bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune related adverse events and their treatment in melanoma patients receiving ipilimumab.
Authors: Cabanillas Gerardo 
Published: September 2018

e14598 Background: Ipilimumab is an immune checkpoint inhibitor approved for the treatment of melanoma. Immune-related adverse events (irAEs) may occur as adverse effects. Most reports on irAEs are from clinical trials, which may not reflect community clinical practice and outcomes. We used a health insurance based database to identify irAEs and their treatment among patients with melanoma that received Ipilimumab, as part of regular care. Methods: We identified all melanoma patients aged 18 and older who received Ipilimumab from the Truven Health Analytics Marketscan database between 2011 and 2014. Patients had continuous insurance coverage from the period of six months prior to Ipilimumab and three months after. We further assessed the treatment for each irAEs. IrAEs were defined base on claims with one or more 228 ICD-9 codes; irAEs had to occur within a 6-month window before treatment. We used summary statistics such as means and standard deviations for continuous variables, frequencies and percentages for categorical variables. Results: The cohort included 1225 patients. Median age was 60 years, 62% were male; 343 (35.44%) patients had one or more irAEs, and 48.6% (211) were treated at least once. Young age and female gender were associated with a higher likelihood of having an irAEs. Endocrinopathies and gastrointestinal diseases were the most common irAEs. The most frequent irAEs was colitis in 27% of patients, followed by hypothyroidism 26%. Six different drugs were used to treat irAEs, and corticosteroids being the most frequently prescribed. Few patients with colitis received Infliximab 14%; and cyclosporine was prescribed in one patient with pancreatitis Conclusions: One third of the patients with melanoma treated with Ipilimumab in the community developed irAEs. Corticosteroids were the most frequent drugs used to treat irAEs. Our results show that toxicity remains high with the use of this agent in clinical practice.
Cyclophosphamide with (+)/without (-) fluorouracil followed by subcutaneous or intravenous interleukin-2 in solid tumors: An off-label experience.
Authors: Lo Re Giovanni , Lo Re Francesco , Doretto Paolo , Del Conte Alessandro , Amadio Maria , Cozzi Cinzia , Adamo Valter , Maruzzi Daniele , Ubiali Paolo , Sandri Paolo 
Published: September 2018

e14621 Background: primary and acquired resistance cause treatment failure to several agents. Recently it is emerging the role of immune surveillance in the control of tumor progression. The immune tolerance correlates with disease progression and FOXP3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) play a relevant role in immunosuppression. Cyclophosphamide (C) and Fluorouracil (FU) seems to reduce these cell populations. Methods: Objective: safety, feasibility, pain control, activity and impact on immune system (Neutrophil/Lymphocyte (N/L), Platelet/L (P/L), Tregs %, Monocytes (M)(103/μL) count.Treatment: 1) C 300 mg/sqm +/- FU 500 mg/sqm day (d) 1, Interleukin-2 (IL-2) 18 MUI/sqm intravenous continuous infusion (i.v.c.i) d 3-5, 17-19 q 29 or 2) C 300 mg/sqm + FU 500 mg/sqm day d 1, IL-2 4.5 MUI subcutaneous (s.c) d 3-6, 17-20 q 29 for 2 cycles. Stable or responding patients (pts) continue therapy for three cycles. Results: from February 2014 to December 2016, 13/14 pts were treated. M/F:1/1. Median age was 68 years and median PS 1 (range 0-2). The primary tumor was bladder, liver, pancreas, neuroendocrine carcinoma and ovary in 2, melanoma, prostate, GIST and breast in 1 pt respectively. Sites of metastases were: lung in 4, liver in 9, lymph’nodes in 9, bone in 5 and spleen in 1 pt respectively. Previous therapy: 1- 2 in 6, ≥ 3 in 8. Six and 7 pts performed treatment 1, 2 respectively. Median number of cycles administered was 2 (range 1-3). Median basal and post-treatment N/L, P/L, M and Treg values were 2, 130, 0.49, 2,9% and 2, 94, 0.55, 10.5%. Pain improvement was obtained on 7/8 pts. The toxicity was manageable as for i.v.c.i as for s.c administration. In addition to universal capillary like syndrome, G3-4 toxicities were diarrhea, bleeding, anemia in 2, proteinuria in 1 pt respectively. Response: 3 PR (2 HCC, 1 pancreas), 2 SD, 4 PD, 5 unevaluable. The duration of response was 2+ and 3 months in 2 HCC pts and 8+ months in pancreatic pt. The crude median PFS and OS was 1 (range1-8+) and 2+ (range 1-18) months Conclusions: C- FU- IL-2 can be considered safe, feasible and meanly active in heavy pretreated pts. Except P/L, no reduction on Tregs, M counts and N/L was observed.
Combined HDAC and BET inhibition to enhance cancer vaccine-elicited T-cell responses.
Authors: Badamchi-Zadeh Alexander , Moynihan Kelly Dare , Provine Nicholas M , Larocca Rafael , Irvine Darrell J , Barouch Dan H 
Published: September 2018

e14632 Background: The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromo and extra terminal (BET) family have recently shown therapeutic efficacy against pancreatic ductal adenocarcinoma, melanoma and lymphoma cancers in murine studies. However, in these studies the role of the immune system in therapeutically controlling these cancers was not explored. Methods: We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor I-BET151, both singly and in combination, on vaccine elicited immune responses. C57Bl/6 mice were immunized with differing vaccines (Adenoviral, protein) in prime-boost regimens, under treatment with RMD, I-BET151, or RMD+I-BET151. Results: The combination RMD+I-BET151, administered during Adenoviral prime-boost vaccination, resulted in the significant increase in the frequency and number of antigen-specific CD8 T cells. RMD+I-BET151 treatment affected vaccine-elicited secondary T cell responses, significantly increasing the frequency of IFN-γ+ splenic CD8 T cells and maintaining their dual IFN-γ+TNFa+ polyfunctionality. These CD8 T cells maintained their protective ability against Listeria monocytogenes, and protected against B16-OVA challenge. The significant augmentation of vaccine elicited CD8 T cell responses under RMD+I-BET151 treatment was additionally observed following protein (OVA+CpG) prime-boost vaccination, resulting in greater protection against B16-OVA challenge and enhanced survival. T-regulatory cell (FoxP3+CD4+) frequency and total CD4 and CD8 cell numbers remained unaltered following RMD+I-BET151 treatment. Conclusions: Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8 T cell responses following immunization by multiple vaccine platforms, and enhanced protection against B16-OVA challenges. We are currently assessing immunological mechanisms of action for this combined HDAC and BET inhibition.
Treating multiple cancers with the human anti-cancer heterologous bi-vaccine (TLNGIS).
Authors: Kraja Shuajp 
Published: September 2018

e14633 Background: Genomic segments of oncogenic viruses, when found inside healthy cell nuclei, can induce changes in the cell’s own genome during division, creating a transmittable change of genetic information. The new malignant cells thus created are recognized as foreign and destroyed by cellular immunity Thymuslymphocytes. Otherwise, unrecognised by the immune system and allowed to breed abnormally, such cells result in a malignant tumour mass, diagnosed as cancer. Based on this original theoretical explanation, we achieved the successful synthetization of a human heterologous anticancer Bi-Vaccine, further successfully confirming its prophylactic and curative abilities through the laboratory and clinic treatment of voluntary patients. Methods: Thymuslymphocytes, prepared though in indoor in vitro cultures and equipped with new and selective genetic information, acquire the ability to recognize cancerous cells as foreign cells, destroying them anywhere in the human body.The Bi-vaccine has been produced as the union of two vaccines: 1.the antitoxin, anti-tumour vaccine which destroys free toxins in the blood stream and in the pertinent cancerous cells; and 2.the thymus lymphocytic vaccine, equipped with new selective genetic information to destroy malignant tumour cells. Results: Thus the Bi-vaccine cures cancer until complete healing and protects subjects of all ages against the uncontrolled growth of malignant cells. The Bi-vaccine is produced in its live and dry state. Results: Over the years, there are treated and cured hundreds of voluntary patients with various forms of cancer. Successful healing in casses with advanced cancer (incurable casses). The Bi-vaccine is patented by European patents office-EP 1523991B1 as an anti-cancer vaccine "Human Heterologous Anti-Cancer Bi-Vaccine”. Conclusions: After more studies of several decades of all cases with different forms of cancer, treated with the “Bi-vaccine”has confirmed a complete success in various forms of cancer. The complementary (TLNGIS) cell to fight globally cancer. Prof. Dr. Shuajp Kraja, molecular biologist/Director of IIB Tirana, Albania Clinical trial information: EP523991 B1.
Outcome of mismatch repair deficient metastatic colorectal cancer (CRC): The Mayo Clinic Experience.
Authors: Jin Zhaohui , Sanhueza Cristobal T. , Johnson Benny , Smyrk Thomas C. , Larson David W. , Nagorney David M. , Hubbard Joleen Marie , Grothey Axel 
Published: September 2018

e15030 Background: Deficiencies in the DNA mismatch repair (dMMR) system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI-H). MSI-H in mCRC is rare and its prognostic and predictive impact on outcome is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI-H in metastatic CRC prior to the immune therapy era. Methods: 75 MSI-H mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous) MSS mCRC pts were identified from 1268 mCRC who had MSI/MMR test results at Mayo Clinic Rochester between 1/1992 and 7/2016. A retrospective review was conducted by using data from electronic medical records (EMR). Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: In the MSI-H group, there were 39 male (52%) and 36 female (48%) pts. Median age at metastatic disease diagnosis was 54.7 years. 35 patients presented with stage IV CRC. Primary tumors location: 38 right side, 11 transverse colon, 15 left side, 11 rectum. The MSS group was well matched (3 mismatches for gender and 1 mismatch for metachronous metastatic disease). Median overall survivals (OS) were 28.1 and 37.4 months for MSI-H and MSS pts, respectively ( p= 0.098). 98.7% MSS pts and 94.7% MSI-H pts had Fluoropyrimidine-based chemotherapy for metastatic disease and there was no median OS difference between these two groups (37.4 vs. 32.3 months p= 0.91). 43 MSI-H and 39 MSS pts had metastasectomy including ablation ( p= 0.51) with longer median OS (82.0 and 69.9 months, p= 0.90) compared to pts without metastasectomy (13.9 and 19.7 months, p= 0.15). Age < 65, metastasectomy, asymptomatic metastatic lesions, BRAF wild type, and multiple metastasectomy were associated with better survival in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis ( p< 0.0001). Conclusions: MSI-H mCRC do not appear to have improved prognosis compared with MSS cancers, in fact, there is a trend toward inferior outcome. In both groups, metastasectomy including multiple metastasectomy should be considered to optimize OS.
Comparative analysis of the effect of bevacizumab maintenance regimens after first-line chemotherapy in patients with metastatic colorectal cancer (MCRC): A single institution experience.
Authors: Song Yeohan , Mohamed AMR , Ismail Hibah , Abdallah Nadine , Surapaneni Malini , Dyson Gregory , Kamgar Mandana , Akhras Alaa , Mettu Jayadev , Ahmed Abdelrahman , Tesfaye Anteneh A. , Philip Philip Agop , Shields Anthony Frank 
Published: September 2018

e15032 Background: The majority of patients with metastatic colorectal cancer (MCRC) will ultimately experience disease progression following initial therapy. Although phase III clinical trials show that continued maintenance therapy improves progression free and overall survival in MCRC, the optimal maintenance regimen with an acceptable safety profile is still undetermined. This study aimed to assess outcomes of bevacizumab-containing maintenance therapy after first line chemotherapy for MCRC. Methods: One hundred thirteen patients (46 males, 67 females) with MCRC diagnosed between 2005 and 2014 who received chemotherapy at Karmanos Cancer Institute were included in this retrospective analysis. Induction treatment for most patients consisted of either 5-FU or capecitabine-based chemotherapy with either oxaliplatin or irinotecan and with or without bevacizumab. Eighty percent of patients who received bevacizumab with induction also received it as part of maintenance therapy. Results: After stratifying for age (dichotomized at 65 years) and induction therapy bevacizumab, there was no difference in PFS for induction regimens with or without bevacizumab (p = 0.67). For patients who received capecitabine as maintenance chemotherapy, the addition of bevacizumab resulted in non-significant larger hazard of a PFS event (HR = 1.46, p = 0.36). Among those who received 5-FU maintenance, the addition of bevacizumab resulted in non-significant smaller hazard of a PFS event (HR = 0.48, p = 0.11). There was no difference in observed toxicities between patients who received bevacizumab and those who did not (p = 0.38), with further sub-set analysis showing no increased toxicities among those who received 5-FU (p = 0.76) and those who received capecitabine (p = 0.16). Conclusions: In patients with metastatic colorectal cancer, there was no difference in efficacy or safety when adding bevacizumab to either 5-FU or capecitabine for maintenance after first line chemotherapy. Based on our results, tolerability and compliance with oral capecitabine ought to be a key factor in determining the choice of maintenance in patients with MCRC.
Relationship between oncogenic mutations (RAS, BRAF and PIK3CA) and tumor location and prognosis in colorectal cancer.
Authors: Inagaki Daisuke , Shiozawa Manabu , Satoyoshi Tetta , Atsumi Yosuke , Murakawa Masaaki , Kazama Keisuke , Higuchi Akio , Yamamoto Naoto , Morinaga Soichiro , Rino Yasushi , Masuda Munetaka , Miyagi Yohei 
Published: September 2018

e15109 Background: Several studies have reported that right-sided colon cancers (RCC) and left-sided colorectal cancers (LCRC) differ in several factors including genetic features. We investigated the difference in clinicopathological characteristics and oncogenic mutation status between patients with RCC and LCRC in all stages and assessed outcome. Methods: This study was a prospective, observational study. Patients were recruited from November 2014 to February 2016. Formalin-fixed paraffin-embedded tissue blocks were collected and DNA wes extracted from tissue sections from 227 cases. There was no double cancer. Mutations in KRAS, NRAS, HRAS, BRAF and PIK3CA were detected by next-generation DNA sequencer. Tumors from cecum to transverse colon were defined as RCC, and tumors from descending colon to rectum were defined as LCRC. The median follow-up period was 521 days. Results: KRAS, NRAS, BRAF and PIK3CA mutations were present in 95 patient (41.9%), 7 patients (3.1%), 10 patients (4.4%) and 23 patients (10.1%) respectively, and there was no HRAS mutation in all patients. RCC was 68 patients and LCRC was 159 patients. Poorly differentiated adenocarcinoma and mutinous adenocarcinoma were significantly more frequent in RCC compared to LCRC (P = 0.031). KRAS mutations were detected in 37 patients with RCC (54.4%) and in 58 patients with LCRC (36.5%). BRAF mutations were detected in 7 patient with RCC (10.3%) and in 3 patients with LCRC (1.9%). KRAS and BRAF mutation in RCC were significantly more frequent than in LCRC (P = 0.012 and P = 0.005, respectively). The incidence of NRAS and PIK3CA mutation was no difference between two groups. In all patients, overall survival was evaluated. On univariate Cox regression analysis, BRAF mutation was associated with significantly poorer overall survival than BRAF wild type (HR = 4.831, P = 0.013). Other oncogenic mutation status and tumor location weren’t associated with overall survival. Conclusions: KRAS and BRAF mutation were more frequent in the patients with RCC compared to those with LCRC in all stages. This study suggested BRAF mutation correlated with poor outcomes in patients with colorectal cancer.
Colorectal cancer sidedeness and its association with survival and tumor biology in operable patients.
Authors: Chan Joseph , Diakos Connie Irene , Chan David Lok Hang , Engel Alexander , Pavlakis Nick , Gill Anthony J , Clarke Stephen John 
Published: September 2018

e15110 Background: Recent data from patients with metastatic disease enrolled on trials of systemic chemotherapy have suggested that the sidedness of colorectal cancer(CRC) is associated with survival differences with better response seen with right sided tumours. The biological explanation for these differences has not been confirmed and there have been concerns that the differences relate predominantly to patient selection in clinical trial design. This study examines survival differences by side in sequential patients with newly diagnosed, operable CRC. Methods: Data for 3281 consecutive patients from the Northern Sydney Local Health District from 1998 to 2012 who underwent surgical resection of their CRC were retrospectively collected. Survival was assessed by log-rank test, association between sidedness and tumor biology by chi squared analysis and multivariate analysis by Cox regression. Results: Overall, there was a survival difference between left and right sided colon cancer and rectal cancer (p < 0.022). However, stage for stage, only stage 3 patients demonstrated a survival difference with right sided colon cancers (median OS 67.1 months, p = 0.009) but not left sided colon cancers (70.4 months p = 0.132) having inferior survival compared to rectal cancers (83.2 months). In terms of biological associations, right sided tumors were more associated with advanced age (p < 0.001), female gender (p < 0.001), more advanced T and m stage (p < 0.001), high grade (p < 0.001), thin walled vessel invasion (p < 0.001), discontinuous extratumoral nodules (DETN) (p < 0.001), peritumoral lymphocytic response (p = 0.002), BRAFV600E mutation (p < 0.001), mismatch repair deficiency (p < 0.001), low lymphocyte-to-monocyte ratio (LMR) (p < 0.001) and high neutrophil-to-lymphocyte ratio (p < 0.001). In multivariate analysis, age (p < 0.001), T stage and m stage (p = 0.001), grade (p = 0.002), extra venous permeation(p = 0.034), DETN (p = 0.09), MMR-BRAF combined status (p = 0.001) and LMR (p < 0.001) remained independently significant. Conclusions: There appears to be a difference in survival related to tumor site only in stage 3 CRC. Differences in tumor biology could account for these findings.
Oncological outcomes in extended intervals time betweeen preoperative chemoradiation with capecitabine and surgery in operable rectal adenocarcinoma: Experience at the National Cancer Institute of Peru.
Authors: Muñoz Miguel Angel , Palacios Manuel Giancarlo , Malca Jenny , Montenegro Paola Catherine , Chávez Iván , Mantilla Raúl 
Published: September 2018

e15158 Background: The literature reports that longer interval between the end of neoadjuvantchemoradiotherapy (CRT) and surgery is associated with a better rate of pathologic complete response (pCR) in rectal cáncer. Optimal interval remains to be defined. The effects of the extended time intervals on the prognosis are not clear. The objective was to assess whether extended time intervals ( < 8, 8-12, > 12-20 and > 20 weeks) between the end of neoadjuvant CRT and surgery improve overall survival (OS), disease-free survival (DFS) and pathological outcomes Methods: Aretrospective study was conducted for 124 patients with rectal adenocarcinoma without evidence of metástasis (T1-4/N0-2/M0) at the time of diagnosis that underwent surgery with curative intent after neoadjuvant CRT with capecitabine and obtained R0 or R1 resection between January 2010 to December 2014 at National Cancer Institute of Peru. Patients undergoing emergency surgery and R2 resection have been excluded. Survival curves were calculated according to Kaplan-Meier method and compared with log-rank test Results: Of the 124 patients, 72 were women (58.1%). The average age was 59.5 years. All received neoadjuvant CRT. Rates of pCR in the four groups were 25.0%, 10.3%, 7.7% and 17.2%, respectively. No significant difference was found between the association of the radial (P = 0.418) and distal edge (P = 0.487), with time interval groups and similarly with resected (P = 0.308) and compromised nodules (p = 0.783). The median OS follow-up time was 39.5 months and for DFS was 34 months. No significant differences were observed in OS (p = 0.739) and DFS (p = 0.902) according to the four groups studied. Conclusions: We found that amplifying the time interval at 31.9 weeks did not change the mean radial and distal edge. It does not affect the mean of resected and compromised nodules and does not improve overall survival and disease-free survival. The present study is the only one that reports these results at these time intervals. It allows to extend the intervals of time for future studies that finally will define the best time interval for the surgery.
Efficacy and safety of paclitaxel/ramucirumab as the second-line chemotherapy in Japanese patients with advanced gastric cancer.
Authors: Kusumoto Tetsuya , Egashira Akinori , Sonoda Hideto , Hashimoto Kenkichi , Uehara Hideo , Kusumoto Eiji , Shinzato Chiaki , Uchino Keita , Sakaguchi Yoshihisa , Ikejiri Koji , Maehara Yoshihiko 
Published: September 2018

e15540 Background: Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer (AGC). Two global randomized phase III trials (REGARD and RAINBOW) showed that survival benefit was significantly observed in patients treated with ramucirumab (RAM) alone and in combination with weekly doses of PTX, compared with placebo, respectively. The purpose of the study is to evaluate the efficacy and safety of weekly dose of PTX combined with RAM practically as the second-line treatment in Japanese patients with AGC refractory to an S-1-containing chemotherapy regimen. Methods: We conducted a retrospective review of the data of 18 patients with AGC who received more than 2 cycles of PTX/RAM combined chemotherapy as the second-line regimen following S-1-based treatment. The objective response rate (ORR), adverse events, progression-free survival (PFS) and overall survival (OS) were analyzed and compared with PTX monotherapy group. Results: Median number of courses were 5 for the PTX/RAM group and the discontinuation of treatment except for disease progression was found in 2 cases (33.3%). The rates of hematological toxicities of higher than grade 3 were 33.3% in the PTX/RAM group, which were higher than those found in the PTX groups. The tumor responses of the PTX/RAM group were 22% for the ORR and 78% for the DCR, compared with 21% and 48% in the PTX group, respectively. The dose intensities of PTX were 72.4% in the former group. The survival data showed that the MST after second-line exposure was 290 days and the median PFS was 131 days in the PTX/RAM group, compared with 159 days and 90 days in the PTX group, which were not significantly different. Conclusions: PTX/RAM might be one of the best regimens for Japanese patients with AGC as the second-line treatment following S-1-containing chemotherapy.