bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative outcomes of minimally invasive and open gastrectomy.
Authors: Glasser Jamie , Schuster Cassandra , Huston Jamie , Shridhar Ravi , Meredith Kenneth Lee
Published: January 2022

271

Background: Gastric cancer(GC) is associated with significant mortality worldwide. Radical gastrectomy with lymphadenectomy is considered the only curative option for GC. Laparoscopic(LG) and more recently robotic(RG) techniques have been developed as a way to potentially decrease the peri-operative morbidity associated with gastrectomy. We sought to compare oncologic outcomes with minimally invasive and open techniques for gastrectomy. Methods: Utilizing the National Cancer Database we identified patients with gastric cancer who underwent gastrectomy. We then stratified technique, RG, LG, or OG. Mann-Whitney U and Kruskal were used to compare continuous variables and Pearson’s Chi-square test was used to compare categorical variables. Unadjusted survival analyses were performed using the Kaplan-Meier method. Multivariate analysis (MVA) was performed to identify predictors of survival. A p < 0.05 was considered significant. Results: We identified 2,530 patients RG, 10,790 in the LG and 25,810 in the OG group with median ages of 66, 66 and 67 years respectively, p < 0.001. There were higher numbers of poorly differentiated tumors in the OG 60% compared to RG (49.7% and LG 49.1%, p < 0.001. Additionally, there were increased numbers of signet ring GC in the OG 16.7%, compared to 13.8% in the RG and 13.8% in the LG, p < 0.001. There were higher numbers of early stage GC’s in the RG and LG compared to more advanced stages (stage II and III in the OG), p < 0.001. RG and LG did demonstrate higher numbers of R0 resections 92.8% and 89.9% compared to OG at 85.2%, p < 0.001. Length of stay was shorter in the RG and LG at 7 (4-10) days compared to 8 days (6-12) in the OG cohort, p < 0.001. Thirty and 90-day mortality rates were higher in the OG (4.3% and 8.3%) compared to 2.1% and 4% in the RG and 2.7% and 5.4% in the LG patients. Median and 5-year survival was higher in the RG (84.7mo and 61%) and LG (90.3mo and 58%) compared to the OG at 48.3mo and 46%, p = 0.001. When adjusted by stage this survival benefit persisted across all stage cohorts (stage 0-1, p = 0.001, stage 2, p = 0.001, and stage 3, p = 0.001). Multivariate analysis revealed that age, sex, Charlson/Deyo score, tumor location, histology, grade, stage, facility volume, and neoadjuvant therapy were all predictors of survival. Conclusions: Robotic and laparoscopic approaches to gastrectomy demonstrate improved median and overall survival compared to conventional open approaches. This benefit was demonstrated across all stages.
Trends in long-term survival after liver resection for gastric cancer liver metastasis: Analysis of a single-center experience over 28 years.
Authors: Ito Hiromichi , Takemura Nobuyuki , Oba Atsushi , Ono Yoshihiro , Sato Takafumi , Inoue Yosuke , Saiura Akio , Takahashi Yu
Published: January 2022

290

Background: While systemic chemotherapy for gastric cancer has evolved significantly in the last decade, the role of surgery for liver metastasis remained controversial. The aims of this study were to examine the trend in outcomes of patients with gastric cancer liver metastasis (GCLM) undergoing resection at our center, and to define the optimal selection criteria for resection. Methods: One hundred and twenty-two consecutive patients who underwent liver resection for GCLMs with curative intent at our institution from 1993 through 2021 were included. The patients were grouped into 2 eras: era I, 1993 to 2010; era II, 2011 to 2021. Our criteria for liver resection included absence of extrahepatic disease, and the limited number of liver metastasis (often 3 or less). Median follow-up was 34 months for all and 71 months for the survivors. Results: There were 63 patients in era I and 59 in era II. The patients in era II received chemotherapy prior to liver resection more often (68% vs 41%, p = 0.004), and their primary tumor was less advanced (T3/4; 66% vs 85%, p = 0.021) with less regional lymph node metastasis (median No. of positive nodes; 4 vs 1, p = 0.034) compared to those in ear I. Median and 5-year disease-specific survival (DSS) were better in era II (not reached, 55%) than in era I (35 months, 35%, p = 0.025). In the multivariate analysis for the entire cohort, elevated CEA (> 50 ng/ml), primary T4, and primary at the proximal stomach emerged as independent factors associated with shorter DSS. Number of these risk factors are highly predictive for long-term survival; among the patients without or with a single factor alone, 5-year DSS was 50%, whereas none of those with multiple risk factors survived beyond 5 years ( p< 0.0001). Conclusions: Long-term outcomes for patients with oligo-GCLM has improved in the modern chemotherapy era. Liver resection should be considered unless they carry multiple risk factors.
DKN-01 and tislelizumab ± chemotherapy as a first-line (1L) and second-line (2L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial.
Authors: Klempner Samuel J , Chao Joseph , Uronis Hope Elizabeth , Sirard Cynthia A. , Kagey Michael , Baum Jason , Song James , Wang Jin , Kim In-Ho , Lee Keun Wook , Oh Do-Youn , Sonbol Bassam Bassam , Wainberg Zev A. , Ajani Jaffer A.
Published: January 2022

292

Background: Despite recent approval of anti-PD-1 antibodies as 1L therapy in HER2(-) advanced GEA, benefit remains modest and limited largely to PD-L1(+) patients (pts), primarily those with combined positive scores (CPS) ≥5. Thus novel therapeutic approaches are needed for this pt population. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated improved clinical outcomes in pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival. Methods: DisTinGuish (NCT04363801) is a Phase 2a single arm 2-part trial; Part A investigated DKN-01 (D) + tislelizumab (TS) + CAPOX as 1L therapy for pts with advanced HER2(-) GEA regardless of DKK1 status; Part B investigated two dosing cohorts of D (300 mg and 600 mg) + TS as 2L therapy for DKK1-high advanced GEA pts. Primary objective was to examine safety and tolerability and secondary objectives evaluated multiple efficacy endpoints including overall response rate (ORR) in a modified intent to treat (mITT) population (>1 dose D). Results: Forty-nine pts enrolled between 01 Sept 2020 and 15 Sept 2021; 25 pts in Part A and 24 pts in Part B (D-300 mg). Key clinicopathologic features and efficacy outcomes are shown in Table. The most common D-related AEs were low grade (G1/2) fatigue, nausea, and diarrhea. Nine pts had D-related ≥G3 toxicities, elevated AST/ALT, elevated alkaline phosphatase, hypophosphatemia, hyponatremia, lymphopenia, neutropenia, diarrhea, vomiting, fatigue all occurring in 1 pt and pulmonary embolism in 2 pts (one G5 event). No new safety signals were observed in Part A or B1. Duration of response (DoR), median PFS and median OS have not been reached for Part A. Last pt enrolled in Part B1 on 15 Sept 2021. Conclusions: The combination of D/TS + CAPOX represents a well-tolerated, active 1L combination, particularly for DKK1-high patients consistent with the proposed mechanism of action. Activity appears to be independent of PD-L1 status. Part B1 is aligned with biomarker enrichment and efficacy and biomarker data will be presented along with updated Part A efficacy data. Clinical trial information: NCT04363801. [Table: see text]
Nivolumab plus ipilimumab in second-line combination therapy for older patients with esophageal squamous cell cancer (AIO-STO-0117 trial).
Authors: Ebert Matthias Philip , Meindl-Beinker Nadja M , Gutting Tobias , Maenz Martin , Betge Johannes , Schulte Nadine , Zhan Tianzuo , Weidner Philip , Hofheinz Ralf-Dieter , Vogel Arndt , Angermeier Stefan , de Wit Maike , Jakobs Ralf , Karthaus Meinolf , Stocker Gertraud , Thuss-Patience Peter C. , Leidig Tobias , Haertel Nicolai
Published: January 2022

303

Background: Overall survival of patients with advanced and refractory esophageal squamous cell carcinoma (ESCC) is poor. Most patients are 65 years or older, present with advanced and metastatic disease and suffer from extensive co-morbidity and decreased functionality. While approved therapies beyond first-line therapy have not been available for decades, just recently treatment with PD-1 antibodies has shown to improve progression-free and overall survival in this patient cohort. Thus, we assessed the combination of nivolumab and ipilimumab in this vulnerable and older patient population. Methods: In this multi-center, open-label phase II trial older patients with ESCC with progression or recurrence of disease following first-line therapy were treated with nivolumab and ipilimumab. Patients had to pass a brief geriatric assessment using the G8 screening tool in combination with the Deficit Accumulation Frailty Index (DAFI). A safety run–in phase was initiated with nivolumab (240mg fixed dose Q2W). Following a safety assessment, patients then went on to receive the combination therapy of nivolumab/ipilimumab (nivolumab 240 mg fixed dose Q2W; ipilimumab 1 mg/kg Q6W), in case safety was critical patients were allowed to continue with nivolumab monotherapy. The primary outcome was overall survival. Progression-free survival, quality of life and adverse events were also assessed. Results: In total 66 evaluable patients (16 female, 50 male) with ESCC were enrolled in this trial after successful geriatric assessment, median age was 70.5 years (range 55-84 years). 44 patients were treated with the combination therapy of nivolumab and ipilimumab, 22 patients with nivolumab only. The primary endpoint was met with a median OS of 7.2 months (95% CI, 5.7 to 12.4 months) (p < 0.006; versus historical control treated with standard chemotherapy). Median PFS was 2.7 months (95% CI, 2.5 to 2.9 months). ORR was 18.2% (95% CI, 9.8 to 29.6), all cases were partial responses. Grade 3 or more treatment related adverse events were observed in ̃25% of patients. Conclusions: The combination therapy of nivolumab and ipilimumab demonstrates improved overall survival and sustained confirmed responses in the second line therapy of older European patients with ESCC. Geriatric assessment is feasible in the setting of a prospective immune therapy trial. Overall, the RAMONA trial confirmed efficacy and safety of combination checkpoint inhibitor therapy in G8 prescreened older patients with ESCC in Europe beyond first line therapy. Clinical trial information: NCT03416244.
Definitive chemoradiotherapy for locoregional recurrence of esophageal squamous cell carcinoma patients after radical surgery: Retrospective study.
Authors: Harada Kentaro , Yamamoto Shun , Ohara Akihiro , Itoyama Mai , Honma Yoshitaka , Kashihara Tairo , Inaba Koji , Ishiyama Koshiro , Oguma Junya , Igaki Hiroshi , Daiko Hiroyuki , Kato Ken
Published: January 2022

314

Background: The prognosis of esophageal squamous cell carcinoma (ESCC) patients with recurrence after radical surgery remains poor, with a median overall survival (OS) of 5-10 months. Locoregional recurrence (LR) have a potential to cure by definitive chemoradiotherapy (dCRT) or surgery. However, there are a few data on clinical outcomes of the patients with LR. We evaluated the efficacy and safety of dCRT for LR after radical surgery retrospectively. Methods: The subjects who had LR after surgery were corrected from medical record between January 2015 and April 2020 in our hospital. LR was defined as recurrence within the regional and supraclavicular lymph nodes after curative surgery. CRT consist of fluoropyrimidine and platinum with radiation at a dose of 50.4-60Gy. Complete response (CR) rate, progression-free survival (PFS), OS, and safety was evaluated. Results: Twenty-five patients who had LR after surgery were analyzed with the median follow-up time of 21.5 (range: 0.47-60.2) months. Patients’ characteristics at the initiation of dCRT were as follows; median age (range): 70 (40-70) years old, male/female: 20 (80%)/5 (20%) patients, PS 0/1/2: 11 (44%)/12 (48%)/ 2 (8%) patients. Chemotherapy regimens were cisplatin and 5-fluorouracil in 23 (92%) patients, nedaplatin and 5-fluorouracil in 1 (4%) patient, and S-1 in 1 (4%) patient. Radiation doses were 60 Gy in 24 (96%) patients and 50.4 Gy in 1 (4%) patient. CR was achieved in 13 (53%) patients. The median PFS was 9.7 (95%CI: 5.6-NA) months, and the median OS was 28.8 (95%CI: 21.2-NA) months. The one-year survival rate was 78.7 (95%CI: 56.1-90.6) % and the three-years survival rate was 25.9 (95%CI: 5.1-54.1) %. Grade 3 or higher adverse events were observed in 3 (12%) patients of neutropenia, in 3 (12%) patients of leukopenia, and in 2 (8%) patients of febrile neutropenia. Treatment-related death due to febrile neutropenia was observed in 1 (4%) patient. No patient presented with severe late toxicity after dCRT. Conclusions: In this study, dCRT for LR after surgery was tolerable and promising efficacy with curative intent.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for unresectable PM from gastric cancer outstanding result from multicenter cohort study.
Authors: Alyami Mohammad , Khomiakov Vladimir , Lintis Alexandru , Piso Pompiliu , Eveno Clarisse , Glehen Olivier ,   ISSPP PIPAC cohort study
Published: January 2022

331

Background: PIPAC is a recent approach for intraperitoneal chemotherapy with promising results for patients with peritoneal metastasis (PM). It is a safe and well-tolerated treatment. Our aim was to report oncological outcomes after PIPAC for gastric PM. Methods: International retrospective cohort study of consecutive patients with gastric PM. Outcome measures were overall survival (OS), radiological response (RECIST), histological response by use of Peritoneal regression grading system (PRGS) and cytology, peritoneal cancer index (PCI) and symptoms. Results: 586 non-selected patients with a median age of 56 (47-64) years, 54% of them were female and underwent a total of 1566 PIPAC procedures. 37% of patients were treated with 2 or more lines of IV chemotherapy, median PCI at first PIPAC was 14 (7-24) and 63% of them were with signet ring adenocarcinoma. Grade III-IV morbidity was 5.1 % and 1.9% died within 30 days from PIPAC procedure. Median OS was 15.4 months from diagnosis and 20.1 months for patient with more than 3 PIPAC. 263/586 patients (44.9%) had ≥3 procedures ( pp: per protocol) with the following outcomes: RECIST: 4.3% complete response 11% partial remission, 44% stable; PRGS1 39% at PIPAC3 and negative cytology at PIPAC3 in 16% of patient. In multivariate analysis, 3 PIPAC or more HR 0.3 (95% CI 0.27-0.51), 2nd and 3rd line of chemotherapy HR 0.48 (95% CI 0.25-0.92) and CRS&HIPEC after PIPAC HR 0.3 (95% CI 0.18-0.51) were predictors for survival. Conclusions: Based on this large multicentre cohort study, PIPAC could be considered as an option for the treatment of PM from gastric cancer. More prospective study will validate this indication in the near future.
CSF-1R inhibitor, pexidartinib, sensitizes esophageal cancer to PD-1 immune checkpoint blockade in a rat model.
Authors: Paskewicz Michael , Omstead Ashten , Zheng Ping , Gorbunova Anastasia , Salvitti Madison , Alleyne Adam , Reed Payton , Ballengee Sydne , Islam Nabeela , Jobe Blair A. , Kelly Ronan Joseph , Zaidi Ali Hussainy
Published: January 2022

333

Background: Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, is a multi-gene tyrosine kinase inhibitor, targeting FLT3, KIT and CSF1R. In particular, pexidartinib by targeting CSF-1R down modulates macrophage mediated pro-survival tumor signaling. Recently, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in multiple solid tumors. Methods: Seventy-two rats underwent an end-to-side esophagojejunostomy to induce gastroesophageal reflux, resulting in EAC carcinogenesis. At 32 weeks postoperatively, tumor bearing animals were randomized to a dose of 30mg/kg of pexidartinib or vehicle control, 5 days on and 2 days off (14 day cycle), for a total of 3 cycles. A PD-1 inhibitor, AUNP-12, at a dose of 3mg/kg or placebo, was administered on day 12 of each cycle. At 38 weeks postoperatively animals were euthanized. Safety and efficacy was evaluated by objective health assessments, pre and posttreatment MRI, RT-PCR, immunofluorescent labeling and a serum cytokine assay. Results: The pexidartinib +/- PD-1 inhibitor (Px+P and Px-P) groups demonstrated no significant difference in daily weight change (p = 0.98) or in mortality (p = 0.59) when compared to vehicle control (V+P and V-P) groups. On post-mortem serum analysis AST (p = 0.01) and ALT (p = 0.001) were elevated, while albumin (p = 0.57) and BUN/creatinine ratio (p = 0.09) were reported within normal ranges, when comparing treatment to placebo groups. Pre to posttreatment, mean MRI tumor volume decreased by 37% and 54% in the Px-P and Px+P animals and increased by 147% and 88% in the V+P and V-P animals, respectively (p = < 0.0001). Overall response rate was 69% and 87% in Px-P and Px+P animals compared to 21% and 13% in V-P and V+P animals, respectively (p = < 0.0001). Downstream gene expression demonstrated upregulation of TNF-α (p = 0.003), IFN-γ (p = 0.002) and IL-6 (p = 0.0001) and downregulation of IL-13 (p = 0.051), IL-10 (p = 0.051), TGF-β (p = 0.024) and Arg-1 (p = 0.0003), in treatment vs. placebo animals. Increased apoptosis (Cas-3 p = 0.0005) and reduced proliferation (Ki-67 p = < 0.0001) were reported in the treatment animals. Higher CD3+CD8+ T cell densities and CD86/CD206 macrophage ratio was reported in treatment groups compared to placebo (p = < 0.0001). Serum cytokine levels significantly displayed upregulation of TNF-α and IFN-γ and downregulation of IL-4 and IL-10 in the treatment animals compared to the placebo. Conclusions: Overall, this study established a promising combinatorial strategy using a CSF-1R inhibitor to overcome resistance to PD-1/PD-L1 axis blockade in an esophageal cancer model, providing the rationale for future clinical strategies.
Applicability of advanced endoscopic balloon-type irreversible electroporation catheter on the esophagus: Preclinical animal study.
Authors: Jeon Han Jo , Choi Hyuk Soon , Park Jin Young , Yoon Ji Young , Park Geon , Sim Jeong Yoon , Bang Eun Joo , Kim Sang Hyun , Lee Kang Won , Lee Jae Min , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai
Published: January 2022

339

Background: Irreversible electroporation (IRE) is a new destructive technique that removes undesirable tissues using an electric field. Main mechanism of IRE is through the creation of permanent, nano-sized pores on the cell membranes, resulting in cell death. It poses, however, one technical challenge as contractions of smooth muscle of the gastrointestinal tract may prevent IRE from effectively electroporate the cell. The present study aims to demonstrate the applicability of this newly designed endoscopic balloon-type IRE catheter in destroying undesired tissues. Methods: The electrical field generated at 1500V with 40 pulses during ablation with the balloon-type catheter in esophagus were simulated using COMSOL Multiphysics. After a pig was anesthetized, a 0.035-inch Jagwire was inserted through the duodenum using a gastroscope. An IRE catheter was then manually advanced into the esophagus along with a guidewire. The fluoroscopy with contrast medium was employed to determine target lesions with clips. Following the sequential ablation along the esophagus, electrical parameters as well as the number of interruptions encountered were recorded. The pigs used in the experiments were sacrificed after 24 hours and tissue specimens obtained were evaluated using H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results: Based on the COMSOL simulation, the heated portion, approximately 57 degrees of Celsius, was observed only at the edge of the electrodes. Fluoroscopy demonstrated the balloon-type catheter was not adjacent to the heart and tightly blocked the lumen of esophagus as it adheres to the mucosal layer during inflation. The IRE catheter was able to overcome muscle contractions during ablative process and deliver all electrical energy of the scheduled sequences. A total of 12 ablations were performed in three pigs, and the success rate of balloon catheter was 91.7% (11/12). Histological slides from H&E staining and TUNEL assay showed nuclei, stained brown, which indicates apoptosis at the ablation site. Conclusions: The IRE balloon-type catheter demonstrated its applicability and effectiveness as an electroporation-based treatment in esophagus as validated in the experimental results. Further studies regarding electrodes improvement to heat-free condition and its safety related assessment would be needed.
CD44v6 high membranous expression as a predictive marker of therapy response in patients with gastric cancer.
Authors: Park Ji-Hyeon , Almeida Gabriela M. , Pereira Carla , Lemos Carolina , Campelos Sofia , Gullo Irene , Martins Diana , Gonçalves Gilza , Leitão Dina , Neto João Luís , André Ana , Borges Clara , Almeida Daniela , Lee Hyuk-Joon , Kong Seong-Ho , Kim Woo Ho , Carneiro Fatima , Almeida Raquel , Yang Han-Kwang , Oliveira Carla
Published: January 2022

342

Background: In gastric cancer (GC), biomarkers that define prognosis and predict treatment response remain scarce. We hypothesized that the extent of CD44v6 membranous tumor expression could predict prognosis and therapy response in GC patients. Methods: Two GC surgical cohorts, from Portugal and South Korea (n = 964), were characterized for the extension of CD44v6 membranous immunoexpression, clinicopathological features, patient survival, and therapy response. The value of CD44v6 expression in predicting response to treatment and its impact on prognosis was determined. Results: High CD44v6 expression was associated with invasive features (perineural invasion and depth of invasion) in both cohorts and with worse survival in the Portuguese GC cohort (HR 1.461; 95% confidence interval 1.002–2.131). Patients with high CD44v6 tumor expression benefited from conventional chemotherapy in addition to surgery (p < 0.05), particularly those with heterogeneous CD44v6- positive and -negative populations (CD44v6_3+) (p < 0.007 and p < 0.009). Conclusions: Our study is the first to identify CD44v6 high membranous expression as a potential predictive marker of response to conventional treatment, but it does not clarify CD44v6 prognostic value in GC. Importantly, our data support selection of GC patients with high CD44v6-expressing tumors for conventional chemotherapy in addition to surgery. These findings will allow better stratification of GC patients for treatment, potentially improving their overall survival.
Association of leptin with migration, invasion, and cancer stem-like properties in gastric cancer cells.
Authors: Park Ki Bum , Chung Kyong-Hwa
Published: January 2022

352

Background: Obesity is a risk factor for various types of cancer, including gastric cancer. Leptin, an adipocyte-derived hormone, may function in stimulating the proliferation of gastric cancer cell. The purpose of this study was to evaluate the role of leptin in gastric cancer. Methods: Leptin level was assessed by ELISA and was compared in obese patients with gastric cancer (n=23) and non-obese patients with gastric cancer (n=23) as a function of their clinicopathological characteristics. Gastric cancer cell lines were studied to investigate the effects of leptin on the Janus kinase/signal transducer and activator of transcription (JAK-STAT) and MEK signaling pathways using wound healing assay, inhibition study, and ELISA. Cancer-initiating cells derived from gastric cancer cell lines were studied to investigate the effects of leptin to the maintenance of stemness and epithelial-mesenchymal transition using invasion assay, RT- PCR, and immunoblotting. Results: Obesity was associated with elevated leptin level and BMI has positive correlation with the leptin level ( p=0.001 for both). Overall survival was not significantly different between the two groups ( p=0.098). Leptin induces the migration and invasion of gastric cancer cells by activating AKT and ERK and up-regulating the expression of vascular endothelial growth factor (VEGF). Pharmacological inhibitors of JAK and MEK signaling pathways decreased both leptin-induced migration and invasion and the leptin-induced expression of VEGF. Leptin increased the mRNA and protein levels of the markers for stemness (CD44) and epithelial-mesenchymal-transition (Snail and N-cadherin). Conclusions: Leptin plays a role in gastric cancer by stimulating the migration and invasion of gastric cancer cells via activating the JAK-STAT and MEK pathways and contributes to the maintenance of cancer stemness and metastatic potential. Leptin presents evidence supporting the adverse effect of obesity in gastric cancer. Treatment targeting leptin-associated signaling pathways could be a potential strategy for managing gastric cancer.
Locally advanced esophageal cancer: Evaluation of prognosis by assessment of the “yp” stage based on the neoadjuvant regimen received.
Authors: Gunadasa Indika , Haydon Andrew , Zalcberg John Raymond , Khu Yin Li , Burton Paul , Brown Wendy
Published: January 2022

356

Background: Neoadjuvant treatment in the form of chemoradiotherapy (nCRT) or chemotherapy (nCT) for resectable oesophageal cancer is the standard of care and improves R0 resection rates and overall survival (OS). The recently reported Neo-AEGIS study demonstrated ongoing equipoise between neoadjuvant chemoradiotherapy and peri-operative chemotherapy for oesophageal adenocarcinoma. There is limited data evaluating the prognostic outcomes by evaluation of the pathological stage after resection (yp stage) based on the neoadjuvant regimen received. The aim of this study was to look at the survival outcomes of patients with oesophageal cancer who received neoadjuvant therapy and to analyze the prognostic significance of pathological stage at surgery (“yp” stage) compared to the clinical stage based on the neoadjuvant therapy received. Methods: This was a single- centre, retrospective study over a fifteen-year period between 2005 and 2019. Consecutive patients with oesophageal and GOJ cancers that underwent resection post neoadjuvant treatment were included. The unit policy was to treat adenocarcinoma of the oesophagus and GOJ with perioperative chemotherapy until 2015 after which it was switched to neoadjuvant chemoradiotherapy in the form of the CROSS protocol. Results: Neoadjuvant treatment with either neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant chemotherapy (nCT) prior to surgical resection was undertaken in 137 patients with resectable oesophageal and GOJ cancers between the years 2005 and 2019. The median age was 65 and 79% of the cohort was male. The majority of tumours were located in the lower oesophagus or GOJ and 96 patients in the cohort were clinical stage 3. 126 patients had adenocarcinoma and 11 patients had squamous cell carcinoma. 72 patients received nCT, and 65 patients received the nCRT. The “yp” stage showed 26 patients achieved a complete pathological response (CPR) and 47 patients were down-staged. The clinical stage was not a predictor of overall survival (p = 0.65). On the other hand, the “yp” stage was a significant predictor of survival (p < 1×10-8). In patients who received nCRT, 18 achieved a complete pathological response compared to 8 patients who had received nCT. Patients who received nCRT showed improved survival compared to patients who received nCT (p = 0.043). Patients who achieved a CPR with neoadjuvant chemotherapy had an OS of 100% compared to OS of 80% in patients who received nCRT (p = NS). Neoadjuvant chemoradiotherapy was associated with less loco-regional recurrences and distant recurrences compared to neoadjuvant chemotherapy. Conclusions: The “yp” stages, as well as down-staging with neoadjuvant therapy are strong predictors of survival. A greater proportion of patients achieved down-staging and CPR following neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy.
Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma.
Authors: Choi Sung Hoon , Kang Beodeul , Cheon Jaekyung , Chon Hongjae , Kim Dae Jung , Kwon Chang-Il , Ko Kwang Hyun
Published: January 2022

387

Background: In a recent phase II trial, nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) demonstrated prolonged survival and unprecedentedly high response rate in patients with advanced cholangiocarcinoma following treatment. We aimed to evaluate the clinical feasibility of this triplet chemotherapy as induction chemotherapy in patients with locally advanced cholangiocarcinoma. Methods: We retrospectively reviewed patients with locally advanced cholangiocarcinoma who were treated with Gem/Cis/nab-P between October 2019 to December 2020. Resectability after induction chemotherapy was evaluated by a multidisciplinary team. Treatment response and surgical pathology were reviewed. Results: Of the 85 patients were included in this study. 46 (54.1%) had measurable lesions. The objective response rate (ORR) and disease control rate in patients with measurable disease were 51.1% and 85.1%, respectively. Fifty-two (61.2%) patients were determined as resectable. Four patients that were judged to be resectable did not undergo surgery due to patient refusal or poor performance status after chemotherapy. Finally, 48 out of 85 patients (56.5%) underwent subsequent curative surgery after induction chemotherapy. There were six complete remission cases (12.5%) in the final pathology, which all reported patients with extrahepatic cholangiocarcinoma. R0 resection was achieved in 46 out of the 48 patients (95.8%). Despite the initial locally advanced cholangiocarcinoma, a pathologic T stage of less than T2 was reported in 44 (95.7%) patients. Lymph node metastasis was confirmed in 13 (27.1%) patients. The overall survival rates in patients who had chemotherapy followed by surgery was better than in those treated with chemotherapy alone ( P = 0.009). Conclusions: Gem/Cis/nab-P as induction chemotherapy showed promising efficacy and clinical feasibility before curative surgery in patients with locally advanced cholangiocarcinoma. This study showed that triplet chemotherapy using Gem/Cis/nab-P has a clear down-staging effect through a high response rate in patients with cholangiocarcinoma
Treatment patterns and clinical outcomes among patients with biliary tract cancers in a large commercially insured US population.
Authors: Valderrama Adriana , Singhal Mukul , Wang Liya , Nepal Bal , Kamble Shital , Grabner Michael , Malhotra Usha , Javle Milind M.
Published: January 2022

398

Background: The American Cancer Society estimates 11,980 new cases of biliary tract cancers (BTCs), including gall bladder and nearby large bile ducts, to occur in the US in 2021. BTCs are characterized by poor prognosis and limited treatment choices. Gemcitabine (GEM) plus platinum chemotherapy is the standard of care. However, there are limited data regarding real-world treatment patterns and clinical outcomes for BTCs patients receiving systemic treatments (ST). Methods: A retrospective cohort study of BTCs patients who received first line (1L) ST, using US private payer Cancer Care Quality Program (CCQP) data and administrative claims from the HealthCore Integrated Research Database (HIRD) between 07/01/2014 - 03/31/2021, was performed. Index date was defined as first claim of ST within 60 days of documented 1L therapy in the CCQP from 01/01/2015 - 09/30/2020. Adult BTCs patients with ≥6 months pre-index enrollment were included. Patients with ampullary cancer, brain/ CNS metastases, other primary cancer before BTCs diagnosis were excluded. Treatment patterns and clinical outcomes were examined. Results: A total of 413 patients [Stage IV (n=315), III (n=44), II/I (n=54)] were identified. The mean (SD) age was 61 (10) years, 55% were female, and there were 67% intrahepatic, 22% gall bladder, and 11% extrahepatic BTCs. There were 150 (36%), 203 (49%), 27 (7%) patients with baseline ECOG scores of 0, 1, 2+, respectively. At pre-index, frequently observed conditions included non-alcoholic liver diseases (75%), hypertension (65%), dyslipidemia (48%), mental health conditions (47%), gallstones (41%), gastrointestinal disorders (39%), and obesity (32%). GEM was commonly used as monotherapy (6%) or in combinations (85%): GEM + Cisplatin (64%), GEM + Oxaliplatin (6%), GEM + Capecitabine (5%), GEM + others (10%). Median overall survival was 11.5 months. The table summarizes clinical outcomes by stage. Conclusions: Most patients with BTCs received 1L GEM-based therapies, experienced poor survival and had high hospitalization rates. These data indicate need for future innovative approaches for management of BTC.[Table: see text]
Pattern and clinical significance of lymph node metastasis from hepatocellular carcinoma.
Authors: Lee Byung min , Choi Jin-Young , Seong Jinsil
Published: January 2022

431

Background: We investigated clinical features and prognostic significance as well as the significance of local treatment on LN metastasis from HCC. Methods: The patients diagnosed of HCC with LN metastasis from 2001 to 2019 were evaluated. The HCC was diagnosed using image study and serum tumor marker based on Korean Liver Cancer Study Group guideline. The LN metastasis was diagnosed in accordance to diagnosis criteria in imaging study. The pattern of LN metastasis was evaluated based on imaging study and stratified by 3 groups: group A, regional LN metastasis group, group B, beyond regional intra-abdomen LN metastasis and group C, extra-abdomen LN metastasis group. Results: A total of 852 patients were included. The local treatment of either resection or RT were performed in 265 patients (31.1%). The OS between 3 groups was significantly different; the 1-year OS was 39.8%, 25.5% and 22.2% for group A, B and C, respectively ( p<0.001). The local treatment group presented favorable features involving better liver function, controlled primary cancer and lesser extra-nodal metastasis than no local treatment group (CP-A: 72.5% vs. 54.2%, control of primary cancer: 44.9% vs. 8.7%, extra-nodal metastasis: 85.3% vs. 52.1%, p<0.001). After propensity score matching (PSM), the features were well balanced between the two groups. The OS was significantly better in the local treatment group even after PSM (1-year OS: 51.8% vs. 26.6%, p<0.001). Local treatment showed superior OS in both LN only metastasis and LN plus extra-nodal metastasis (62.3% vs. 31.6% vs. 45.0% vs. 23.4%, p<0.001). In LN only metastasis patients, the dynamics of disease progression showed no difference between two groups ( p=0.651). Conclusions: This study showed that the survival and pattern of failure were significantly different depending on the location of LN metastasis. In patients with regional LN metastasis, active local treatment would enhance the survival of patients.
Toripalimab plus bevacizumab as first-line treatment for advanced hepatocellular carcinoma: A single-arm phase II study.
Authors: Hao Chunyi , Du Chengyou , Peng Baogang , Zhang Wu , Shan Yunfeng , Lv Ang , Wu Jianhui , Shang Changzhen , Luo Xuan , Wei Jinxing , Xiao Heng , Qiu Jianguo , Hua Yunpeng , Shen Shunli , Wang Ting , Dai Shengjie , Chen Xiang , Yan Shican , Hao Chunyi
Published: January 2022

435

Background: Anti-PD-1/PD-L1 combining with antiangiogenic agents has showed encouraging anti-tumor efficacy for treating advanced hepatocellular carcinoma (HCC). Toripalimab, a humanized monoclonal antibody against PD-1, has already been approved for melanoma, nasopharyngeal carcinoma and urothelial carcinoma in China. Therefore, we aimed to assess the safety and efficacy of toripalimab plus bevacizumab as a first-line treatment for unresectable HCC. Methods: This is a multicenter, single-arm, open-label, phase II study. Patients with unresectable locally advanced or metastatic HCC, BCLC stage C or B, Child-Pugh stage A, ECOG PS ≤ 1, at least one measurable lesion, no prior systemic therapy, were enrolled and treated with toripalimab (240mg, IV, D1) plus bevacizumab (15 mg/kg, IV, D1) every 3 weeks as first-line treatment until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoints were tolerability and objective response rate (ORR, per RECIST 1.1 by investigators). The secondary endpoints included the ORR (per mRECIST by independent review committee), the disease control rate (DCR) and progressive free survival (PFS), DoR, time-to-progression (TTP), time-to-response (TTR) and OS. Tumor response was assessed every 6 weeks. Results: As the data cut-off dateofJune 23, 2021,54 pts were enrolled (males 48; median age 54 years [range 26-68]; ECOG PS 0-1; 87.0% with HBV infection; 74.1% in BCLC stage C; 74.1% had received previous local treatment). All pts received at least one cycle of toripalimab plus bevacizumab treatment with median cycles 10 [range 1-18]. Among 52 evaluable patients, per RECIST v1.1, ORR was 32.7% (17/52) with 1 CR and 16 PR, and DCR was 78.8% (41/52); per mRECIST, ORR was 46.2% (95% CI: 32.2-60.5%) and DCR was 94.2% (95% CI: 84.1-98.8%). The median PFS was 9.9 months (95%CI: 5.5-11.0) and median OS has not reached. Most treatment related adverse events (TRAEs) were grade 1-2. Grade ≥3 TRAEs occurred in 25.9% pts, SAEs occurred in 27.8% pts, and grade ≥3 irAEs occurred in 11.1% pts. No treatment-emergent adverse event (TEAE) leading to death occurred in the study. Conclusions: Toripalimab in combination with bevacizumab as first-line treatment showed promising antitumor activity in patients with advanced HCC, and a manageable safety profile. A randomized phase 3 trial of toripalimab plus bevacizumab versus sorafenib (NCT04723004) are ongoing to further validate the efficacy of combination as first-line treatment in advanced HCC patients. Clinical trial information: NCT04605796.
A retrospective single centre study exploring the efficacy of sequential tyrosine kinase inhibitors (TKI) in patients with hepatocellular cancer.
Authors: Roberts Catherine , Kaina Phillipa , Propper David , Diamantis Nikolaos , Delderfield Rachael , Karuri Alice , Reyes Marilyn , Nijjar Rajinder , Slater Sarah
Published: January 2022

443

A retrospective single centre study exploring the efficacy of sequential tyrosine-kinase inhibitors (TKI) for patients with hepatocellular carcinoma. Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. In the UK patients with advanced or intermediate disease despite locoregional treatments are offered a tyrosine-kinase inhibitor (TKI). Sorafenib (SOR) remains the approved first-line choice, with lenvatinib (LEN) and regorafenib (REG) used as either alternative first line or second line therapies, respectively. Previous studies have shown increased overall survival when comparing a single drug to placebo; however few have studied outcomes for patients treated with one or more TKIs. Methods: Data was collected from patients who received TKI therapy for HCC between January, 2016 and September, 2020, within the Barts Health NHS Trust, London. The Electronic Medical Record system was used to gather information pertaining to treatment. The non-parametric Pearson correlation coefficient was calculated using IBM SPSS software to explore the duration of TKI therapy and overall survival. Results: 64 patients were included in the cohort, 17% (n=11) female, 83% (n=53) were male. Median age was 68 years (range 38 - 92 years) and median survival from diagnosis was 18 months (range 4 - 106 months). 51 patients received one TKI, 12 patients received two and 1 patient received three sequential TKIs There was no significant correlation between the number of cycles of SOR or LEN received and overall survival ( p = 0.387), but there was a statistically significant correlation in the group of patients who received SOR and then REG (rs = 0.973, p = 0.000). There was also a statistically significant correlation (rs = 0.360, p = 0.004) between the cumulative number of cycles of TKI treatment and overall survival for all patients (i.e. SOR only, LEN only and those who received more than one TKI). Conclusions: Our analysis suggests that across the cohort, a longer duration of TKI treatment (measured in cycles) may be associated with increased overall survival for patients with advanced HCC. Further data is required to explore the impact on quality of life during therapy. [Table: see text]
Association of early alpha-fetoprotein response with survival in patients with HBV-related hepatocellular carcinoma receiving lenvatinib.
Authors: Wang Nanya , Shi Jiyu , Liu Bo
Published: January 2022

448

Background: Lenvatinib is a standard first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes to lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels. Methods: This was a retrospective analysis of the medical records of consecutive patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for > 1 month at The First Hospital of Jilin University between November 2018 and May 2021. Early AFP response was defined as a > 20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. We evaluated radiological response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as well as progression-free survival (PFS), and overall survival (OS) in AFP responders and non-responders. Potential prognostic factors for PFS and OS were assessed using univariate and multivariate Cox proportional hazards models. Intergroup differences were compared using a Mann–Whitney U test for continuous variables, a Fisher’s exact test for categorical variables and a log–rank test for survival data. Results: Medical records from 79 patients were screened and a total of 46 patients were included in the analysis; 84.4% had received lenvatinib in first-line, 63% were Child-Pugh class A, 56.4% had extrahepatic metastases, 35.6% had portal vein thrombosis and 10.3% and 87.2% had BCLC stage B and C disease, respectively. Of the 46 patients, 65.2% (n = 30) were early AFP responders and 34.8% (n = 16) were AFP non-responders. Baseline characteristics were balanced between early AFP responders and non-responders, except for age (≥60 years: 43.3% vs. 12.5%; p = 0.0366) and presence of portal vein thrombosis (46.7% vs. 13.3%; p = 0.0277). The median follow-up time was 18.0 (IQR, 3-29) months. Early AFP responders versus non-responders had a significantly higher objective response rate (34.5% vs 6.3%, p = 0.0349), disease control rate (82.8% vs 50.0%; p = 0.0203) and a longer median PFS (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p = 0.028). Multivariate analysis confirmed that early AFP response (HR, 0.366; 95% CI, 0.169-0.795; p = 0.0110), ECOG PS of 0 (HR, 0.497; 95% CI, 0.323-0.877; p = 0.0326) and ALBI grade 1 (HR, 0.411; 95% CI, 0.277-0.863; p = 0.0283) were independent prognostic factors for longer PFS. Conclusions: AFP is an important prognostic factor and a predictive biomarker of survival benefit for patients with HBV-related uHCC receiving treatment with lenvatinib.
Final clinical outcome and biomarker analysis of sintilimab plus a bevacizumab biosimilar (IBI305) for advanced hepatocellular carcinoma: A phase Ib clinical trial.
Authors: Zhang Wen , Gong Caifeng , Bi Xinyu , Xuenan Peng , SUN Yongkun , Wang Yan , Zhou Hui , Zhao Hong , Cai Jianqiang , Zhou Ai-Ping
Published: January 2022

455

Background: The combination of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) antibodies manifested high efficacy in advanced hepatocellular carcinoma (HCC), which still needs to be further verified. We aimed to evaluate the safety and activity of this strategy with different doses, as well as to explore potential predictive biomarkers. Methods: In this two-part phase Ib study, patients with advanced or metastatic HCC were enrolled. Part 1 was dose escalation trial with sintilimab plus bevacizumab biosimilar (IBI305) 7.5 mg/kg (initial dose) or 15 mg/kg (escalated dose). Part 2 was extension in each tolerable dose group. Peripheral blood samples and tumor tissue specimens were collected before treatment to detect serum cytokines and tumor immune microenvironment (TiME) by multiplexed bead immunoassays and multicolor immunofluorescence. Results: Fifty patients were enrolled in final analysis. Among all, IBI305 7.5 mg/kg was administered in 29 patients and 21 patients with 15 mg/kg. The most common adverse event suspected to be treatment-related was hypertension (32%), proteinuria (26%) and fever (26%). The incidence of the grade 3-5 adverse events in group 15 mg/kg was 28.6%, while 13.8% in 7.5 mg/kg group. Overall, the ORR was 34% (17/50) and the DCR reached to 78% (39/50). The median PFS was 10.5 months (95%CI, 8.4-12.7) and the median OS was 20.2 months (95%CI, 16.1 -24.3). The ORR for 7.5 mg/kg and 15 mg/kg were 31% and 38%, respectively. Further analysis showed that responder patients (CR+PR+SD≥12 weeks) had significantly higher level of serum CD137 than those with non-responder group (PD+SD≥12weeks) (median, 32.8 versus 19.8 pg/mL, P = 0.034). Patients with a high level of CD137 ≥ 31.8 pg/mL had longer PFS (mPFS:14.2 vs. 4.1months, P = 0.001) and OS (mOS: NR vs.15.6months, P = 0.023). In addition, the TiME analysis demonstrated that the density of M1 macrophages (CD68+CD163-) in stroma was related to efficacy (P = 0.033), longer PFS (P = 0. 024) and OS (P = 0.046). Conclusions: The sintilimab plus IBI305 is well tolerated and effective, IBI305 of 7.5 mg/kg could be also optional to some patients. The serum CD137 and M1 macrophages are potential predicting biomarkers for the combination therapy Clinical trial information: NCT04072679.