bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel porcupine (PORCN) inhibitor RXC004: Evaluation in models of RNF43 loss of function cancers.
Authors: Bhamra Inder , Adams Nick , Armer Richard , Bingham Matilda , McKeever Helen , Phillips Caroline , Thompson Ben , Woodcock Simon
Published: September 2018

e14094

Background: Wnt signalling initiates oncogenic pathways involved in tumour initiation, growth, differentiation and metastasis.1 Targeting the Wnt pathway is an attractive approach to cancer treatment. Porcupine (PORCN) is a membrane-bound O-acyltransferase dedicated to the palmitoylation of Wnt ligands, an essential step in the processing of Wnt into active ligands.2 A PORCN inhibitor may benefit patients with cancers in which Wnt signalling is implicated. It has been shown that PORCN inhibition is efficacious in cell lines with upstream mutations in this pathway, eg RNF43 loss of function.3 Methods: Analysis of TCGA data was carried out to identify cancer types harbouring RNF43 mutations.4 Redx PORCN inhibitor RXC004 was evaluated in vitro for Wnt pathway inhibition and anti-proliferative effects using assays previously described for early lead compounds.5Anti-tumour effects of RXC004 were evaluated using a pancreatic CAPAN-2 xenograft in SCID Bg. mice and a gastric PDX model in nu/nu mice. Both models have RNF43 loss of function mutations. Results: TCGA data revealed that both gastric cancer and pancreatic cancer exhibit mutations in the RNF43 gene (18% and 4% respectively),4expected to result in loss of function. RXC004 showed activity in preclinical models of cancers with this genetic background. RXC004 significantly inhibited tumour growth in a CAPAN-2 pancreatic cancer xenograft and in a gastric cancer PDX model when dosed orally once or twice daily. Conclusions: Taken together, these data indicate that RXC004 is a potent inhibitor of tumour growth in RNF43 loss of function preclinical cancer models. RXC004 will be evaluated in a first in human Phase 1 study in 2017. Phase 1a aims are to characterise the safety profile and PK/PD relationship in cancer patients and establish a Phase 1b dose. The efficacy of RXC004 in gastric and pancreatic cancer patients prospectively selected for RNF43 loss of function mutations will be the focus of Phase 1b expansion groups. 1 . Nat. Rev. Cancer, 2013, 13 (1): 11-26.2. J. Biol. Chem., 2012, 287 (27): 23246-23254. 3. PNAS, 2013, 110 (31): 12649-12654 4. Sci. Signal, 2013, 269 (6): 1-34; Cancer Discov., 2012, 2 (5): 401-404 5. AACR Annual Meeting, 2015, 75 (15): abs. 5071.
Markers of response to PD-1 inhibition.
Authors: Hiltermann Thijo Jeroen Nicolaas , Hijmering-Kappelle Lucie , Groen Harry J.M.
Published: September 2018

e14505

Background: Nivolumab (Nivo) has a durable tumour response in 20 % of patients. While a PD-L1 IHC complementary diagnostic has been approved, there is a need to identify a predictive biomarker with greater diagnostic accuracy. Serum biomarkers predicted by the cancer immunogram (Blake Science 2016) and response to Nivo defined by a clinical benefit ≥6 month (DR) and response by CR, PR or SD according to RECIST v1.1 are shown. Methods: Advanced NSCLC pts progressing after 1L platinum-based chemotherapy were treated with Nivo. Baseline blood markers drawn: CRP, absolute lymphocyte count, plasma glucose and LDH. Kaplan-Meier used to estimate survival data. Cox regression was used to predict associations with possible (bio-) markers and survival (age, gender, ECOG PS, histology, presence of brain metastasis, CRP, LDH, glucose, lymphocyte count). Results: Patient characteristics see table. 20% showed a DR with CR (n = 3), PR (n = 31 of 33) and SD (n = 9 of 20). Only ECOG PS was associated with OS and PFS. Soluble biomarkers were not. When tumour response (RECIST or DR) was added to the regression model ECOG PS was no longer significant but responses were. HR for PFS for DR was 0.07 (0.03-0.14) and HR according to the classical RECIST1.1 was 0.22 (0.16-0.32). HR for OS for DR 0.09 (0.03-0.21) and for classical RECIST1.1 0.26 (0.17-0.40). Conclusions: Serum blood markers at baseline were not associated with survival. Response to treatment as DR seems a stronger predictor for survival than RECIST. 45% of pts with SD had a DR. [Table: see text]
Model-based prediction of outcome of the atezolizumab Phase 3 study OAK in non-small cell lung cancer based on early tumor kinetic data.
Authors: Claret Laurent , Jin Jin Y , Winter Helen , He Pei , Ballinger Marcus , Rittmeyer Achim , Gandara David R. , Girish Sandhya , Joshi Amita , Bruno Rene
Published: September 2018

e14517

Background: Standard early endpoints (ORR, PFS) are often poor predictors of overall survival (OS) for immunotherapies. Model-based tumor kinetic (TUK) metrics may offer an alternative (Claret, JCO 2009 and 2013). We investigated the predictive performance of TUK metrics using early data from atezolizumab clinical trials in patients (pts) with non-small cell lung cancer (NSCLC). Methods: OS benefit with atezolizumab (atezo) vs. docetaxel (doc) was observed in both Phase II POPLAR (hazard ratio 0.73, p = 0.040, n = 297, Fehrenbacher Lancet 2016) and Phase III OAK (HR = 0.73, p = 0.0003, n = 850, Rittmeyer Lancet 2016) studies although PFS was similar between arms. A multivariate model linking baseline patient characteristics and tumor growth rate (TGR, estimated using time profile of sum of longest diameters of target lesions, RECIST 1.1) to OS was developed using POPLAR data and qualified to predict outcome by PD-L1 status in both POPLAR and OAK. This model was used to predict OAK OS outcome based on patient characteristics and estimated TGR from TUK data at several OAK data cut-offs ranging from 10 to 122 weeks. Results: In POPLAR, TUK profile in atezo and doc arms crossed at about 25 weeks with more initial shrinkage in doc-treated patients and slower TGR in atezo-treated patients. A lognormal OS model with albumin and number of metastatic sites as independent baseline prognostic factors and estimated TGR predicted OS HR in sub-populations of pts based on baseline PD-L1 expression both in POPLAR as well as in OAK e.g model-predicted OAK HR: 0.73 [0.63-0.85]. Based a retrospective analysis on TUK data cuts, the POPLAR OS model predicted significant OS HR in OAK as soon as 40 week cut-off: HR: 0.67 [0.56-0.80] with success in 99% of the replicates with only 50% of the total number of tumor assessments. At this 40 week data cut, immature observed OS HR was 0.84 [0.59-1.21, p = 0.347] and HR only reached significance at 70 weeks. Conclusions: Model predictions based on TUK can be used to predict success early before maturation of OS data as shown with OAK. The model-based biomarker TUK metric TGR has strong potential as an alternative early endpoint to evaluate efficacy in cancer immunotherapy studies.
Evaluation of clinical endpoints as surrogates for overall survival in patients treated with immunotherapies.
Authors: Kaufman Howard , Schwartz Lawrence Howard , William William N. , Sznol Mario , del Aguila Michael , Whittington Craig , Fahrbach Kyle , Xu Yingxin , Masson Eric , Dempster Sara , Vergara-Silva Andrea Leninka
Published: September 2018

e14557

Background: In immuno-oncology (IO), the correlation between clinical trial endpoints, specifically, objective response rate (ORR), disease control rate (DCR) or progression free survival (PFS), and overall survival (OS) is poorly understood. The effect of IO agents as opposed to chemotherapy, is not on tumor cells, but on immune cells and OS benefit has been observed in absence of PFS benefit. However, decisions on registration trials often rely on PFS from Phase II trials. Methods: We conducted a systematic literature review with PubMed and Embase (Jan. 2005–Nov. 2016), supplemented with oncology conference proceedings (2014–2016). Eligible studies were randomized controlled trials (RCT) that investigated ≥1 immune checkpoint blockers (CBs) targeting programmed death proteins (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and reported their relative effect on OS and on ≥1 of the clinical endpoints, DCR, ORR, and PFS. Log-transformed hazard ratios were fitted using weighted regression models to determine the power of relative effects on clinical endpoints to predict OS effects, with correlation coefficients estimated and presented with adjusted R2 (high values indicating better goodness-of-fit). Results: This analysis included 18 RCTs involving 7140, patients. Most studies (10/18) evaluated the efficacy of CBs vs conventional chemotherapy, whereas 8 studies compared the efficacy of ≥1 CB. Among trials that evaluated anti-CTLA-4, the adjusted R2 for the relative efficacy of CBs on DCR, ORR, PFS, and relative efficacy of CBs on OS were 0.160 ( P= 0.156), 0.016 ( P= 0.332), and 0.000 ( P= 0.623) respectively. Among trials that evaluated either anti-PD-1 or anti-PD-L1, the adjusted R2 were 0.038 ( P= 0.401), 0.066 ( P= 0.251), and 0.432 ( P= 0.032), for DCR, ORR and PFS respectively. Among trials that evaluated CBs in melanoma, the adjusted R2 were 0.030 ( P= 0.267), 0.028 ( P= 0.279), and 0.192 ( P= 0.154), for DCR, ORR, and PFS respectively. Conclusions: No clear correlations were observed between relative effects of conventional clinical endpoints and OS for CBs. New surrogate endpoints may be needed to better predict OS benefit for CBs and other forms of cancer immunotherapy.
Relationship of lymphocyte and eosinophil counts and immune-related adverse events in recipients of programmed death-1 (PD-1) inhibitor therapy: A single-center retrospective analysis.
Authors: Diehl Adam , Yarchoan Mark , Yang Ting , Scott Blake , Johnson Burles Avner , Hopkins Alexander , Azad Nilofer Saba , Jaffee Elizabeth M. , Grossman Stuart A.
Published: September 2018

e14586

Background: Inhibition of the PD-1 checkpoint can cause immune activation in non-target tissues, resulting in immune-related adverse events (irAE) in up to 50% of patients. Biomarkers that are associated with irAEs in patients treated with PD-1 inhibitors may have implications for patient selection and clinical management. Methods: We performed an IRB-approved retrospective chart review of adult solid tumor patients treated with nivolumab or pembrolizumab at a single institution from January 2015 until November 2016. Patients were excluded if concurrently receiving investigational therapies, or on unreported clinical trials. Data were collected on treatment history, leukocyte counts, and irAE, defined as adverse events with a potential immunologic basis with grading performed using CTCAE v.4.0. Results: 172 patients were included (lung n = 54; melanoma n = 61; kidney n = 25; esophageal n = 12; bladder n = 8; other tumors n = 12) with median age 67. 18% were treated with concurrent ipilimumab. 31% experienced an adverse event of any grade with a mean time to develop an irAE of 3.5 months. Of those with an irAE, 85% required treatment, 68% were grade ≥ 2, 32% were grade 3 or 4 and 35% required therapy discontinuation due to the irAE. In univariate analysis, a higher ALC at both the start of therapy and at 1 month was associated with increased risk of an irAE of grade ≥ 2 (p < 0.05). A higher absolute lymphocyte count (ALC) or higher absolute eosinophil count (AEC) at 1 month into therapy was associated with increased risk of all irAE (p < 0.05) as well as irAE requiring treatment (p < 0.05). In addition, in a multivariate regression analysis including age, race, tumor type, prior chemotherapy, prior radiation, and concurrent ipilimumab therapy, an ALC > 2000 at the start of therapy was a significant predictor of irAE of grade ≥ 2 (p < 0.05 and OR 2.0), as was an ALC > 2000 at 1 month into therapy (p < 0.05 and OR 1.86). Conclusions: These results suggest that high lymphocyte and eosinophil counts early in the course of anti-PD1 therapy may be associated with a higher risk for clinically significant irAE.
Development of the combined positive score (CPS) for the evaluation of PD-L1 in solid tumors with the immunohistochemistry assay PD-L1 IHC 22C3 pharmDx.
Authors: Kulangara Karina , Hanks Debra Ann , Waldroup Stephanie , Peltz Lindsay , Shah Supriya , Roach Charlotte , Juco Jonathan Wes , Emancipator Kenneth , Stanforth Dave
Published: September 2018

e14589

Background: Developing clinically relevant and highly reproducible scoring methods for PD-L1 to identify patients who will respond effectively to anti-PD-1 therapy is key in the development of companion or complementary diagnostic assays. Methods: Scoring method for PD-L1 IHC 22C3 pharmDx in NSCLC have only captured the percentage on stained tumor cells using the tumor proportion score (TPS) (Roach et al. 2016, Appl Immunohistochem Mol Morphol.) (Garon et al. 2015, N Engl J Med.). In the KN012 study 2 out of 11 responders to pembrolizumab were detected with the TPS for the gastric indication. More and more additional data indicate that in some tumor indications PD-L1 staining on both tumor and tumor-associated immune cells is associated with clinical outcome. Therefore a method evaluating both tumor and immune cells in one sitting using the combined positive score was evaluated. Results: Scoring the same patient specimens with the new combined positive score method resulted in the detection of 9 out of 11 responders. Our internal inter- and intra- observer data shows that the CPS can be scored reproducibly with an overall agreement point estimates of 93% for intra-observer and an overall agreement of 87.6% for inter-observer reproducibility in gastric carcinoma. Additionally, CPS builds on the scoring method for NSCLC as it shares the same denominator, namely total number of tumor cells. CPS is evaluated based on the number of PD-L1 positive cells (tumor, lymphocytes and macrophages) in relation to total tumor cells, and hence allows the capture of tumor and immune cells in a single read. Conclusions: Our data demonstrates that the CPS scoring method is reproducible when scored by pathologists and clinically relevant for a number of indications.
Intraepithelial CD94+ tumor-infiltrating lymphocytes in a context of HLA-E overexpression as a new immune checkpoint to predict prognosis in colorectal carcinomas.
Authors: Bossard Celine , Eugene Juliette , Jouand Nicolas , Dansette Delphine , Leveque Edouard , Podevin Juliette , Matysiak Tamara , Bezieau Stephane , Chetritt Jerome , Kerdraon Olivier , Fourquier Pierre , Thibaudeau Emilie , Mosnier Jean-François , Jarry Anne , Gervois Nadine
Published: September 2018

e14592

Background: A better understanding of the immune-modulating interactions between tumor cells and immune cells underlying the balance between immune control and immune resistance in colorectal cancer (CRC) is crucial for the design of immunotherapies. We have previously demonstrated that overexpression of the human MHC class Ib molecule - HLA-E/β2 microglobulin - by tumor cells in CRC was associated with an unfavorable prognosis, suggesting its involvement in immune escape. However, the specific receptor of HLA-E/β2m - CD94/NKG2A, inhibitory or CD94/NKG2C, activating - expressed by tumor-infiltrating lymphocytes (TIL), as well as the influence of the microsatellite status in HLA-E/β2m overexpression, remain unknown. Methods: We investigated in the primary tumor of 245 CRC patients 1) the association of HLA-E/β2m overexpression and the density of CD94+ intraepithelial TIL (IEL-TIL) with the microsatellite status, 2) the nature of CD94+ TIL and the receptor expressed - CD94/NKG2A or CD94/NKG2C - and 3) the prognostic influence of CD94+ IEL-TIL. Results: HLA-E/β2m was preferentially overexpressed in MSI compared with MSS CRC (44,6 % vs 18,4 % respectively, p = 0.0001), and significantly associated with a high density of CD94+ IEL-TIL in MSI (0,9% in HLA-E/β2m+ vs 0,2% in HLA-E/β2m– CRC, p = 0,001), and in MSS CRC (0,38% vs 0,15%, p < 0,0001). These CD94+ TIL mostly corresponded to CD8+ αβ T cells preferentially expressing the inhibitory NKG2A chain. Finally, a high density of CD94+ IEL-TIL was independently associated with a worse OS (p = 0.03). Conclusions: These results strongly suggest that HLA-E/β2m - CD94/NKG2A interactions, preferentially up-regulated in MSI CRC, represent a promising inhibitory immune checkpoint. From a clinical point of view, this inhibitory immune checkpoint could be blocked by the new anti-NKG2A monoclonal antibody.
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.
Effect of bilateral supraclavicular lymph nodes irradiation in stage III lower thoracic esophageal squamous cell carcinoma after radical surgery.
Authors: Deng Min , Gong Youling
Published: September 2018

e15555

Background: Surgery is the most important treatment for patients with lower thoracic esophageal squamous cell carcinoma (LT-ESCC) at stage III, but the locoregional failure is common, especially mediastinal and supraclavicular lymph nodes metastases. Postopearative radiotherapy (PORT) is benefit for those patients. However, the clinic target volume (CTV) remains controversial, especially whether or not including bilateral supraclavicular lymph nodes radiotherapy. Methods:79 patients of lower LT-ESCC at stage III who had undergone radical surgery and PORT were enrolled. 51 patients received the PORT CTV without bilateral suparclavicular lymph nodes region (group A), while 28 patients received the CTV with suparclavicular region (group B). Results: Totally, 26 patients had the tumor recurrences of supraclavicular lymph nodes. Among them, 23(45.1%) patients had the metastasis in group A, 3(10.7%) patients had the metastasis in group B. Univariate analysis showed the bilateral supraclavicular region RT can decrease of supraclavicular lymph nodes recurrence (p = 0.007). However, it could not prolong the overall survival (p = 0.273) or control the distant metastasis (p = 0.760).The Cox analysis revealed it was independent factor to control supraclavicular lymph node recurrence (HR = 0.027; 95 % CI 0.068-0.757; p = 0.016). PORT includingsupraclavicular region didn’t increase the radiotherapy complications, such as radiation pneumonia (p = 0.354), radiation esophagitis (p = 0.456), gastrointestinal reaction (p = 0.809), neutropenia (p = 0.470), thrombocytopenia (p = 0.137) and anemia (p = 0.642). Conclusions:PORT including bilateral supraclavicular region can reduce the metastasis of supraclavicular lymph nodes in LT-ESCC at stage III, and it does not increase radiotherapy complications. However, it can’t prolong OS or control the distant metastasis. Chemotherapy is essential to control distant metastasis and prolong OS.
Nimotuzumab plus paclitaxel and cisplatin as 1st line treatment for unresectable esophageal squamous cell carcinoma: Long term follow-up of survival in a phase II study.
Authors: Zhang Xiaodong , Jia Jun , Lu Ming , Wang Xicheng , Gong Jifang , Li Jie , Li Jian , Li Yan , Zhang Xiaotian , Lu Zhihao , Yu Jing , Sun Zhiwei , Yang Ying , Shen Lin
Published: September 2018

e15573

Background: The role of anti-epidermal growth factor receptor (EGFR) targeting treatment in esophageal squamous cell carcinoma (ESCC) is still uncertain. We conducted a prospective phase 2 study of paclitaxel, cisplatin, and nimotuzumab (TPN) as first-line treatment in unresectable or metastatic ESCC (NCT01336049). The objective response rate was 51.8%. Here we reported long-term follow-up results of that initial trial. Methods: 59 patients were enrolled from Mar 2011 to Apr 2013 and treated with the TPN regimen (nimotuzumab 200mg weekly, paclitaxel 175mg/m2 on day1, and cisplatin 30mg/m2 on day1 and 2, repeat every 3 weeks for total six cycles). Patients were allowed to receive sequential radiotherapy in case of local-regional disease or controlling symptom. Results: 56 of 59 patients were eligible for evaluation. After a median follow-up of 32.2months, the median progression-free survival (PFS) and overall survival (OS) were 18.1±4.2 months (95% Confidence: 9.8-26.4) and 26.2±10.0 months (95% Confidence: 6.6-45.8) in 29 patients with unresectable local-regional disease, while those were 6.6±0.4 months (95% Confidence: 5.8-7.5) and 11.5±3.7 months (95% Confidence: 4.2-18.8) respectively in 27 patients with metastatic disease. Patients of male, with multiple lymph node station metastasis, visceral metastasis, no response to TPN treatment, and without radiotherapy had worse OS. Even in some patients with multiple stations lymph node metastasis or recurrent disease of local-regional lymph node metastasis, TPN with sequential radiation seemed could bring longer survival time. But multivariate cox-regression analysis only confirmed that the TPN treatment was associations with OS. Compared with those of complete and partial response, patients of stable disease and progression had poor OS (HR = 2.32, 95% CI: 1.03-5.05, p = 0.03). Conclusions: the combination of nimotuzumab, paclitaxel, and cisplatin is effective as first-line treatment for patients with unresectable and metastatic ESCC, especially those with sequential radiotherapy. Clinical trial information: NCT01336049.
Erythropoietin and hepatocellular carcinoma: What is patients survival outcome?
Authors: Abdel-Wahab Reham , Hassan Manal , Lacin Sahin , Shalaby Ahmed S , Afshar-Kharghan Vahid , Kaseb Ahmed Omar
Published: September 2018

e15660

Background: Erythropoietin (Epo) is a glycoprotein that stimulates cell proliferation and angiogenesis. Both, hypoxia and anemia are triggering factors that induce Epo overproduction. Although, previous studies reported that Epo induces angiogenesis in hepatocellular cancer (HCC), the relationship between Epo and HCC remains unclear .Our study aims to assess Epo level in HCC patients and evaluate its prognostic roles. Methods: We enrolled 766 HCC patients from MD Anderson Cancer Center Between 2001 and 2014. Under IRB approval, baseline patients’ clinical characteristics were retrieved from medical records. Based on the plasma level of Epo, we classified our patients into two groups: group 1 (N = 407) had normal serum level ( < 20mIU/ml) and group 2 (N = 359) had higher level (≥20mIU/ml). Median overall survival (OS) was estimated by kaplan meier curve and log rank test. We used multivariate hazard ratio (HR) and 95% Confidence interval (CI) to determine the independent effect of Epo on the prognosis of HCC patients. Results: Univariate analysis showed that higher level of Epo had a statistically significant association to a higher Child Pugh Score (CTP), and an advanced stage in Barcelona clinic liver cancer (BCLC) and Cancer of the Liver Italian Program (CLIP). Median OS and 95%CI was 16.1 months (12.7 – 19.4) in group 1 compared to 11.4 months (8.6 – 14.3) in group 2 ( P< .0001). The same significant difference was achieved among HCC patients with cirrhosis ( P = .005) and without cirrhosis ( P= .002). The estimated multivariate HR and 95%CI for elevated Epo level was 1.4 (1.04 – 1.9) (P = .03) in the absence of cirrhosis, while it was 0.97 (0.79 – 1.2) (P = .8) in the presence of cirrhosis after adjustment for several confounding factors. Conclusions: Abnormal Epo level in the plasma is significantly associated with a worse clinico-pathological characteristics and a shorter OS. Previous studies showed that HCC stimulates erythrocytosis and increases Epo production. Although, our study concluded that Epo is an independent prognostic factor among non-cirrhotic HCC patients only. Future studies are warranted to understand the mechanistic pathways of Epo effect in HCC patients and its variation in the presence and absence of cirrhosis.