When transepithelial permeability of rat distal colon is evaluated on the basis of transepithelial electrical resistance, age does not have an effect. Age likewise did not affect the decrease in resistance brought about by phorbol ester exposure. However, age was shown to correlate with increased transepithelial permeability when diffusion of the nonelectrolyte, D-mannitol, was used as an indicator. A phorbol ester-induced increase in transepithelial permeability to D-mannitol was observed to increase with age. Basal permeability to D-mannitol was significantly higher in older rats when the animals were allowed to age on a high-fat diet. Distance from the rectum was shown to be a potential complicating factor in these studies, since distal colon closer to the rectum was observed to have lower transepithelial permeability. The potential effect of such increased leakiness on the increased frequency of colon cancer in older individuals is discussed.

No abstract

No abstract

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as > 5% to < 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.

No abstract

e21034 Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resulted in significant improvement in the outcomes of patients with activating EGFR mutations. But the ideal treatment of patients harboring uncommon, or compound mutations is not well defined. This multicentric audit was conducted to study the distribution, treatment pattern, and outcomes of patients with uncommon or compound EGFR mutations. Methods: This was a multicentric retrospective study that included patients with uncommon (mutations other than Exon 19 deletions and Exon 21 L858R) or compound (double or complex) mutations treated during the period of 2017-2020. Statistical analysis was done using SPSS version 20.0. Descriptive statistics were used wherever appropriate. Kaplan Meier Aanlaysis was performed for estimation of PFS and OS. Results: Total 99 patients with uncommon or compound mutations were included in the study. The median age was 55 years (25-82 years). Majority were males (n=65,67%) and 47 (47%) were smokers. Sixty-seven patients (68 %) had a single uncommon mutation and the remaining 32 (32%) had compound mutations. Most common mutations were exon 20 insertion (n=34, 35%) and T790M (N=16,16%). Other frequent mutations observed were exon 18 G719X (n=7,7%) and exon 21 L861Q (n=3,3%). Twenty-three patients (n=23,23%) were eligible only for best supportive care. Thirty-two patients (32%) received first-generation TKI, 30 patients (30%) received palliative chemotherapy and 11 patients (11 %) received Osimertinib. Gefitinib with chemotherapy was used in 2 patients and combination of Gefitinib with Afatinib was used in one patient. Overall response rate and clinical benefit rate with first line treatment was 23% and 35% respectively. Response could not be assessed in 14 patients. Median PFS was 5 months (95% CI 3.4-6.9) and median OS was 8.3 months (95% CI 3.3- 13). In patients who received any form of systemic treatment, median PFS was 6.2 months (95% CI- 3.3-9.1) and OS was 11 months (95% CI -8.9-13.9). Conclusions: The most frequent uncommon mutations in India are exon 20 insertion followed by compound mutations and exon 20 T790M mutation. Outcomes of patients with these rare mutations are dismal in the real world setting with the available treatment options.

e18862 Background: There are limited data available from India on the real-world use of checkpoint inhibitors. Hence we did this analysis across India to study the pattern of use and outcomes with checkpoint inhibitors. Methods: This was a retrospective multicentric protocol. Patients who received immunotherapy from January 2016 to October 2021 were included. The baseline demographic, previous treatment, response, date of progression, date of death and status were noted. SPSS version 20 was used for analysis. Descriptive statistics were performed. Kaplan Meier method was used for estimation of progression-free survival (PFS) and overall survival (OS). COX regression model was used to identify factors impacting OS. Results: We identified 308 patients in the study. The median age was 58.5 years (Interquartile range 51-66 years) and there was a male preponderance (249, 80.8%). The 3 commonest sites of use were head and neck cancer in 144 patients (46.8%), lung cancer in 81 (26.3%) and renal cell carcinoma in 31(10.1) patients. The ECOG PS was 0-1 in 215 (70%), 2 in 71 (23.1), 3-4 in 21(6.8%) and not documented in 1(0.3%) patient. The two most common checkpoint inhibitors used were nivolumab and pembrolizumab 255 (82.8%) and 37(12%) patients respectively. These were used in curative setting in 6 patients (1.9%) and palliative in rest all. 43(14%) patients received them as first-line in, 129 (41.9) as second-line and beyond the second line in 130 (42.2%) patients. The response rate was 24% (n = 74). The median PFS was 4.067 (95%CI 3.45-4.67) and the median OS was 10.0 months (95%CI 6.2-13.8). Among the factors tested for impact on OS the ECOG PS 0-1 ( HR-0.493 95%CI 0.324-0.749; P = 0.001), non head and neck site of the disease (HR-2.134 95%CI 1.164-3.911) and reception of immunotherapy in first line setting (HR -0.533 95%CI 0.295-0.963: P = 0.037) had an favorable impact on OS. Conclusions: Checkpoint inhibitors provide similar efficacy as those seen in pivotal studies in real-world settings.

No abstract