bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib study of anlotinib plus TQB2450 as a second-line investigational therapy in advanced hepatocellular carcinoma (aHCC).
Authors: Zhang Wen , SUN Yongkun , Zeng Huiying , Zhu Zheng , Liang Meng , Han Yue , Yan Dong , CHEN BO , Huang Zhen , Bi Xinyu , Zhao Hong , Zhou Ai-Ping 
Published: June 2022

e16184 Background: The combination of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitor (TKI) manifested high efficacy in front-line therapy for aHCC, which still deserves further exploration in second-line therapy. Anlotinib, an oral multi-targeted TKI that mainly blocks VEGF/VEGFR pathway, has been approved for several solid tumor types in china. Anlotinib plus TQB2450, a novel anti-PD-L1 mAb, might be a promising strategy. This study aimed to evaluate the efficacy and safety of this regimen as second-line treatment in aHCC patients (pts). Methods: Pts with aHCC, ≥18 years, Child Pugh class A-B (scores ≤ 8), ECOG PS of 0-1, BCLC stage B or C, ≥ 1 measurable lesion (per RECIST v1.1) and progressed/tolerated after first-line treatment were eligible. Pts received anlotinib (10-12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200mg, iv, d1, q3w). In the dose-escalation stage, anlotinib dose was explored from 10mg to 12mg. Dose expansion was performed after the determination of the maximum tolerable dose. Tumor assessment was evaluated according to the RECIST 1.1 per investigators, supplemented by iRECIST. The primary endpoints were ORR and safety. Secondary endpoints included PFS, DCR and OS. Results: 19 pts were enrolled between 16 May 2019 and 16 Jan 2020. The median age of pts was 52 years (range: 37-67), 89.5% pts were male, 94.7% pts were ECOG 0 and 78.9% had BCLC staging C. Both 10mg and 12mg were tolerable during the dose-escalation stage. At the cut off date (Jan 29, 2022), the median follow-up duration was 9.13 months. Of the 19 evaluable patients, 4 had PR, 8 had SD, 5 had PD, and 2 pts were NE. Confirmed ORR was 23.5% (95%CI: 6.8-49.9), DCR was 76.5% (95%CI: 50.1-93.2). The median PFS was 5.49 (3.46-7.51) months, and median DOR of 12.95 (5.26-20.63) months was achieved. Treatment-related adverse events (TRAEs) of any grade were recorded in 73.7% pts, ≥ grade 3 TRAEs were observed in 7 patients, with gastrointestinal reaction (15.8%), leucopenia (5.3%), neutropenia (5.3%), thrombocytopenia (5.3%), ALT increased (5.3%). Conclusions: Anlotinib plus TQB2450 was tolerable and showed preliminary antitumor activity in pre-treated aHCC. Further investigation in larger population is warranted. Clinical trial information: NCT03825705.
A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL.
Authors: Fulgenzi Claudia A.M. , Cortellini Alessio , D'Alessio Antonio , Thomas Robert , Tait Paul , Ross Paul J. , Young Anna-Mary , Talbot Thomas , Goldin Robert , Ward Caroline , Bengsch Bertram , Sharma Rohini , Pinato David J. James 
Published: June 2022

e16195 Background: Trans-arterial chemoembolization (TACE) is the gold-standard for intermediate stage HCC. We hypothesised the ischemic and cytotoxic effect of TACE to boost anti-cancer immunity and to synergise with the anti PD-1 pembrolizumab (pembro). We designed a phase Ib study to test the safety and preliminary efficacy of pembro after TACE in intermediate HCC. Methods: PETAL study will enroll up to 32 patients with intermediate HCC to receive pembro 200 mg every 3 weeks for up to 1 year or until disease progression or unacceptable toxicity. The first safety-run-in phase includes 6 patients: if no dose limiting toxicities (DLTs) emerge over a 21-day window after first pembro, the others are enrolled in the expansion phase. Pembro is given within 30 days after 1 or 2 TACEs. The first phase includes 1 patient scoring Child-Pugh (CP)-B7 and the remaining have to be CP-A. Safety is the primary endpoint and is measured as the incidence of treatment-related adverse events (TRAEs), graded according to NCI CTCAEv4. Efficacy is the secondary endpoint and is evaluated as progression free survival (PFS) from first TACE, according to mRECIST criteria. Survival is estimated using Kaplan-Meier method. All the patients who have received at least one dose of pembro are evaluable for safety. Results: At the time of data cut-off, on the 14th of January 2022, 14 patients had received at least one dose of pembro. The median age was 72 (IQR: 63.3-74.6), 79% were male, 71% were cirrhotic, 29% had viral hepatis and 43% ECOG PS 1. One patient had Child-Pugh (CP) class B7 and 13 had A. The median number of nodules was 1.5 (IQR:1-2.8), and 4.1 cm (IQR: 3.7-4.5) the median diameter. Overall, 5 patients received 2 TACEs and 9 had 1. Patients received a median of 4.5 cycles (IQR: 2.3-6.5) of pembro. No DLTs emerged in the first phase. Treatment-related adverse events (TRAE) of any grade (G) were reported in 86% of participants, 21% of participants experienced G3 TRAEs, and there were no G4 or G5 TRAEs. Specific skin-related toxicity was the most frequently reported (35%) TRAE. No patients had treatment-related liver toxicity. Causes of treatment discontinuation were PD (n=7), TRAEs (n=1), clinical deterioration in the CP B patient (n=1), COVID pandemic (n=2) and withdrawal of consent (n=1); at the time of data cut-off, mPFS from first TACE was 10.8 months (95%CI: 6.63-14.97). Conclusions: Adjuvant pembro following TACE is manageable and tolerable with signs of activity. These results prompt the investigation in larger trials. Clinical trial information: NCT03397654. [Table: see text]
Gemcitabine plus cisplatin versus non-gemcitabine and cisplatin regimens as neoadjuvant treatment for cholangiocarcinoma patients prior to liver transplantation.
Authors: Abdelrahim Maen , Esmail Abdullah , Xu Jiaqiong , Umoru Godsfavour , Saharia Ashish , McMillan Robert , Ghobrial Rafik Mark 
Published: June 2022

e16202 Background: Cholangiocarcinoma (CCA)management is constantly being updated in view of existing evidence in order to establish practice guidelines and consensus statements. Here, we evaluate and compare the potential efficacy of chemotherapy combination of Gemcitabine plus Cisplatin versus non- Gemcitabine and Cisplatin regimens as a neo-adjuvant treatment for cholangiocarcinoma patients prior to liver transplantation. Methods: In this prospective study, patients with locally advanced, unresectable, hilar, or intrahepatic CCA with no evidence of extrahepatic disease or vascular involvement were treated with either the combination of neo-adjuvant Gemcitabine plus Cisplatin with no radiation or other standard options of neo-adjuvant treatment. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center in collaboration with the same institution’s transplant center according to an open-labeled, and centers-approved clinical management protocol. Patients were listed for liver transplantation if they had a minimum of six months of scans showing response or confirmation of disease stability. This report, which was censored on November 30, 2021, was an initial prospective study of patients treated under this ongoing clinical treatment protocol. Results: Out of a total of 707 liver transplant recipients, 37 patients were confirmed with a diagnosis of CCA and only 18 patients (11 males and 7 females) with a median age of 61.83 [interquartile range (IQR): 58.27-68.74] met inclusion criteria. Of the 18 patients enrolled, 10 received Gemcitabine/Cisplatin, while 8 patients received either Gemcitabine monotherapy or Capecitabine or FOLFIRI alone or with Cetuximab. Days for recurrence after transplantation was 603 (IRQ: 603-603) in the Gemcitabine/Cisplatin group and 285 (267-374) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.18). The median days of follow-up in the Gemcitabine/Cisplatin group were 753 (621-885) days versus 1050 (618-1489) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.25). In the non-Gemcitabine/ Cisplatin group, overall survival was 75% (95% CI 31-93%) at both years 1 and 2; 63% (95% CI 23-86%) at both years 3 and 4. In the Gemcitabine/ Cisplatin group, overall survival was 100% (95% CI 100-100%) at both years 1 and 2; 67% (95% CI 5-95%) at both years 3 and 4. Three patients in the non-Gemcitabine/ Cisplatin group died at 328 days, 340 days, and 896 days, respectively. One patient in the Gemcitabine/ Cisplatin group died at 885 days. Conclusions: To our knowledge, this is the first report to show improved overall survival outcomes with Gemcitabine plus Cisplatin as neo-adjuvant treatment with no concomitant radiation compared to non-Gemcitabine/ Cisplatin regimens in patients with CCA prior to liver transplantation.
Inflammatory bowel disease and coexistence of neuroendocrine neoplasms: A review of the literature.
Authors: Karam Imad , Trikalinos Nikolaos 
Published: June 2022

e16206 Background: Inflammatory bowel disease (IBS) has been associated with colorectal adenocarcinoma, but its co-occurrence, causal or coincidental, with the more rare neuroendocrine tumor (NET) histology is not well understood.The incidence of carcinoid tumors has been increasing and chronic inflammation can be theoretically associated with carcinogenesis, including the development of carcinoid tumors. We aim to describe the reported literature on patients with IBS who also developed NET and summarize the characteristic findings reported in eachcase. Methods: This is a descriptive retrospective review of all cases of patients with IBD who developed NET reported in literature. We performed a Pubmed search with select keywords for IBS and NET, including ‘Inflammatory bowel disease’, ‘Ulcerative colitis’, ‘Crohn’s disease, and ‘Neuroendocrine Tumors’, or ‘carcinoid’. Extracted information included age, gender, inflammatory bowel disease type, number of years with IBD, treatment received for IBD, tumor site, indication for surgery, the extent of IBD, coexisting tumors, pathological findings, distant metastasis at diagnosis, and survival. Results: Out of 539 articles we identified 87 cases reports between 1970 and 2021. The mean age of patients was 43.61 years. IBS included ulcerative colitis in 46% (40) and Crohn’s disease in 51.7% (45) of patients. The male to female ratio was 1.7:1. The median number of years with IBS before diagnosis of NET was 12.5 years.Of the patients, 36.6% percent (31) were reported to receive treatment for IBS; of these 61.3%(19) were treated with steroids, 42% (13)mesalamine, 29%(9) azathioprine, 12.9% (4) infliximab, 6.4%(2) adalimumab, 3.2%(1) methotrexate, and 3.2% (1) mercaptopurine. Three patients 3.4% (3) initially underwent colectomy with ileostomy. IBS was diffuse in 20.7%(18) of the cases. The ileum was involved in a total of 35.6% (31) and the rectum in 4.6%(4). A mass was found upon regular screening imaging or regular surveillance in 8%(7) of the cases. The NET site was in the rectum in 20.7%(18), in the ileum 19.5%(17), and in the appendix in 19.5%(17). The indication for surgical intervention was due to refractory symptoms in 19.5% (7) of the cases and obstruction in 12.6%(11). About 35.6%(31) of NET cases were reported as well-differentiated, 5.7% (5) as poorly differentiated. Grade was high in 3.4% (3) and low in 5.7%(5) of the cases. Metastasis was reported to lymph nodes in 11.5% (10) and the liver in 5.7%(5). 13.8%(12) had a coexisting adenocarcinoma and 11.5%(10) died from NET. Conclusions: Most NETs in patients with IBS are in younger patients with non-diffuse disease, take a considerable time to develop, are low grade and localize in ileum, appendix and rectum. It is important to consider NET in patients with IBD who develop refractory or obstructive symptoms, especially when considering imaging / endoscopies to assess IBS status and response.
HRAS expression predicts Lenvatinib responsiveness in human primary gastroenteropancreatic neuroendocrine tumor cells.
Authors: Liverani Chiara , Spadazzi Chiara , Bongiovanni Alberto , Pieri Federica , Foca Flavia , Calabrese Chiara , Ercolani Giorgio , Cavaliere Davide , De Vita Alessandro , Miserocchi Giacomo , Cocchi Claudia , Vanni Silvia , Ranallo Nicoletta , Severi Stefano , Sansovini Maddalena , Guariniello Anna , Sbrancia Monica , Martinelli Giovanni , Ibrahim Toni , Mercatali Laura 
Published: June 2022

e16211 Background: Neuroendocrine neoplasms (NENs) are a rare group of heterogeneous tumors, with clinical presentation ranging from indolent and small lesions to very aggressive, metastatic and therapy refractory forms. Despite a high number of trials, few drugs have been introduced in the clinical practice and therapeutic options for systemic intervention are limited. The recent TALENT trial demonstrated the efficacy of Lenvatinib, a multi-tyrosine kinase inhibitor (MKI), in the treatment of patients with advanced well differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing from targeted therapies or somatostatin analogues with no other treatment indication. Lenvatinib might represent a novel therapeutic opportunity for these rare tumor patients. However, the treatment approach with MKI lacks clinically validated tissue or blood biomarkers to guide patient selection and improve efficacy. Methods: Here we established 11 human primary cultures from patients with GEP-NEN of different grades and sites of origin and assessed the antitumor activity of Lenvatinib compared with standard treatment agents. All primary cultures were molecularly characterized to identify possible predictors of response. Results: Lenvatinib exerted a significant inhibition of cell growth in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder with survival inhibition higher than 15%, and 5 as non-responder with survival inhibition lower than 15%. A high expression of HRAS in the tumor tissues compared to the matched healthy tissues significantly correlated with responsiveness of primary cells to Lenvatinib. All 5 non-responder patients showed low expression of HRAS, while of the 6 responder patients, 5 showed a high HRAS expression and only 1 low. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) correlated with response. Conclusions: In conclusion, we believe that the evaluation of HRAS expression and mutation might be of great interest in GEP-NET patients receiving Lenvatinib to improve patient selection.
A systematic review of the literature on gastrointestinal tract amyloidomas: Presentation, management and outcomes.
Authors: Viteri Malone Mariuxi Alexandra , Kaur Anahat , Kumar Abhishek 
Published: June 2022

e16220 Background: Gastrointestinal tract amyloidomas are uncommon malignancies, and little is known regarding this entity. AL amyloidosis and Amyloidomas mostly occurs in association to plasma cell dyscrasias such as multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and Waldenstrom’s macroglobulinemia (WM), although it has been also described in the absence of plasma cell dyscrasias. In general, plasma cell dyscrasias and systemic amyloidosis either AL or AA are typically treated with systemic therapy followed by Hematopoietic Stem Cell Transplant (HSCT) if patient is eligible. Nowadays, there are several systemic approaches that may or may not include autologous stem cell transplant. 56 On the contrary, localized amyloidomas have been mostly managed surgically and for the most part local amyloidomas are considered to have excellent prognosis. To this date there is no standard of care to guide clinicians in the management of local gastrointestinal amyloidomas. To the best of our knowledge this is the largest systematic review of gastrointestinal amyloidomas. The objective of this study was to evaluate the characteristics, treatments available, outcomes and surveillance these patients. Methods: We conducted a systematic review of cases reported in the literature from 1962-2021 that included a total of 62 cases reported in the literature. Patients with Gastrointestinal Amyloidomas reported in English literature were included in the analysis. We described and summarized the patient’s characteristics, treatments, clinical presentations, outcomes, and surveillance. Results: The systematic review of reported clinical cases included 62 patients. In these patients, the most common site of amyloid deposition was the stomach (45%). The median age of diagnosis is 64.4 years old, has a 2:1 prevalence among males (63%) to females (37%), abdominal pain is the most common type of presentation (41%) although patients could also be asymptomatic. There is a high curative rate (100%) with resection alone. Among patients treated with a type of systemic therapy, an 80% achieved a complete response. The minority of cases reported a type of surveillance post treatment and among those, the 62% pursued serial clinical evaluations alone. Conclusions: To our knowledge, this is the first and largest systematic review of the literature in Gastrointestinal Tract Amyloidomas. This is more common among males, and seems to have an excellent curative rate (100%) with surgery alone. Systemic therapy is an option for those with non-resectable amyloidomas. Serial clinical evaluations should be part of the standard surveillance care in these patients.
Auxiliary diagnosis of periampullary carcinomas by comprehensive next-generation sequencing.
Authors: Yin Lei , Yuan Mingming , Xia Xuefeng , Yu Wen-Long 
Published: June 2022

e16221 Background: Periampullary carcinoma, originating from ampulla, head of pancreas, common bile duct and duodenum, is a group of highly heterogeneous tumors with similar clinical presentations and anatomical sites but totally different prognosis. This study aims to investigate the potential diagnostic value of molecular testing in patients with periampullary carcinomas. Methods: This study retrospectively recruited patients diagnosed with periampullary, common bile duct, head of pancreas and duodenum cancers whose tumor tissue or circulating free DNA samples were sent to perform parallel hybridization-based next-generation sequencing of cancer-related genes ranging from 59 to 1021. Differentiated mutated genes were compared between different cancers using Fisher’s exact test and p < 0.05 was significant. Results: A total of 199 patients were enrolled in this molecular analysis, including 74 periampullary carcinomas, 43 duodenal cancers, 31 cancers of the common bile duct and 51 pancreatic head carcinomas. The top five most commonly mutated genes in these cancers were listed in the table. Fisher’s exact test suggested that ARID1A and LRP1B mutations were more frequently identified in duodenal cancer compared to periampullary cancer (p = 0.016 and 0.010, respectively). Compared to common bile duct carcinoma, periampullary cancer had more APC mutations and less ERBB3 mutations (p = 0.017 and 0.027, respectively). Strikingly, there was no APC mutation identified in pancreatic head cancer. Conclusions: Many common mutations were detected in periampullary, common bile duct, head of pancreas and duodenum cancers, such as TP53, KRAS and CDKN2A. However, APC mutation was not detected in pancreatic head carcinoma that is characterized by the worst prognosis. Genetic testing may facilitate distinguish the prognosis of periampullary carcinoma and assist in the differential diagnosis of pancreatic head carcinoma.[Table: see text]
Assessing surrogacy using restricted mean survival time ratio for overall survival in liver cancer immunotherapy studies.
Authors: Pang Herbert , Leung Tiffany H , Ho James C. M. , Lam Wendy WT , Wang Xiaofei F. 
Published: June 2022

e16222 Background: Recently, immunotherapy has played a crucial role in treating liver cancer, one of the major cancers that contributes to global cancer burden. Overall survival (OS) is widely applied in cancer trials to evaluate the treatment effects of new therapies. However, it requires more patients and longer follow-up time comparing with progression-free survival (PFS). In addition, while assessing the treatment effects of cancer immunotherapy, proportional hazard (PH) assumption is often violated due to issues such as delayed treatment effects. Restricted Mean Survival Time (RMST) ratio is increasingly used for treatment effect evaluation when the PH assumption is violated. Such change prompts an important question whether the surrogacy value of PFS will be affected when RMST ratio is used to characterize treatment effect. The aim of this study is to examine the feasibility of using PFS as a surrogate endpoint for OS when the treatment effect is measured using hazard ratio (HR) versus RMST ratio. Methods: The surrogacy of PFS on OS was evaluated through examining the association between PFS and OS using HR and RMST ratio. Seven immunotherapy studies published between 2000 and 2021 were included (Table). Information of examined studies such as treatment arms information, OS and PFS were collected. RMST ratio for PFS and OS were calculated based on the Kaplan-Meier plots extracted from each article using WebPlotDigitizer 4.4. The weighted least square regression lines and R^2 between OS and PFS for HR and RMST ratio were calculated. Results: Among 7 immunotherapy studies, 4 gave placebos to the control arms as treatments. 2 provided Sorafenib and 1 assigned the same drug as treatment arm but with different schedule. All 7 studies had OS and PFS as the endpoints. 2 studies violated the PH assumptions. Based on the data extracted from examined articles, a moderate correlation (0.52) between PFS and OS was observed for HR while low correlation (0.10) was observed for RMST ratio. Conclusions: The R^2 values differ greatly depending on whether HR or RMST ratio was used for assessing surrogacy. Our finding may have important implications for the design of future immunotherapy liver cancer trials. For future work, increasing the number of included studies for a more comprehensive analysis is needed. Moreover, trial-level surrogacy analysis should be conducted to complement the study-level investigation.[Table: see text]
Gastrointestinal melanoma: Outcomes of surgery and immunotherapy.
Authors: Mazal Sarah , Najmi Maleka , Ahmad Maria , Aguirre Katherine , Elhanafi Sherif , Philipovskiy Alexander , Gaur Sumit , Konstantinidis Ioannis 
Published: June 2022

e16224 Background: Most knowledge on gastrointestinal (GI) melanoma is limited to anal melanoma. Our aim is to examine the impact of surgical treatment and the utility of immunotherapy on GI (other than anal) melanoma. Methods: The National Cancer Database (2004-2016) was reviewed for patients who were treated for GI melanoma. Kaplan-Meier method and log-rank test were used to make survival comparisons. Results: We analyzed data from 731 patients with gastrointestinal melanoma (esophageal:97, gastric:57, small bowel:87, colonic:31, rectal:459). A minority of patients had metastatic disease at the time of diagnosis (esophageal:14.4%, gastric:17.5%, small bowel:4.6%, colonic:19.4%, rectal: 16.3%) and small proportion received immunotherapy (esophageal:16.5%, gastric:15.8%, small bowel:15%, colonic:6.5%, rectal:20.3%). Patients who had resection with negative margins had an improved survival irrespectively of the magnitude of surgery (for example rectal melanoma: OS: no surgery:7.9mo, local excision:23.3mo, partial proctectomy:23.5mo, total proctectomy:18.4mo; p < 0.001 and OS for R0 margins:29.4mo vs R1:13.5mo vs R2:5mo;p < 0.001). The use of immunotherapy was associated with improved survival in metastatic disease for rectal melanoma (OS:10.8mo vs 5.7mo; p = 0.01). Conclusions: Excision with negative margins is associated with improved outcomes in gastrointestinal melanoma. The use of immunotherapy should be considered in the presence of metastatic disease.