bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of apatinib as third or later line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma: A post-marketing phase IV study.
Authors: Li Jin , Qin Shukui , Wen Lu , Wang Junsheng , Deng Wenying , Guo Weijian , Jia Tongfu , Jiang Da , Zhang Guifang , He Yifu , Zhong Haijun , Ba Yi , Lin Xiaoyan , Yang Jianwei , Zhao Jun , Bai Yuxian , Wu Xiangyuan , Gao Feng , Sun Ying , Hou Zhiguo
Published: June 2021

e16034

Background: Apatinib, a small molecule multi-target tyrosine kinase inhibitor with high selectivity for VEGFR-2, has been approved for the treatment of advanced gastric cancer or gastroesophageal adenocarcinoma in China by significantly improving progression-free survival (PFS) and overall survival (OS). Here, we report safety and efficacy data from an open-label, single-arm, multicenter, phase IV trial of apatinib as a third-line or later line treatment for advanced gastric cancer. Methods: Eligible patients had histologically or cytologically confirmed advanced gastric cancer or gastroesophageal junction adenocarcinoma; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; and adequate haematological and hepatic function; and failure of at least two lines of chemotherapy. Patients received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety, and secondary endpoints included PFS and OS. Results: The intention-to-treat population (ITT) included 2004 patients. At baseline, the median age was 59 (range, 19-85) years, ECOG performance status of 0/1/2 (%) was 15.4/68.8/15.1, and stage III/IV was 3.5/96.4; 98.8% had metastases, and among which metastatic foci≤2/ > 2 was 64.5/34.2 (%), respectively. 89.6% of the patients were given apatinib 500mg as the initial does and the median treatment duration was 56 days. After a median follow-up of 126.5 days, adverse events (AEs) occurred in 95.1% of the patients and 70.3% were grade ≥3. 87.9% of the patients experienced treatment-related AEs (TRAEs), of which 51% had grade ≥3, 12.3% and 16.8% reduced dose and discontinued the treatment, respectively. 57 (2.9%) TRAEs-related deaths were reported, mainly because of gastrointestinal bleeding (16 cases), upper gastrointestinal haemorrhage (7), cerebral haemorrhage (2), and gastric perforation (1). The incidence of TRAEs of special interest was 74.3%; 38.1% of patients developed grade≥3, mainly including hypertension (26.3%), bleeding (5.1%), proteinuria (4.5%), and hand-foot syndrome (3.1%). In an ITT population, median PFS was 2.7 months (95%CI 2.23-2.79) and median OS was 5.8 months (95% CI 5.42-6.11). Conclusions: This study confirms that apatinib has a well-established and manageable safety profile and survival benefit as third or later line therapy for patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma. Clinical trial information: NCT02426034.
Safety and efficacy of anti-EGFR monoclonal antibody (SCT200) as second-line therapy in advanced esophageal squamous cell cancer.
Authors: Bai Ming , Deng Ting , Ba Yi
Published: June 2021

e16046

Background: The mainstay treatment of esophageal squamous cell carcinoma (ESCC) involves chemotherapy and immunotherapy. However, alternative therapies are required for patients refractory or intolerant to the existing therapies. Methods: In this single-arm, multicenter, open-label phase Ib study, 30 patients received an intravenous infusion of SCT200, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, 6.0 mg/kg once a week for six weeks, followed by 8.0 mg/kg once every two weeks until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty patients were enrolled between July 2018 and May 2019. The ORR was 16.7% (95%CI: 5.6%–34.7%). The median PFS and OS was 3.1 months (95%CI: 1.5–4.3) and 6.8 months (95%CI: 4.7–10.1) respectively. Numerical difference without a statistical significance in ORR was observed in patients with different EGFR expression (≥50%: 25.0% vs. < 50%: 0%, P = 0.140) or TP53 mutation abundance ( < 10%: 23.8% vs. ≥10%: 0%, P = 0.286). Improved median PFS (3.4 vs. 1.4 months, P = 0.006) and OS (8.0 vs. 4.2 months, P = 0.027) were associated with TP53 mutation abundance of < 10%. The most common treatment-related adverse events of grade 3 or 4 (occurring in ≥2 patients) were hypomagnesemia (7 [23.3%]) and rash (2 [6.7%]). No treatment-related death occurred. Conclusions: SCT200 monotherapy as second- or further-line for advanced ESCC showed favorable efficacy, with an acceptable safety profile. TP53 mutation abundance might serve as potential predictive biomarkers. Clinical trial information: NCT03817567. [Table: see text]
Predictors of survival after metastasectomy of oligometastatic recurrence following gastroesophageal cancer treatment.
Authors: MacKenzie Malcolm , Ma Lucy Xiaolu , Epsin-Garcia Osvaldo , Suzuki Chihiro , Bach Yvonne , Allen Michael J , Darling Gail Elizabeth , Swallow Carol Jane , Brar Savtaj Singh , Yeung Jonathan , Kalimuthu Sangeetha , Wong Rebecca , Panov Elan David , Veit-Haibach Patrick , Chen Eric Xueyu , Elimova Elena , Jang Raymond Woo-Jun
Published: June 2021

e16060

Background: Recurrent gastroesophageal (GE) carcinomas carry a poor prognosis and are usually treated with palliative chemotherapy (CTX). However, recent studies suggest that certain patients with oligometastatic recurrence can have long term survival after metastasectomy. Appropriate patient selection for metastasectomy remains a challenge, as few predictors of overall survival (OS) after metastasectomy have been identified. Our primary aim was to identify predictors of OS following metastasectomy in GE cancers. Methods: We conducted a retrospective study of GE cancer patients treated from 2007 to 2015 using the Princess Margaret Hospital Cancer Registry. We included patients who underwent curative-intent surgery or definitive chemoradiation (CRT) for localized GE cancer who then had single organ recurrence treated with metastasectomy. The probability of OS from date of recurrence was estimated with the Kaplan Meier method. Predictors of OS after metastasectomy for isolated recurrence were determined using Cox proportional hazards analysis. Covariates included time to recurrence (interval from curative-intent surgery or completion of definitive CRT), site of recurrence (lung/non-lung), sex, age and race (Asian/Non-Asian). Within the multivariable model, predictors with a p-value less than 0.05 were deemed significant. Results: Of 44 patients, median age was 58 years (28-78), and 59% were male. Primary sites were: esophagus 25%, GE junction 41% and gastric 34%. Treatment of the primary was: surgery alone 13%, surgery and (neo)adjuvant CTX 76%, and CRT 11%. Recurrent sites were brain 22%, ovary 20%, lung 18%, bone 7%, adrenals 7%, liver 7%, distant lymph node 6%, and other 13%. The median follow up time was 38.9 months. The 1, 3 and 5-year (yr) OS following metastasectomy were 79% (95% CI 68-92%), 40% (27-58%) and 28% (16-49%). Univariable analysis revealed that time to recurrence greater than 1 yr (HR=0.45 95% CI 0.21-0.93, p=0.032) and lung site recurrence (HR=0.16 95% CI 0.04-0.67, p=0.012) were associated with longer OS. On multivariable analysis, only lung site recurrence was significant (HR=0.12 95% CI 0.03-0.54, p=0.0056). The 1, 3 and 5-yr OS for patients after resection of isolated lung recurrence were 100% (95% CI 100-100%), 86% (63-100%) and 69% (40-100%). Conclusions: In our study, patients with isolated pulmonary recurrences demonstrated prolonged overall survival following metastasectomy. These patients could be considered for resection following recurrence of GE cancer. [Table: see text]
Treatment outcomes for stage T1b-2 esophagogastric adenocarcinomas.
Authors: Diab Maria , Khalil Lana , Goyal Subir , Switchenko Jeffrey M. , Alese Olatunji B. , Akce Mehmet , Wu Christina , El-Rayes Bassel F. , Shaib Walid Labib
Published: June 2021

e16085

Background: Treatment of localized esophageal, gastroesophageal junction (GEJ), and stomach cancer is neoadjuvant therapy with either chemoradiation or chemotherapy followed by surgery. Treatment for T1b-2 stage disease is not well evaluated and this stage is underrepresented in prospective studies. The aim of this study is to evaluate survival outcomes among the three treatment modalities (neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiation (NACRT), and upfront surgery (US)) in this population using the National Cancer Database (NCDB). Methods: Patients (pts) with clinical stage T1b-2N0 and any pathological stage (excluding metastatic) adenocarcinoma of the esophagus, GEJ, and stomach treated with neoadjuvant therapy or upfront surgery, with or without adjuvant chemotherapy (AC), were identified between 2004 and 2015 in the NCDB. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazard models were used to identify the association between the three treatment modalities and overall survival (OS). Results: A total of 2260 pts were analyzed. The median follow-up was 66.6 months. The median age was 67 years. Most pts were White (86%) and male (77%). 1018 (45%) had moderately-differentiated grade, while 946 (42%) had poorly-differentiated/undifferentiated grade. The most common site of disease was the lower third of esophagus (34.1%). 161 pts (7%) received NACT, of whom 45 pts received AC; 537 pts (24%) received NACRT, of whom 40 pts received AC. 1562 pts (69%) underwent US, of whom 146 pts received AC. US with AC was associated with the best survival, followed by NACT with AC; median OS was 90.1 and 86.8 months for surgery with AC and NACT with AC, respectively. NACRT was associated with the worst survival (39.5 and 40.2 months with and without AC, respectively). The 5-year OS rates were 59.8%, 58.5%, 52.1%, 44.9%, 37.3%, and 37.8%, for US, NACT, and NACRT, with and without AC, respectively. The rate of tumor upstaging was highest in the NACT group, followed by the NACRT group, and lowest in the US group. Postsurgically, 62 (39%) and 48 (30%) pts in the NACT group and 198 (37%) and 161 (30%) pts in the NACRT group had upstaging in their T and N stages, respectively, compared to 214 (13%) and 326 (21%) pts in the US group. For the 1107 pts who also had pathological T1b-2N0 stage disease following US, no difference in survival was observed with or without AC. Conclusions: Upfront surgery with adjuvant chemotherapy and perioperative chemotherapy are associated with the best survival compared to preoperative radiotherapy. This is the largest study to address the best approach for the treatment of T1b-2 stage disease.
PRIME-HCC: Phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.
Authors: Pinato David James , Cortellini Alessio , Pai Madhava , Spalding Duncan , Talbot Thomas , Goldin Robert D. , Gupta Aneta , Cole Tom , Ward Caroline , Yip Vincent S. , Dhillon Tony Singh , Slater Sarah , Sodergren Mikael , Tait Paul , Habib Nagy A. , Thomas Robert , Sharma Rohini
Published: June 2021

e16131

Background: There are no approved peri-operative anti‐cancer therapies for patients with hepatocellular cancer (HCC) who are candidates for liver resection (LR). Combination immunotherapy induces radiologically measurable responses in > 25% of patients with HCC, providing a rationale for neoadjuvant use in surgical candidates. Methods: PRIME‐HCC is a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab (3 mg/kg, day 1 and day 22) plus ipilimumab (1mg/kg, day 1 only) combination prior to LR in early-stage HCC. The primary objective of the study is to determine the treatment-related adverse events (trAE) and delays to surgery. Efficacy endpoints include overall response rates (ORR) by RECIST v1.1 and pathologic responses on resection specimens. Results: At the data censoring time of Jan 29th 2021, 7 patients were enrolled, all were of Child-Pugh class A, with cirrhosis (n = 6, 85.7%) secondary to viral etiology (n = 4, 57.2%). Male/female ratio was 6/1 and median age was 66 (range: 57-70). The median diameter of the dominant liver lesion was 3.3 cm (inter quartile range, IQR 1.2, range 1.1-4.1 cm) and the median number of nodules was 2 (IQR 0.5; range 1-3). Study part I (n = 6) was completed with no surgical delays. TrAEs of all grade were observed in 6/7 safety-evaluable patients (85%). TrAEs of grade >2 occurred in 3 patients (42%) and included grade 3 transaminitis (n = 1), grade 2 thyroid toxicity (n = 1), grade 2 infusion reaction (n = 1) and fatigue (n = 1). One patient was diagnosed with cholangiocarcinoma after dosing and was removed from efficacy analyses. ORR according to RECIST v1.1 criteria in efficacy-evaluable patients (n = 5) was 20%, including 1 partial response and 4 disease stabilisations. Pathological responses were observed in 3 out of 5 pathologically evaluable patients (60%). Conclusions: Neoadjuvant immunotherapy with nivolumab plus ipilimumab is tolerable, does not compromise management of patients on a radical pathway of care and is characterised by anti-tumour efficacy in early-stage HCC. Clinical trial information: NCT03682276.
A new staging system for radiotherapy-based treatment of hepatocellular carcinoma: A multicenter cohort study.
Authors: Su Ting-Shi , Liang Shi-Xiong , Li Li-Qing , Liu Qiu-Hua , Zhu Xiao-Fei , Liang Ping
Published: June 2021

e16155

Background: External beam radiation therapy has been used as a palliative to radical treatment of hepatocellular carcinoma (HCC) depending on different tumor status, liver function and patient's general state of health. The existing models of HCC staging cannot perfectly predict the prognosis of radiotherapy. In this study, we aimed to set up a new staging system for radiotherapy-based treatment by incorporating bilirubin-albumin (ALBI) grade and tumor status for the prognostic classifications of HCC. Methods: This multicenter cohort study included 878 HCC patients who received radiotherapy-based treatment. A new staging system was established: stage I, solitary nodule without macrovascular invasion or 2-3 nodules with no more than 3.0 cm each other and PS 0-2 (Ia: ALBI-1 grade; Ib: ALBI-2 or 3 grade); stage II: 2-3 nodules with anyone more than 3.0 cm or ≥4 nodules and PS 0-2 (IIa: ALBI-1 grade; IIb: ALBI-2 grade); stage III: macrovascular invasion or regional lymph node metastasis or distant metastasis and PS 0-2 (IIIa: ALBI-1 grade; IIIb:ALBI-2 grade); stage IV: ALBI-3 grade without stage I patient or/and PS score 3-4. The new modified staging system and the existing staging systems, such as the BCLC, TNM, CNLC staging systems were used for prognostic analysis. All patients were separated into different stages and substages. The long-term overall survival outcomes and time-dependent receiver operating characteristic (ROC) were analyzed. Results: A training cohort of 595 patients underwent stereotactic body radiotherapy (SBRT) from 2011 to 2017 and an external validation cohort of 283 patients underwent intensity-modulated radiotherapy (IMRT) from 2000 to 2013 were included into establishing and validating the new staging system. In the training cohort, the median follow-up time was 55 months (range, 6–100 months), and the new staging system had a good discriminatory ability to separate patients into different stages with 4 notably different curves and substages with 7 notably different curves. BCLC staging could not differentiate stage 0 to A, and stage C to D in these selected patients. TNM staging could not completely distinguish stage IIIb to IV, but also stage Ia to Ib. CNLC staging could not differentiate among stage IIIa, IIIb, and IV. In the external validation, the median follow-up time was 95 months (range, 9–120 months), and the new staging system also had a good discriminatory ability to separate patients into different stages with 4 notably different curves and substages with 7 notably different curves. The new staging system had a better area under curve of time-dependent ROC than BCLC, TNM and CNLC staging in both SBRT and IMRT cohorts. Conclusions: The new modified (Su’s) staging system could provide a good discriminatory ability to separate patients into different stages and substages after radiotherapy treatment. It may be used to supplement the other HCC staging systems.
Molecular alterations, tumor microenvironment and clinical correlations in Thai cholangiocarcinoma patients.
Authors: Bamrungwong Panuchai , Oranratnachai Songporn , Sornmayura Pattana , Incharoen Pimpin , Iemwimansa Nareenart , Trachu Narumol , Panthan Bhakbhoom , Monnamo Nanamon , Sae-Lim Pakatorn , Charoenyingwattana Angkana , Panvichien Ravat , Sirachainan Ekaphop , Chantratita Wasun , Reungwetwattana Thanyanan
Published: June 2021

e16176

Background: The systemic treatment option of unresectable and advanced cholangiocarcinoma (CCA) is limited. The mainstay of treatment is gemcitabine and 5-FU based chemotherapy. Recently, there is the role of promising immunotherapy in MSI-HI CCA. This research aims to study molecular alterations and tumor microenvironment in Thai CCA patients in order to explore the novel treatment and the clinical correlations. Methods: Thirty-six CCA patients in Ramathibodi Hospital between year of 2018 and 2020 with adequate tissue were enrolled. NGS by ThermoFisher (comprehensive panel) for molecular profile and immunohistochemistry (IHC) staining for tumor microenvironment protein expression (CD3, CD4, CD8, CD20, CD138, CD163, FOXP3), and PD-L1 were performed. Clinical data was retrieved from electronic medical record. Survival analysis, univariate and multivariate analysis were performed by Cox-regression analysis. Stata version 16.0 was used for statistical analysis. Results: Intrahepatic CCA was the most common type of CCA in our population (81%). The top 10 common mutations were TP53 (69%), KMT2D 58%), KMT2B (52%), ARID1A (50%), FAT1 (50%), NOTCH3 (44%), FANCA (42%), SMAD4 (42%), EPHA2 (39%), and ARID1B (39%). We also found the interesting targetable genes in our CCA patients, such as, KRAS (33%), MTOR (33%), HER2 (31%), EGFR (31%), FGFR2 (28%), BRCA2 (25%), PIK3CA (22%), NTRK1 (19%), BRCA1 (17%), NTRK3 (11%), and BRAF (8%). Three patients had ALK fusion gene, 1 patient had NTRK1 fusion and the other one had NTRK3 fusion gene. Twelve out of 36 patients (33%) had MSI-HI and 56% of patients had TMB ≥ 10 mutations/megabase. The clinical factors significantly correlated with poor overall survival (OS) were unresectable disease, stage IV, bilirubin > 1.2, and CEA ≥ 22.5. The NF1, MTOR, HER2 mutations, and FOXP3-negative in stromal cells were significantly associated with longer OS, whereas EGFR, APC, FGFR2, and BRCA1 mutations might correlated with better OS. Conclusions: Our study demonstrated the unique molecular profile of Thai CCA patients. We found high prevalence of MSI-HI and high TMB in our population, together with the promising potential of targetable genes for developing targeted therapy in the future. FOXP3 expression was probably one of potential predictive biomarker for immunotherapy. Larger cohort should be explored.
Dispersion in total cost of care for Medicare fee-for-service (FFS) patients with metastatic pancreatic cancer receiving FDA-approved/NCCN Category 1 regimens at teaching versus non-teaching institutions.
Authors: Latimer Helen , Tomicki Samantha , Dieguez Gabriela , Cockrum Paul , Kim George P.
Published: June 2021

e16244

Background: Teaching institutions receive additional funding from Medicare & Medicaid Services (CMS) to provide specialized, quality care. Objectives: To analyze the dispersion in total cost of care (TCOC) for Medicare FFS patients (pts) with metastatic pancreatic cancer (m-PANC) treated at teaching (teach) or non-teaching (non-teach) institutions. Methods: We identified pts with m-PANC using ICD-9/10 diagnosis codes in the 2016-18 Medicare Parts A/B/D 100% Research Identifiable Files. Study pts had 2+ claims with a pancreatic cancer diagnosis and Medicare FFS coverage for 6 months pre- and 3 months post-metastasis diagnosis. Study pts were treated with NCCN Category 1 regimens: 1L gemcitabine monotherapy (gem-mono), 1L gemcitabine/nab-paclitaxel (gem-nab), 1L FOLFIRINOX (FFX), and 2L liposomal irinotecan-based regimen (nal-IRI). Pts were attributed to teach or non-teach institutions based on plurality of chemotherapy claims. TCOC reflects insurer-paid services per line of therapy (LOT) for 3 categories: chemotherapy/supportive drugs (chemo/Rx), inpatient care (IP), and other outpatient care (OP). We grouped pts by quartile (qrt), evaluated drivers of TCOC, and mean rates of admissions (admits/pt). Results: We identified 3,908 (teach) and 2,632 (non-teach) pts taking NCCN Category 1 regimens. There was a similar mix of patients in both cohorts, with gem-mono pts making up only 3% of the sample. Gem-nab accounted for 73% and 70% of pts in teach and non-teach institutions, respectively. For gem-nab, FFX, and nal-IRI pts, median TCOC was similar in both cohorts. However, median TCOC for the two non-generic drugs in our study, gem-nab (teach: $36,332; non-teach: $40,135) and nal-IRI (teach: $31,526; non-teach: $39,360), were lower at teach institutions than non-teach institutions. The components of TCOC are similar between teach and non-teach institutions in all qrts. In both cohorts, % IP costs for all regimens increased between the first and fourth qrt (teach:14% to 23%, non-teach:14% to 26%). In the teach cohort, nal-IRI pts had the lowest admits/pt in all qrts. In the non-teach cohort, there was no discernable pattern, although nal-IRI pts had the lowest admits/pt in the second and fourth qrt. Conclusions: For non-generic regimens like nal-IRI and gem-nab, median TCOC was lower at teach institutions than non-teach institutions. There were no consistent differences in TCOC dispersion or admissions between cohorts. Across qrts, chemotherapy accounted for approximately half the TCOC. However, IP costs were proportionally higher in the fourth qrt, especially for non-teach institutions. Despite nal-IRI pts being on the second LOT, both median TCOC and admits/pt across qrts were lower than gem-nab and FFX in teach institutions. In the non-teach cohort, median TCOC were similar among nal-IRI, gem-nab, and FFX.
Anticoagulation outcomes in patients with venous thromboembolism following Whipple surgery for pancreatic cancer: Single center experience.
Authors: Balanchivadze Nino , Purtell James P , Kuriakose Philip , Clark Julie , Springer Kylie , Divine George , Kwon David S. , Dobrosotskaya Irina Y.
Published: June 2021

e16255

Background: Venous thromboembolism (VTE) is a common complication in patients with pancreatic cancer (PC). Incidence of major bleeding and clinically relevant non-major bleeding is 14%-20% in patients with cancer who receive anticoagulation therapy (AT). Whipple procedure is a complex surgical intervention offering potential cure in patients with resectable PC; however, surgery can affect drug absorption, which may reduce effectiveness of AT or exacerbate drug related adverse events. Our aim was to assess incidence of bleeding in PC patients who had whipple procedure with subsequent VTE. Methods: Retrospective analysis of medical records for all adult patients with PC who underwent whipple procedure and developed VTE (between July 1, 2010, and July 1, 2020) at Henry Ford Hospital was performed. Multiple variables and outcomes were analyzed by two-group comparisons, univariate analysis, and Cox regression. Results: A total of 32 patients were included in the analysis. The mean (standard deviation [SD]) age was 67.4 (11 y) years, 16 (50%) patients were men, and 16 (50%) were women, (20 [63%] White; 11 [34%] Black; 1 [3%] Asian). The median Khorana score was 3 (range, 2–4). Of the 32 patients, 6 (19%) had upper extremity VTE, 11 (34%) had lower extremity VTE, 10 (31%) had a pulmonary embolism, 7 (22%) had intra-abdominal VTE, and 7 (22%) had recurrent VTE. All patients with upper extremity VTE had a peripherally inserted central catheter (PICC) or a venous port at the time of VTE diagnosis. Most of the patients (28 or 88%) received AT. Whereas 13 (41%) patients had at least one bleeding episode, 19 (59%) had no bleeding. Twenty-two (68%) patients did not need PRBC transfusion, while 4 (13%) patients required > 4 units packed red blood cell transfusion. No significant association between bleeding and AT was observed ( p = .590). Patients with a bleeding event had lower hemoglobin levels ( p = .030) and were more likely to receive blood transfusion ( p = .005). Cox regression analysis did not show patient age, ethnicity, type of AT used, recurrent VTE, and neoadjuvant chemotherapy treatment to be significantly associated with bleeding or death. A total of 14 (44%) patients were alive at the time of analysis. Conclusions: In patients with PC and VTE who received AT after whipple procedure, the incidence of bleeding was higher than what has been reported in patients with cancer in general, regardless of type of AT administration. Patients with central venous catheters might be at increased risk of upper extremity VTE and this subset of patients may benefit from various risk reducing strategies. Caution is recommended while managing AT in this complex patient population, and more studies are needed to assess factors specifically associated with AT and bleeding after whipple procedure.
Humanized anti-DEspR monoclonal antibody to improve overall survival in xenograft pancreatic peritoneal carcinomatosis nude rat model.
Authors: Gromisch Christopher , Gromisch Matthew Stannard , Grinstaff Mark , Herrera Victoria L.M. , Ruiz-Opazo Nelson
Published: June 2021

e16262

Background: Pancreatic adenocarcinoma (PDAC) with peritoneal carcinomatosis (PPC) has the worst median overall survival (mOS) among all PDAC metastasis. Novel therapeutic approaches are needed for PPC. The Dual Endothelin-1/VEGF-signal-peptide Receptor (DEspR) is a cell surface receptor which regulates PDAC tumor cell and cancer stem-like cell (CSC) anoikis resistance, tumorigenicity, and tumoral angiogenesis. To translate these findings into a novel anti-cancer therapy, we evaluated the efficacy, empirical safety, pharmacokinetics, and pharmacodynamics of a recombinant, humanized, anti-DEspR hinge-stabilized IgG4S228P monoclonal antibody, hu-6g8, in a PPC xenograft tumor nude rat model. Methods: We used a Panc1 CSC-derived xenograft tumor model of PPC developed via intraperitoneal injection of two million Panc1 CSCs functionally isolated for anoikis resistance. Isolated CSCs had variable DEspR expression, thus modeling CSC-heterogeneity. For efficacy studies, PPC-rats were randomized to receive a single intravenous injection of either 3mg/kg or 15mg/kg hu-6g8, 100mg/kg gemcitabine, or saline, given 3 weeks after CSC injection with palpable PPC tumors. Blood samples were collected to monitor for hematological adverse events (AEs) and vital organs were collected to evaluate for hu-6g8-induced apoptosis. Pharmacokinetics was assessed in a separate study cohort by sequential blood draws after rats received a single dose of 3 mg/kg or 15 mg/kg hu-6g8. In a 3rd cohort, pharmacodynamics were assessed by vital organ collection and immunohistochemistry after rats received either a single-iv injection of 3mg/kg hu-6g8 or IgG4 isotype control. Results: Single dose 15 mg/kg hu-6g8 treatment significantly improved median overall survival (189 days, n = 0.0007) with 3 mg/kg hu-6g8 being comparable to 100 mg/kg gemcitabine (92 vs 115 days, n = 0.62). No hematological AEs were observed in hu-6g8 treated rats, and there was no evidence of increased apoptosis by hu-6g8 in normal tissues by immunohistochemistry of activated Caspase-3. Hu-6g8 demonstrated an average elimination half-life of 46.1 hrs in a two-compartment model. Biodistribution of the antibody showed predominant uptake, albeit heterogenous, and induction of activated caspase 3+ apoptosis in the peritoneal tumors by 24-hours with minimal off-target binding. Conclusions: Treatment with monoclonal hu-6g8 significantly improved survival in a model of PCC with excellent tumor specificity and minimal off-target effect.
Detection of FGFR3 alt in plasma cfDNA in metastatic UC patients receiving Erda therapy.
Authors: Sarfaty Michal , Teo Min Yuen , Funt Samuel Aaron , Lee Chung-Han , Aggen David Henry , Ratna Neha , Regazzi Ashley Marie , Lenis Andrew Thomas , Chen Ziyu , Al-Ahmadie Hikmat A. , Brannon Angela Rose , Berger Michael F. , Solit David B. , Rosenberg Jonathan E. , Bajorin Dean F. , Iyer Gopa
Published: June 2021

e16519

Background: The pan-FGFR inhibitor erdafitinib (erda) is FDA-approved for pretreated mUC pts harboring FGFR2/3 alterations. We explored concordance of FGFR3 alt profiles between primary tumor and cfDNA using the next generation sequencing assay MSK-ACCESS. We also correlated changes in FGFR3 cfDNA mutant allele fraction (MAF) with response to erda. Methods: After consent on an approved biomarker protocol, plasma samples were collected from mUC pts on erda at baseline, on treatment (tx), and at progression along with patient clinical characteristics. Baseline tumors were sequenced with MSK-IMPACT and plasma samples sequenced with MSK-ACCESS, a cfDNA platform that sequences select exons and introns of 129 genes and uses unique molecular indexes to detect somatic mutations down to 0.1% MAF. Results: Between 8/2019-12/2020, 18 pts started erda 8mg daily and had plasma drawn for MSK-ACCESS. Three pts increased to 9mg daily, 7 required dose reductions and 10 had dose interruptions. Treatment was discontinued in 13 pts for disease progression and 3 for toxicity. Median PFS was 3.7 months. FGFR3 S249C was the most frequent alt detected (11/18, 61%), then Y373C (3/18, 16%), and R248C (2/18, 11%) (Table). FGFR3 alt were detected in 15/18 (83%) baseline plasma samples, all of which were of the same alt as tumor tissues. In 3 samples, additional FGFR3 alt were detected, including 1 pt with an FGFR3-TACC3 fusion and hotspot mutations found only in cfDNA. FGFR3 MAF decreased in 7 of 9 pts on erda, 2 of whom declined to undetectable levels. Conclusions: A high degree of concordance of FGFR3 alt was observed between primary tumors and cfDNA. Most erda responders displayed reduction of FGFR3 cfDNA MAF. FGFR3 alts exclusive to cfDNA were found in a small subset of pts. Further pt accrual and follow-up are ongoing to assess for correlations between erda response/progression and changes in FGFR3 cfDNA MAF, and to assess whether cfDNA can identify resistance mechanisms.[Table: see text]
Genome-wide circulating tumor DNA monitoring for bladder cancer treatment management and organ preservation.
Authors: Nordentoft Iver , Christensen Emil , Birkenkamp-Demtröder Karin , Deochand Sunil , Maloney Dillon , Lauterman Tomer , Patel Kristofer , Bourzgui Imane , Ramaraj Nidhi , Viborg Lindskrog Sia , Agerbaek Mads , Jensen Jørgen Bjerggaard , Kandasamy Ravi , Tavassoly Iman , Oklander Boris , Zviran Asaf , Dyrskjøt Lars
Published: June 2021

e16527

Background: Bladder cancer (BC) is the 9th most commonly diagnosed cancer worldwide and each year responsible for 165,000 deaths. Neoadjuvant combination chemotherapy, followed by radical cystectomy, is used for the management of localized muscle-invasive bladder cancer. One of the critical challenges in this therapeutic regimen is monitoring the tumor load to assess therapeutic efficacy – this is typically performed by assessing pathological downstaging in the cystectomy specimen. A high frequency of patients presents with T0N0 at cystectomy (no indication of residual disease), and consequently, it is vital to investigate organ preservation approaches to identify those patients who may qualify for bladder preservation. For precision oncology, we need to develop quantitative and non-invasive diagnostic methodologies to help the oncologist tailor the treatments to individual patients and monitor them for further clinical decision-making. Methods: Cell-free DNA (cfDNA) mutation detection has shown significant promise in its ability to monitor minimal residual disease and disease relapse by detection of cancer mutations in the peripheral blood. However, the combination of low tumor fraction and limited input material obtained from a typical plasma sample restricts the probability of detecting low metastatic burden in cfDNA through current deep targeted sequencing methods. Results: Here we present results from applying whole-genome sequencing (WGS) of cfDNA. We integrate a genome-wide mutation and copy number monitoring approach coupled with advanced signal processing and Artificial Intelligence (AI) for measuring the tumor load from low-input blood samples (̃1mL of plasma) with ultra-sensitive detection. The increased sensitivity allowed clinical detection of tumor fraction down to 8*10-5 and recurrence detection sensitivity achieving > 65% at the first two months post-surgery. The WGS cfDNA approach is being evaluated on a patient cohort of more than 50 bladder cancer patients with longitudinal plasma sampling during neoadjuvant chemotherapy (response measure), pre-cystectomy (complete response measure), and post-surgery (relapse monitoring). Conclusions: The results indicate the clinical potential of genome-wide mutation integration as an ultra-sensitive, non-invasive diagnostic method for bladder cancer clinical management and bladder organ preservation.
Plasma and urine free glycosaminoglycans as monitoring and predictive biomarkers in metastatic renal cell carcinoma: A prospective observational study.
Authors: Gatto Francesco , Bratulic Sinisa , Jonasch Eric , Limeta Angelo , Maccari Francesca , Galeotti Fabio , Volpi Nicola , Lundstam Sven , Nielsen Jens , Stierner Ulrika
Published: June 2021

e16540

Background: No liquid biomarkers are approved in renal cell carcinoma (RCC). In metastatic RCC (mRCC), there is a need to predict and monitor response noninvasively to guide the choice of treatment. Urine and plasma glycosaminoglycan (GAGs) profiles – or GAGomes - are promising biomarkers reflective of RCC metabolism. Here, we explored if GAGomes could predict and monitor response noninvasively. Methods: A single-center prospective consecutive series of mRCC patients elected for first-line therapy was enrolled between June 2016 - April 2019 at Sahlgrenska University Hospital, Gothenburg, Sweden. Response was assessed by the investigator as progressive disease (PD) versus non-PD. Plasma and urine GAGomes were measured at treatment start, after 6 weeks, and every 3rd month in a blinded central laboratory. We conducted Bayesian estimation to correlate GAGomes to response and to design GAG scores to classify PD. So-trained GAG scores were validated to predict PD vs. non-PD at treatment start or after 6 weeks. Results: Fifty patients with treatment-naïve mRCC were enrolled (median age: 68.5 years, 33% female). All received tyrosine-kinase inhibitors (37 sunitinib, 4 pazopanib, 9 cabozantinib). The median follow-up time was 3.5 months, totaling 65 response evaluation visits - 23 PD and 42 non-PD. PD was compatible with alterations in 40% of the detectable GAGome features. These were used to design a plasma, urine, and combined GAG progression score to classify PD vs. non-PD at response evaluation. The area-under-the-curve (AUC) was 0.91 in plasma, 0.98 in urine, and 0.99 when combined. In validation, the AUC to predict PD at treatment start was 0.64 in plasma, 0.63 in urine, and 0.71 when combined (N = 50); and, after 6 weeks, 0.75 in plasma, 0.66 in urine, and 0.80 when combined (N = 47). The combined GAG progression score had 62% sensitivity and 86% specificity to PD at treatment start and 67% and 87% after 6 weeks. Conclusions: GAGomes correlated with treatment response in mRCC. GAG scores were validated for the early prediction of response. Their clinical utility remains to be ascertained. Clinical trial information: NCT02732665.
Real-world treatment patterns and overall survival in previously treated advanced renal cell carcinoma patients receiving nivolumab in the UK.
Authors: Waddell Tom , Fife Kate , Griffiths Richard , Sharma Anand , Dhokia Poonam , Gordon Jason , Groves Lara , Hurst Michael , Sugrue Daniel , Tsang Carmen , Mckenna Stephen , Houghton John , Carroll Robert
Published: June 2021

e16561

Background: CheckMate 025 demonstrated favorable efficacy and safety results for nivolumab monotherapy in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, real-world evidence on treatment patterns and clinical outcomes is limited. Methods: This multi-centre, retrospective cohort study examined treatment patterns and overall survival (OS) in aRCC patients treated with nivolumab monotherapy. Eligible patients who initiated nivolumab at second-line (2L) or beyond (index) between 01 March 2016 and 30 June 2018 were sampled from four UK centers. Data were extracted using an electronic case report form from index to earliest of: most recent visit; death; end of follow up (31 May 2019). Results: Overall , 151 patients were included in analyses (mean age at index 66.9 years, 72.2% male, median follow-up from index 15.2 months), with 109 (72.2%) and 42 (27.8%) receiving nivolumab at 2L and ≥ third-line (3L+), respectively. Key clinical characteristics are outlined in Table 1. All 2L nivolumab patients had received first-line (1L) tyrosine kinase inhibitors (TKI), pazopanib (57.8%), sunitinib (30.3%), or both in sequence (10.1%). After 2L nivolumab, 3L cabozantinib (36/52, 69.2%) was most common. Most 3L nivolumab patients received 2L TKI (31/36, 86.1%) - commonly axitinib (70.9%). After 3L nivolumab, most patients received fourth-line cabozantinib (8/12, 66.7%). Median time on line of therapy (LOT) decreased with LOT progression: from 7.8 months at 1L to 4.6 months at fifth-line (5L). The proportion of patients who discontinued treatment due to adverse events decreased by LOT, (28.6%, 22.7%, 16.0% and 0%, and 34.7%, 28.1%, 0% and 0% from 2L to 5L, overall and for nivolumab treatment, respectively). Overall, median OS from nivolumab initiation was 19.2 months [95% CI, 16.9-27.0]. Patients who received 2L nivolumab had longest median OS (23.0 months [95% CI, 17.2, not reached]), comparable to CheckMate 025 (25.8 months [95% CI, 22.2-29.8]). Median OS for 3L+ nivolumab patients was 12.4 months [95% CI, 8.8, 23.2]. Among 2L nivolumab patients, 73.9%, 46.2%, and 33.6% survived 12, 24, and 36 months, respectively. For the same respective timeframes, 52.4%, 24.7%, and 18.6% of 3L+ nivolumab patients survived. Conclusions: This study provides real-world evidence on the characteristics, treatment patterns and effectiveness of 2L or ≥ 3L nivolumab monotherapy in previously treated aRCC patients. OS results from UK routine clinical care were comparable to those found in CheckMate 025.[Table: see text]
First-line therapy in patients with metastatic renal cell carcinoma (mRCC): Results from consecutive patients over 25 years in a single institution.
Authors: Fristrup Niels , Donskov Frede
Published: June 2021

e16574

Background: Immune checkpoint inhibitors (ICI) have demonstrated improved activity in metastatic renal cell carcinoma (mRCC). Real-world data comparing the effectiveness of ICI with interleukin-2 (IL-2) is limited. Methods: We retrospectively assessed consecutive patients with biopsy-proven mRCC at our institution between 1994 and 2020. Patients were classified into four groups based on first-line therapy: vascular endothelial growth factor (VEGF) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, IL-2, or ICI. The primary endpoint was overall survival (OS). Kaplan-Meier method was used to compare OS between treatment groups. We used Cox proportional hazards models to adjust for prognostic covariates. Results: A total of 1424 patients were treated with first line therapy; 51% received VEGF, 3% received mTOR, 40% received IL-2, and 6% received ICI. Median follow-up was 97.6 months. Except for the mTOR group, baseline characteristics were largely balanced between the treatment groups. Median OS in the ICI group compared with IL-2, mTOR and VEGF was 40.1, 17.6, 6.3 and 14.7 months (p < 0.001), respectively, and the 5-year survival rate was 36%, 20%, 9% and 14%, respectively. After adjusting for IMDC and MSKCC individual risk factors, histology, age, gender, year of treatment initiation, low sodium, and location of metastases (lung, liver, bone, lymph node), the hazard ratio (HR) (95%CI) for OS with VEGF as reference was 0.50 (0.33-0.74, p = 0.001) for ICI, 0.81 (0.70-0.92, p = 0.002) for IL2, and 1.09 (0.79-1.52, p = 0.6) for mTOR. Conclusions: In this largest single institution cohort to date, patients with mRCC who received CPI achieved longer OS.[Table: see text]
Combination of immunotherapy and tyrosine kinase inhibitor in first-line metastatic renal cell carcinoma: A real-world Indian experience.
Authors: Rauthan Amit , Patil Poonam , Murthy Nitin Yashas , Somashekhar SP , Zaveri Shabber , Aswath Rajashri , V Prathyush
Published: June 2021

e16576

Background: Immuno-oncology (IO) agents in combination with oral tyrosine kinase inhibitors (TKIs) has become a standard first line therapy in metastatic renal cell carcinoma (mRCC) patients. Various combinations such as pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib and pembrolizumab + lenvatinib have all shown better results than sunitinib. There is very limited data about this from India. Methods: This is a single center, retrospective study of mRCC patients, who received first line treatment was nivolumab or pembrolizumab with axitinib or lenvatinib. The endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AE). Results: Between Jan 2019 to Jan 2021, 22 patients were treated with IO + TKI combination. 12 patients received axitinib, and 10 lenvatinib. Age range was 35 to 78 years with 18 males and 4 females. IMDC risk stratification showed 3 favorable (13.6%), 13 intermediate (59%) and 6 poor risk (27.2%) patients. 2 patients (9%) achieved complete response(CR), 13 (59%) partial response (PR), 4 (18.2%) had stable disease and 3 (13.6%) progressed. The ORR was 68%. Median PFS was 22 months (1 month- 24 months). OS at 1 year was 92%, and median OS was not reached. Grade 3/4 immune related adverse events (AEs) were seen in 3 (14.2%) patients (1 colitis,1 pneumonitis,1 encephalitis), for whom the IO was discontinued. TKI related grade 3/4 AEs were seen in 8 patients (38%), and were managed with dose reductions. Conclusions: Combination IO + TKI is a very effective first line therapy in mRCC. An ORR of 68%, median PFS of 22 months and 1 year OS of 92% is the best we have seen in our patients. The efficacy of this combination is seen in all IMDC subgroups. The combination is well tolerated, and the TKI AEs are comfortably managed with dose reduction. IO combinations should be preferred over single agent TKIs (sunitinib or pazopanib) as first line therapy.
Features of genes copy number in normal, primary tumor, and lymph nodes metastases cells in patients with cervical cancer.
Authors: Kecheryukova Madina M. , Snezhko Aleksandr V. , Verenikina Ekaterina V. , Menshenina Anna P. , Adamyan Meri L. , Ardzha Anna Yu. , Kit Oleg I. , Kutilin Denis S.
Published: June 2021

e17503

Background: Early stages of cervical cancer (CC) can be treated with surgery or radiation therapy, metastatic CC is incurable, and therefore new diagnostic approaches based on highly effective molecular markers are required. As such markers, the Copy Number Variation (CNV) is of great interest. Purpose of the study: to analyze the peculiarities of genes CNV in normal cells, primary tumor and lymph nodes tumor metastases cells in patients with CC. Methods: Tissue sections from FFPE-blocks of 300 patients with CC were used for the study. Primary tumor, tumor metastatic and normal cells were isolated using non-contact laser microdissection (Palm MicroBeam, Carl Zeiss). DNA was extracted from the cells using the phenol-chloroform method. Determination of 14 genes CNV (LAMP3, PRKAA1, TORC2, FOXO3, HDAC5, MEF2C, MLXIPL, EP300, HNF4A, TP53, SREBF1, SREBF2, PPARGC1A, and CCND1) was performed by Real-Time qPCR method. Statistical analysis was performed using the Mann-Whitney test; Bonferroni's correction was applied to correct multiple comparisons. Results: An increase in the CNV of LAMP3 and TORC2 genes by 2.5 and 3.2 times (p < 0.05), respectively, and a decrease in the CNV of TP53 and FOXO3 genes by 2.3 and 2.0 times (p < 0.05), respectively, were found in the primary tumor cells relative to normal cells. The effect of the simultaneous change in the CNV of LAMP3, TORC2, TP53 and FOXO3 genes was observed in 60% of the sample, and LAMP3 and TP53 genes - in 80%. In cells of lymph nodes tumor metastases an increase in the CNV of CCND1 and TORC2 genes by 2.0 and 3.5 times (p < 0.05), respectively, was found, as well as a decrease in the CNV of PPARGC1A gene by 2.1 times (p < 0.05) relative to normal cells. A simultaneous change in the CNV of CCND1, TORC2, and PPARGC1A was observed in 70% of the sample, and CNV of CCND1 and TORC2 genes - in 85%. Primary tumor and metastases cells differed in the CNV of CCND1 (2.5 times higher in metastatic cells), LAMP3 (3.0 times lower in metastatic cells) and FOXO3 genes (2.0 times higher in metastatic cells). Conclusions: Thus, the primary tumor and lymph nodes metastases cells differ in the level of genes CNV from normal cervix cells. Accordingly, the CNV of LAMP3, TORC2, TP53 and FOXO3 genes may have the potential for diagnosing a primary cervical tumor, and the CNV of CCND1, TORC2 and PPARGC1A genes for diagnosing its metastases to regional lymph nodes.
Association of alterations in DNA damage repair and Notch pathways with high tumor mutational burden in patients with cervical cancer.
Authors: Zou Dongling , Li Zirong , Liu Jing , Gao Yunong , Zheng Hong , Yuan Mingming , Wang Haixia , Yuan Li , Wang Dong , Liu Jingshu , Chen Rongrong , Xia Xuefeng , Zhou Qi
Published: June 2021

e17511

Background: The outstanding efficacy of pembrolizumab reported in study KEYNOTE-158 led to FDA approval of pembrolizumab in the treatment of patients (pts) with positive PD-L1 expression (CPS ≥1) cervical cancer (CC) and tumor mutational burden-high [TMB-H, ≥10 mutations/megabase (mut/Mb)] solid tumors including CC. This study aims to investigate the immunotherapy-related molecular characteristics in pts with CC. Methods: The study recruited pts with CC whose tissues were send to perform parallel hybridization-based next-generation sequencing and/or immunohistochemistry of PD-L1 with 22C3 assay. KEGG pathway enrichment analysis was conducted to explore whether the differentiated mutated genes (DMGs) that were more frequently mutated in the TMB-H cohort were enriched in certain pathways. In addition, pair-wise comparison of TMB and PD-L1 was analyzed to identify the proportion of pts who might benefit from immunotherapy. Results: Among 249 pts with TMB evaluated, median TMB was 5 muts/Mb (range: 0 - 58.56 muts/Mb). The prevalence of microsatellite instability was 1.2% (3/255). The threshold of TMB was defined as 10 muts/Mb according to KEYNOTE-158. Consequently, 47 pts were considered as TMB-H and 202 pts were TMB-L. Regardless that TERC amplification was only found in the TMB-L group (9.5%, 19/202), Fisher’s exact test identified 98 genes with significantly higher alteration frequency in the TMB-H group compared with TMB-L group, including MLL2/3, TERT, PIK3CA, LRP1B, EP300 and ARID1A. Pathway enrichment analysis suggested that these DMGs were mainly enriched in mismatch repair, Notch, homologous recombination and Fanconi anemia pathways. There was no evident correlation between TMB and MSI (spearman r=0.2401, p=0.0101). The positivity rate of TMB or PD-L1 was 71.9%. Conclusions: Mutations in DNA damage repair and Notch pathways may explain TMB-H in pts with CC who might may serve as surrogate markers for TMB in CC.