bluuebunny/crossref_metadata_2025 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.
Effect of obesity on resection margins in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemotherapy.
Authors: Asawa Palash , Vusqa Urwat Til , Karna Rahul , Shah Shivani , Sweeney Ryan , Jayakrishnan Thejus , Srinivasamaharaj Srividya , Samhouri Yazan , Monga Dulabh K.
Published: June 2022

e16229

Background: Obesity has been associated with decreased survival in patients with pancreatic ductal adenocarcinoma (PDAC). However, exact reasons remain unclear. Reduced response to chemotherapy because of obesity-induced desmoplasia has been proposed as a mechanism for the suboptimal response to treatment and therefore worse outcome. To this end, we attempted to determine the effect of obesity on the efficacy of neoadjuvant chemotherapy in patients with resectable and potentially resectable PDAC who underwent surgical resection. We assessed rates of microscopic tumor-free margins as a surrogate for treatment response. Methods: We performed a retrospective review of all patients diagnosed with PDAC from 2017-2019 at Allegheny Health Network. Obesity was defined as BMI > 30 kg/m2. Patients with resectable and potentially resectable disease who eventually received surgical treatment were included.Demographics, treatment details, and surgical pathology results were reviewed. Two-sided Mann-Whitney U test and Fischer’s exact test were used to evaluate differences between groups with continuous and categorical variables, respectively. A p value of < 0.05 was considered as level of significance. Results: Out of 121 patients who received and completed treatment at our institution, 29 patients underwent neoadjuvant chemotherapy followed by surgical resection. Most patients were female (61%), Caucasians (90%), had stage I (76%) and potentially resectable disease (72%). Eleven (38%) patients were categorized as obese and remaining non-obese. Among patients who underwent surgery after neoadjuvant chemotherapy, 10 out of 11 patients (90.9%) had microscopic tumor-free margins in the obese group when compared to 17 out of 18 patients (94.4%) in the non-obese group. (Table). Conclusions: Our study revealed no significant difference in obese patients compared to non-obese patients in terms of tumor-free margins assessed microscopically after surgical resection. Our study is limited by its small sample size, retrospective nature, and unidentifiable confounding factors that could potentially affect outcomes. Larger scale studies are needed to investigate the effect of obesity on treatment outcomes in resectable and potentially resectable pancreatic cancer patients treated with neoadjuvant chemotherapy.[Table: see text]
Venous segmental resection in locally advanced pancreatic tumors.
Authors: Gevorkyan Yuriy A. , Katelnitskaya Oksana V. , Kit Oleg I. , Maslov Andrey A. , Soldatkina Natalya V. , Petrov Dmitriy S. , Kolesnikov Vladimir E. , Savchenko Dmitriy A. , Tolmakh Roman E. , Dashkov Andrey V. , Ilchenko Sergei A. , Trifanov Vladimir S. , Kolesnikov Evgeniy N.
Published: June 2022

e16243

Background: Surgical treatment is considered the main treatment for pancreatic cancer improving the patient survival. The most common obstacle to surgery with R0 resection is the involvement of the great vessels. Recently, venous resections have been increasingly performed for this type of tumors. Our purpose was to evaluate radicality of surgical treatment and postoperative morbidity in patients with locally advanced pancreatic cancer. Methods: The study included patients with locally advanced pancreatic cancer (T3 N0-1 M0) with damage to the venous segment (portal vein system) confirmed by CT angiography. Results: Over a 5-year period, 73 (18.9%) of 386 operated-on patients with pancreatic cancer underwent surgeries for pancreatic ductal adenocarcinoma with venous resection. The frequency of wedge venous resection was 24.7% (18), segmental resection with end-to-end anastomosis - 46.6% (34), prosthetics - 26% (19), prosthetics with replantation of the splenic vein - 2.7% (2). The postoperative morbidity rate was 30.1%. Within 30 days after surgery, the mortality rate reached 5.5% (4 patients). The main causes were bleeding and thrombosis of the reconstruction area. Only patients with venous segment replacement developed thrombotic complications. Microscopically complete resection was performed in 87.7% of cases (64 patients). During the follow-up period, the 1-year survival rate reached 90%, and the recurrence-free rate was 93%. Conclusions: Surgical treatment for locally advanced pancreatic tumors with damage to the portal vein system shows an acceptable rate of postoperative complications due to the vascular stage, and a high rate of reaching a negative resection margin. Initial assessment of the need for venous resection is required in patients with pancreatic tumors, as well as expanding the extent of surgical intervention due to venous resection to achieve R0 resections.
Timing of onset of systemic treatment in asymptomatic patients with metastatic pancreatic cancer: An international expert survey and case-vignette study.
Authors: Augustinus Simone , Van Laarhoven Hanneke W.M. , Cirkel Geert A. , de Groot Jan Willem , Groot Koerkamp Bas , Macarulla Teresa , Melisi Davide , O'Reilly Eileen Mary , van Santvoort Hjalmar , Mackay Tara , Besselink Marc G , Wilmink Johanna
Published: June 2022

e16256

Background: The number of asymptomatic patients diagnosed with metastatic pancreatic cancer (mPDAC) is increasing, mostly due to increased use of imaging. Traditionally, systemic therapy is started immediately on disease detection. However, one perspective is that delaying therapy may preserve/maintain quality of life for longer. The impact on survival is unknown. The aim of this study was to gain further insights into current perspectives and clinical decision making regarding timing of start of systemic treatment in asymptomatic patients with mPDAC. Methods: An online survey (11 questions and 9 case vignettes) was sent to all first and last authors of published clinical trials on mPDAC over the past 10 years and medical oncologists of the Dutch Pancreatic Cancer Group. Differences in preferred treatment (i.e. immediate vs. delayed) between continents and years of experience (i.e. < 5 years, 5-10 years, > 11 years) were analyzed using the Fisher’s exact test. Results: Seventy-eight of 291 (27%) medical oncologists responded from 15 countries over 4 continents (62% Europe, 23% North America, 10% Asia, and 5% Australia). Most respondents worked in an academic hospital (73%) and reported more than 11 years’ experience (76%). The majority (63%) preferred immediate start of chemotherapy after diagnosis of metastastic disease. Thirty-two percent favored delayed treatment; 5% at symptom occurrence, 5% at objective disease progression, and 22% either at symptom occurrence or objective disease progression (whichever comes first). For the case vignettes, immediate treatment was preferred in 6/9 cases (67%). In the 3 remaining cases, delayed treatment was favored (case context: just one small lung metastasis, older age, significant comorbidities). The recommended timing of treatment (i.e. immediate or delayed treatment) was different between continents in 1/9 cases (11%, p = 0.012) and between years of experience in 5/7 cases (56%, all p < 0.001); medical oncologists from Europe and with < 5 years of experience preferred delayed treatment more often. Conclusions: This international survey based on case-vignettes indicated that immediate treatment was mostly preferred in asymptomatic patients with mPDAC. However, in one-third of cases, delayed treatment initiation was favored (e.g., due to patient selection and oncologists preference). The relation between timing of systemic treatment initiation and outcome in mPDAC is unknown and warrants further investigation.
Initial clinical results of the first commercial clinical blood test dedicated to the early detection of pancreatic ductal adenocarcinoma (PDAC).
Authors: King Thomas C.
Published: June 2022

e16258

Background: The IMMray® PanCan-d blood test for early detection of PDAC has been commercially available in 45 U.S. states since the laboratory’s licensure in August 2021. This is the first clinically-available blood test dedicated to the early detection of PDAC, combining an 8-plex biomarker signature with CA19-9 in a proprietary algorithm. Here we report the initial results of this assay. Methods: All orders received and results reported were reviewed for the IMMray PanCan-d test between August 4, 2021 and February 11, 2022. Serum specimens were processed at the Immunovia, Inc. laboratory in Marlborough, Massachusetts. Demographic information of individuals undergoing testing is based on the completed test requisition submitted by their health care providers. All information was de-identified prior to this analysis. Results: The median age of those tested was 59 years and 46% were male. 76% of patients were referred because of a history of familial pancreatic cancer. Germline mutation prevalence is reported in the table below. 12% of patients had IPMNs or mucinous cystic neoplasms, 2% had chronic pancreatitis and 3% had new onset Diabetes Mellitus. Table. Demographics of Individuals Tested with the IMMray PanCan-d test 80.5% of IMMray PanCan-d results were negative, 1.1% were high-risk signature present, and 11.5% were borderline. These results are fully consistent with validation studies for this assay in high-risk surveillance populations (Brand RE et al Clin Transl Gastroenterol, doi: 10.14309/ctg.0000000000000468). 6.9% of individuals tested had a CA19-9 value of less than 2.5 U/ml, which we identify as presumptively Lewis null (le/le) and CA19-9 non-secretors. Given that CA19-9 contributes significantly to calculated decision values for the IMMray PanCan-d test, individuals with a CA19-9 less than 2.5 U/ml receive a result of test not performed. Conclusions: The commercial availability of a biomarker assay for the early detection of PDAC resulted in a testing population with demographics and referral criteria similar to that of PDAC high-risk surveillance programs in the U.S. IMMray PanCan-d test results were as expected based on prior validation studies.[Table: see text]
Retrospective analysis of management and outcomes of patients with malignant biliary obstruction.
Authors: Chan Abigail Sy , Chandler Natasha , Dong Brian , Rios Perez Cristian Daniel , Xue RuoBing , Hu Huirong , Kong Maiying , Sharma Vivek R.
Published: June 2022

e16266

Background: Malignant biliary obstruction (MBO) is commonly associated with pancreaticobiliary cancers (PBCa). It increases the risk for cholangitis, hepatic failure, and deconditioning, which delays systemic therapy. This study aims to identify predictors associated with MBO outcomes after biliary decompression. Methods: This single-center, retrospective study analyzed patients with MBO from 2016-2020 who underwent biliary drainage. Patient demographics, cancer history, intervention type, and date of last follow up were obtained. Descriptive statistics were used to summarize relevant variables. Baseline characteristics were compared using Chi squared tests. Kruskal Wallis test was used to identify whether there were significant difference among multiple groups. Results: Of the 59 patients included, mean age was 62 years and 75% had PBCa. Baseline characteristics were presented in Table. The mean survival time from MBO diagnosis was 227 days (range: 16-1446). Overall, 39% survived at the end of 6 months follow up. Of the 29 patients who received chemotherapy after decompression, they were younger (57 vs 66 years old, p = 0.004). History of prior chemotherapy was significantly associated with increased 180-day mortality (OR 0.75, CI 0.58-0.97, p = 0.033). There were no differences based on sex, race, primary cancer, stage, intervention type or bilirubin levels in chemotherapy initiation or 6-month survival. In those with MBO as initial presentation of cancer, they were older, had pancreatic or biliary cancer, non-metastatic disease, unresected primary tumors, treatment-naïve, and no survival difference compared to later MBO presentation. Conclusions: Diagnosis of MBO is significantly associated with mortality (61% at 6-months) in our patient population, similar to historical controls of 40-60%. This data suggests that younger patients and those treatment naïve were associated with receipt of subsequent therapy and better 6-month survival, respectively.[Table: see text]
A systemic review and meta-analysis of FOLFIRINOX vs gemcitabine plus nab-paclitaxel in the neoadjuvant treatment of localized pancreatic cancer.
Authors: Fatima Zainab , Alhabhbeh Ammar , Darweesh Mohammad , Laswi Hisham , Manthri Sukesh
Published: June 2022

e16272

Background: Localized pancreatic adenocarcinoma (PDAC) includes resectable, borderline resectable, and locally advanced cancers. In potentially resectable pancreatic cancer, the role of neoadjuvant therapy is evolving and guidelines from expert groups are conflicting. Although limited, randomized trials have shown that neoadjuvant chemotherapy (NCT) can provide survival benefits in patients with localized PDAC. Studies have compared FOLFIRINOX (FFN) with Gemcitabine plus nab-Paclitaxel (G-nP) as first-line NCT for PDAC, but no consensus has been established. As a result, we performed an updated meta-analysis to assess the difference in overall survival between two chemotherapy regimens. Methods: PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception to December 2021 to identify studies comparing FFN with G-nP in the neoadjuvant settings for localized PDAC. The primary outcome was the overall survival of patients and secondary endpoints were RECIST partial or complete response, resection rate and R0 resection. The effectiveness of FOLFIRINOX and G-nP in terms of overall survival in patients with localized PDAC was compared using hazard ratios (HR) and 95% confidence intervals (CI). In addition, the heterogeneity of the studies was evaluated using Cochrane's Q test of heterogeneity and the I2 statistic. Pooled analysis of HR was performed with Stata 17 METAN using random effect model and P of 0.05 was considered statistically significant. Results: We identified 10 studies that met our inclusion criteria. All studies were retrospective and 5 of them were carried out in the United States. The total numbers of patients preoperatively treated with FOLFIRINOX versus G-nP were 988 and 719, respectively. In this meta-analysis compared to G-nP, neoadjuvant FFN was associated with significant prolonged overall survival (HR = 0.72, 95% CI: 0.63–0.82, P < 0.001). FFN group had a significantly higher RECIST partial and complete response rate than the G-nP group, with an OR of 1.65 (95 % CI 1.02-2.68, p = 0.04). For resection rate and R0 resection, FFN group had ORs of 1.65 (95% CI 0.94-2.90, p = 0.08) and 1.91 (95% CI 0.95-3.81, P = 0.07) respectively, both outcomes were statistically insignificant. Conclusions: Results of our meta-analysis show that for localized pancreatic cancer, neoadjuvant treatment with FFN was associated with better survival than G-nP. One limitation to our current study was that all included studies were designed retrospectively. Further randomized clinical trials are needed to explore the ideal neoadjuvant chemotherapy for PDAC.[Table: see text]
Frequency of loco-regional complications and their IMPACT on hospitalization outcomes in patients with pancreatic cancer.
Authors: Shah Mihir , Kumi Dennis Danso , Deenadayalan Vaishali , Ahuja Kriti , Abate Elias , Goyal Aakash , Gupta Shweta
Published: June 2022

e16278

Background: Despite advances in medicine, pancreatic cancer continues to have a grim prognosis. It is not well studied if certain loco-regional complications pose higher prognostic risk than others and thus may be useful in estimating longevity and targeting care. Methods: National Inpatient Sample (NIS) was queried to identify adult patients with underlying pancreatic cancer between 2016-2018. Relative frequency and diagnosis of locoregional complications as principal diagnosis in these patients were identified and top 5 loco-regional complications were studied and compared for all-cause mortality, mean length of stay (LOS), mean total hospital charges (THC). Statistics were performed using the t-test, univariate and multinomial logistic regression. Results: There were 112,230 adult hospitalizations for pancreatic cancer. Top 5 loco-regional complications were cancer pain (8.6%), upper GI bleeding (UGIB) (8.4%), gastroduodenal obstruction (5.7%), failure to thrive (5%) and acute liver failure (2.8%). Mortality rate of all pancreatic cancer admissions was 7% and all loco-regional complications studied were associated with significant increased odds of mortality, the highest in patients with acute liver failure (AOR- 5.33, p < 0.001). All Loco-regional complications studied were associated with statistically significant increased LOS with the highest among patients admitted with UGIB (p < 0.001). UGIB was also associated with the highest THC whiles cancer pain admissions had a lower charge (p < 0.001). Conclusions: Among Loco-regional complications in pancreatic cancer that were studied, cancer associated pain was the most frequent while acute liver failure was the most fatal (5x higher odds of mortality). UGIB was associated with the longest hospital LOS (6 more days) and the highest THC (over $100,000 extra per admission) whereas cancer associated pain was associated with the shortest length of stay and lowest total charge. Further efforts are needed to improve outpatient pain management in pancreatic cancer patients to prevent these admissions.[Table: see text]
MiR-198 sensitizes pancreatic cancer to gemcitabine treatment through downregulation of VCP-mediated autophagy maturation.
Authors: Marín-Müller Christian , Li Dali , Lu Jian-Ming , Liang Zhengdong , Vega-Martínez Osvaldo , Fisher William , Chen Changyi , Yao Qizhi Cathy
Published: June 2022

e16290

Background: The mechanism of human pancreatic ductal adenocarcinoma (PDAC) resistance to nucleoside analog and first-line chemotherapy drug gemcitabine is not clearly understood, but some studies have associated it with increased autophagy. In cancer biology, autophagy plays dual roles as it can promote tumor suppression during early stages, but in established tumors, it plays a crucial role in tumor growth by enhancing survival under metabolic and therapeutic stress. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of a network of tumorigenic factors, including the Valosin-containing protein (VCP), which has been reported to play an important role in autophagy. In this study, we investigate whether the repression of VCP through miR-198 replacement disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment. Methods: MIAPaCa2 cells with forced overexpression of mesothelin (MSLN) and AsPC-1 cell lines and, CDX and PDX mouse models were used for gemcitabine sensitization studies. For miR-198 replacement, a miR-198 expression vector-loaded lactic co-glycolic-acid-modified polyethylenimine polyplex (LPNP-p198) was used. Autophagy disruption experiments were run over miR-198 and/or VCP overexpressing cell lines. Nude mice were used for subcutaneous and orthotopic CDX models and SCID/Beige were used for the subcutaneous PDX model. Results: Cell lines were treated with LPNP-p198 in combination with gemcitabine and cell growth was significantly inhibited when compared to gemcitabine alone. Additionally, it was determined that miR-198 disrupts the autophagy maturation process and, that it is then restored by overexpression of VCP. LPNP-p198 can effectively enter tumor cells and induce tumor sensitization in vivo, resulting in an 80-90% reduction of tumor burden and metastatic spread in the LPNP-p198 plus gemcitabine group when compared to controls, with the concomitant downregulation of VCP expression in the tumor tissue. In addition, this group had the fewest mice with jaundice, ascites, and metastases to the abdominal cavity, spleen, liver, and kidney. Finally, to address the potential of the observed effect in the context of the heterogenic nature of PDAC, we confirmed our findings in a PDX mouse model, where a marked reduction in tumor burden was observed in the LPNP-p198 plus gemcitabine group compared to controls. Conclusions: Our findings indicate that miR-198 replacement disrupts the autophagy maturation process and sensitizes PDAC cells to gemcitabine through VCP repression, indicating a potential therapeutic strategy for targeting gemcitabine-resistant PDAC and, establishing the use of LPNPs as a prototype for effective nucleic acid delivery in vitro and in vivo, with potential to be used from bench to clinic.
Systematic investigation of immune-related lncRNA landscape reveals a potential long non-coding RNA signature for predicting prognosis in kidney renal clear cell carcinoma.
Authors: Liu Kepu , Li Zhibin , Ruan Dongli , Wang Huilong , Wang Wei , Zhang Geng
Published: June 2022

e16510

Background: Increasing evidence has revealed that long non-coding RNAs (lncRNAs) play a crucial role in cancer immunity. However, the comprehensive landscape of immune infiltration-associated lncRNAs and their potential roles in the prognosis and diagnosis of kidney renal clear cell carcinoma (KIRC) remains largely unexplored. Methods: The transcriptomics data, expression profiles, and clinical information of KIRC patients were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. Novel lncRNAs were identified by a custom pipeline. The infiltration of immune cells was calculated by ssGSEA. K-means consensus method was used to cluster KIRC samples in different groups. Immune-related lncRNAs were obtained by differential expression analysis based on these groups. Univariate Cox regression, LASSO regression, and multivariate Cox regression analysis were performed on GEO datasets to construct an immune-related lncRNAs signature for predicting the prognosis of KIRC. And then, validated the prognostic signature in TCGA data. Results: Based on 261 samples from KIRC patients, tens of thousands of novel lncRNA genes were identified. KIRC samples were clustered into three immune clusters based on the infiltration of immune cells. Based on these groups, 241 immune-related lncRNAs were obtained. Moreover, a large part of immune-related lncRNAs could be detected in urinary samples of KIRC. Through a series of analyses, three immune-related lncRNAs were identified as a prognostic signature for KIRC. KIRC patients in the high-risk group had a shorter OS than those in the low-risk group both in the training set (P < 0.001) and TCGA data (P < 0.001), respectively. The AUC was 0.9 in the training set. Univariate and multivariate Cox regression analysis confirmed that the immune-related lncRNAs signature could be an independent prognostic factor both in the training set and TCGA data. Conclusions: All these findings provide a more comprehensive lncRNAs catalog for investigating the lncRNAs and provide a novel approach for the effective prediction of clinical outcomes in KIRC.