and 9 were unrelated umbilical cord blood transplantation (UCT). Median age was 4 years. At a median follow up of 46.5 months, 12 of 17 (70 %) MST and 3 out of 9 (33.33 %) UCT were cured of thalassemia. Three (11.53 %) patients died due to transplant related mortality. Average cost of MST was 6 lakhs and that of UCT was 20 lakhs.

A multicentre comparison between Child Pugh and Albumin-Bilirubin scores in patients treated with sorafenib for Hepatocellular Carcinoma.

BACKGROUND & AIMS: The Albumin-Bilirubin (ALBI) grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the subclassification by points (5-15) within the CP classification. METHODS: We retrospectively analysed data from patients treated with sorafenib for HCC from 17 centres in United Kingdom and France. Overall survival (OS) was analysed using the Kaplan-Meier method and a Cox regression model. Discriminatory abilities of the classifications were assessed with the log likelihood ratio, Harrell's C statistics and Akaike information criterion. RESULTS: Data from 1019 patients were collected, of which 905 could be assessed for both scores. 92% of ALBI grade 1 were CP A5 while ALBI 2 included a broad range of CP scores of which 44% were CP A6. Median OS was 10.2, 7.0 and 3.6 months for CP scores A5, A6 and >A6, respectively (P < 0.001), Hazard Ratio (HR) = 1.60 (95%CI: 1.35-1.89, P < 0.001) for A6 vs A5. Median OS was 10.9, 6.6 and 3.0 months for ALBI grade 1, 2 and 3, respectively (P < 0.001), HR = 1.68 (1.43-1.97, P < 0.001) for grade 2 vs 1. Discriminatory abilities of CP and ALBI were similar in the CP A population, but better for CP in the overall population. CONCLUSIONS: Our findings support the use CP class A as an inclusion criterion, and ALBI as a stratification factor in trials of systemic therapy.

Improving Outcome of Hodgkins Disease with Autologous Hematopoietic Stem Cell Transplantation.

We report analysis of all consecutive Hodgkins disease patients undergoing autologous hematopoietic stem cell transplant from September 1999 to December 2014. Out of total 38 patients 26 were males and 12 were females. 32 were adults and 6 were pediatric (<18 years). None were elderly. Median age was 28 years (9-61). All received BEAM protocol as conditioning regimen. Median engraftment time for granulocytes was 12 and 14 days for platelets. Thirty three (86.84 %) patients achieved complete remission out of which 8 (24.24 %) had further relapse. Transplant related mortality occurred in 4 (10 %) patients. Finally 26 (78.78 %) patients were disease free at median follow up of 60 months and median disease free survival (DFS) was 35 months. DFS was 66.66 and 65 %, respectively on 3 and 5 years. While overall survival was 70.83 and 70 % on 3 and 5  years, respectively.