bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment strategy for lateral spreading superficial esophageal squamous cell carcinoma.
Authors: Kawakubo Hirofumi , Suda Koichi , Mayangai Shyuhei , Nakamura Rieko , Wada Norihito , Kitagawa Yuko
Published: January 2019

169

Background: ESD is the one of the options of treatment even for lateral spreading (size is over 5 cm) esophageal squamous cell carcinoma (L-S ESCC). Some patients have to undergo additional treatment because tumor is invaded to submucosal layer or lymphovascular invasion. On the other hand, wide resection by ESD could cause the delay of additional treatment because of the treatment for esophageal stricture after ESD. Thus, treatment strategy for L-S ESCC has to include additional treatment after ESD. Methods: From January 2010 to December 2014, 49 cases of l L-S ESCC were resected by surgery or ESD. Diagnosis, treatment methods and outcomes are evaluated. Results: In 49 cases of L-S ESCC, 32 cases were treated by ESD and 17 case were treated by surgery. Average size of tumor treated by ESD is 59.4 mm(50-85 mm). Accuracy of estimated depth of invasion by endoscopy for ESD cases is 65.7%. Four of 32 cases of ESD underwent additional therapy (3 for surgery and 1 for CRT) because of pT1b (SM2) or lymphvascular invasion, and one case has lymph-node metastasis. Rate of stricture after ESD is 20.0% for sub-circumference ESD and 77.8% for circumference ESD instead of steroid injection. Average time and duration for control of esophageal stricture by Balloon Bougie is 13.5 times and 18 weeks. Average size of tumor treated by surgery is 76.5 mm(50-130 mm). Accuracy of estimated depth of invasion by endoscopy for surgical cases is 47.1%. Seven cases in 17 (41.2%) have lymph node metastasis. One case died by recurrence after surgery and 48 cases were survived without any recurrences. Conclusions: Accuracy of estimated depth of invasion by endoscopy for L-S ESCC is cute low compared to normal superficial ESCC. Most of strictures after sub-circumference ESD could be prevented by steroid injection. However control of strictures after circumference ESD is difficult. Thus, diagnostic ESD should not be performed for circumferencial lesions of L-S ESCC for the patients who will select CRT for additional treatment, and CRT should be selected for first treatment of these cases. Long survival could be obtained by ESD or surgery for the patients of L-S ESCC by our treatment strategy.
Enrollment of esophago-gastric cancer patients in a clinical fast-track program and it’s affect on time to treatment and quality of life.
Authors: Burnett Atuhani S. , Mouhanna Jack , Ramirez-Garcialuna Jose , Lee Emma , Breau Julie , Diovisalvi Mary , Alcindor Thierry , Asselh Jamil , Vanhuyse Marie , Alfieri Joanne , David Marc , Mueller Carmen L. , Spicer Jonathan D. , Cools-Lartigue Jonathan , Ferri Lorenzo
Published: January 2019

180

Background: Esophago-gastric cancers are aggressive malignancies requiring numerous investigations to plan complex multi-modal therapy. The path from initial diagnosis to treatment can be associated with a long delay. This delay and complex patient trajectory may impact quality of life. Given the poor prognosis and highly symptomatic nature of upper GI cancer, a clear and timely access to treatment of crucial importance. We sought to determine the impact of a newly implemented streamlined and structure interdisciplinary pathway for newly diagnosed esophageal and gastric cancer on access times to treatment and quality of life (QoL). Methods: A streamlined pathway for patients referred to a high volume Upper GI Cancer clinic was generated with input from physicians, nutritionists, specialized nurses, and social workers. New diagnosis of esophageal or gastric cancer from 2014-16 were enrolled in this program and consenting patients completed serial QoL questionnaires (ESAS) at baseline, pre-treatment, 1 month post treatment. Dysphagia (DS) was quantified on a 5 point scale. Time intervals (days) were evaluated at various points between diagnosis and start of treatment (diagnosis, CT imaging, first visit with upper GI program, start of treatment). Data presented as median(IQR), * p < 0.05. Results: Of the 251 patients with Upper GI cancer, 153 (61%) consented to participate including 140 esophageal/EGJ and 13 gastric cancer patients. Clinical stage distribution was 17.9% I, 30.7% II, 42.6% III, 8.7% IV. Of the 82 Esoph/EGJ patients with completed QoL questionnaires, 15 (18.3%) patients had severe dysphagia (DS = 3-4) and were prioritized for treatment. Patients with severe dysphagia had reduced time from index endoscopy to treatment (29 (16.3-39.3) vs 43 (32.8-68.0)days)* and first Upper GI clinic to treatment (15 (8.0-23.0) vs 25 (21.0-36.0)*. ESAS surveys showed increased QoL for both patients with and without dysphagia from baseline to pre-treatment indicating that simply entry into the streamlined program improved QoL. Conclusions: Structured interdisciplinary investigative and treatment programs for upper GI cancers can expedite time to treatment and improve QoL.
Randomized phase III study of gemcitabine plus S-1 combination therapy versus gemcitabine plus cisplatin combination therapy in advanced biliary tract cancer: A Japan Clinical Oncology Group study (JCOG1113, FUGA-BT).
Authors: Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Katayama Hiroshi , Ueno Makoto , Ikeda Masafumi , Ozaka Masato , Sugimori Kazuya , Fukutomi Akira , Hara Hiroki , Mizuno Nobumasa , Yanagimoto Hiroaki , Sano Keiji , Tobimatsu Kazutoshi , Yane Kei , Nakamori Shoji , Sata Naohiro , Yukisawa Seigo , Ishii Hiroshi , Furuse Junji ,   Japan Clinical Oncology Group (JCOG)
Published: January 2019

205

Background: Gemcitabine (GEM) plus cisplatin (GC) is the standard of care for advanced biliary tract cancer (BTC). However, GC is considered to be toxic because of nausea, vomiting, and appetite loss, and inconvenient due to requiring hydration before and after administration. GEM plus S-1 (GS) was reported to be promising with preferable efficacy and acceptable toxicity profile (UMIN000001685). This phase III study aimed to confirm the non-inferiority of GS to GC in terms of overall survival (OS). Methods: Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable biliary tract adenocarcinoma (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), an ECOG-PS of 0–1, and adequate organ function. In the GC arm, 1 g/m2 of GEM and 25 mg/m2 of cisplatin was infused on days 1 and 8 of a 21-day cycle. In the GS arm, 1 g/m2 of GEM was infused on days 1 and 8, and S-1 60, 80, or 100 mg/day according to body-surface area was administered from days 1 to 14 of a 21-day cycle. The primary endpoint was OS and the secondary endpoints included progression-free survival (PFS), response rate (RR), adverse events (AEs), clinically relevant AEs defined as any of grade 2 or more fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea. The sample size was calculated to be 350 with a one-sided alpha of 5%, a power of 80%, non-inferiority margin of 1.155 in terms of hazard ratio (HR). Results: From May 2013 to March 2016, 354 patients were enrolled. The non-inferiority of GS to GC was demonstrated (median OS: 13.4 months (m) in GC and 15.1 m in GS, HR 0.95; 90% confidence interval (CI), 0.78 to 1.15; P = 0.046 for non-inferiority). Median PFS was 5.8 m in GC and 6.8 m in GS (HR 0.86, 95% CI, 0.70-1.07). RR was 32.4% in GC and 29.8% in GS. Preliminary AEs data demonstrated that both treatments were generally well tolerated, although clinically relevant AEs were observed 34.7% in GC and 31.2 % in GS. Conclusions: GS demonstrated non-inferiority to GC in OS with good tolerability and was considered as new convenient option of standard of care without hydration for advanced BTC. Clinical trial information: UMIN000010667.
Genomics-driven precision medicine for advanced pancreatic ductal carcinoma (PDAC): Early results from the COMPASS trial (NCT02750657).
Authors: Aung Kyaw Lwin , Fischer Sandra , Denroche Rob , Jang Gun Ho , Dodd Anna , Creighton Sean , O'Kane Grainne M. , Albaba Hamzeh , Moura Shari , Holter Spring , Moffitt Richard , Yeh Jen Jen , Krzyzanowski Paul , Dhani Neesha C. , Hedley David W. , Notta Faiyaz , Wilson Julie , Moore Malcolm J. , Gallinger Steven , Knox Jennifer J.
Published: January 2019

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Background: COMPASS is a prospective study with the primary aim to identify predictive mutational and transcriptional features in advanced PDAC for improved patient stratification and treatment selection. Methods: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy for whole genome sequencing (WGS) and RNA sequencing (RNASeq). Fresh tumor tissue was acquired by image guided percutaneous core needle biopsy of locally advanced primary or metastatic tumors. Laser capture microdissection was performed for all cases to ensure high-resolution genomic analyses. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results: Of 63 patients who underwent a tumor biopsy between December 2015 and June 2017, WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Three patients with an ‘unstable’ genomic subtype, including two with a novel ‘duplicator’ phenotype, responded well to m-FOLFIRINOX. Of two cases with the same germline BRCA2 mutation, only the chemotherapy responder had loss of heterozygosity and genomic hallmarks of double stranded break repair deficiency. Approximately 25% of tumors displayed the basal-like RNA expression signature and these were chemotherapy resistant, with tumor shrinkage mainly observed in those with the classical RNA subtype (P = 0.003). Thirty percent of patients had potentially actionable genetic alterations. Conclusions: Prospective comprehensive genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes providing the impetus for further studies. Clinical trial information: NCT02750657.
A randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study.
Authors: O'Reilly Eileen Mary , Oh Do-Youn , Dhani Neesha , Renouf Daniel John , Lee Myung Ah , Sun Weijing , Fisher George A. , Hezel Aram F. , Chang Shao-Chun , Vlahovic Gordana , Takahashi Osamu , Yang Yin , Philip Philip Agop
Published: January 2019

217

Background: Durvalumab (D) and tremelimumab (T), monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, have shown efficacy as monotherapy/combination therapy in multiple cancer types. Herein, we report a randomized phase 2 study to evaluate efficacy and safety of D monotherapy with or without T (D+T) in previously treated mPDAC. Methods: Part A was a lead-in safety and signal-seeking study with plans to expand to Part B as a nonrandomized or randomized controlled study pending efficacy signal. Eligible pts had progressive disease (PD) following front-line 5-FU- or gemcitabine-based therapy. In Part A, pts were randomized to D (1.5 g IV Q4W) or D+T (D 1.5 g IV + T 75 mg IV Q4W × 4 doses → D 1.5 g IV Q4W) for up to 12 months (mo) or until confirmed PD or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate per RECIST 1.1. Results: In Part A, 65 pts were randomized to D (n = 33) or D+T (n = 32). Due to a pretreatment death, 64 pts received therapy. Eleven pts (34.4%) in D+T and 10 (31.3%) in D had treatment-related adverse events (trAEs); 7 (22%) in D+T and 2 (6%) in D had grade ≥3 trAEs. Common trAEs: fatigue (12.5%), diarrhea (12.5%), and hypothyroidism (9.4%) in D+T; fatigue (9.4%), diarrhea (6.3%), and pruritus (6.3%) in D. Grade ≥3 trAEs were diarrhea (9.4%), fatigue (6.3%) in D+T and ascites (3.1%), hepatitis (3.1%), and increased lipase (3.1%) in D. In D+T, 3 (9.4%) pts and 1 (3.1%) in D discontinued therapy due to trAEs. No trAEs resulted in death. In D+T, 1 (3.1%) pt had a durable confirmed partial response (PR) > 12 mo and disease control rate (DCR) was 9.4%. In D, 2 (6.1%) pts had unconfirmed PRs, and the DCR was 6.1%. Median PFS in both arms was 1.5 mo, and median OS was 3.1 mo in D+T and 3.6 mo in D. Biomarker analyses (tumor mutation burden, PD-L1 and microsatellite status) are currently being evaluated. Conclusions: Typical safety profiles were observed for D or D+T in mPDAC. Part B was not enrolled as the threshold for efficacy was not met in Part A. D and D+T had modest activity in second-line non-selected mPDAC, underpinning the need for multimodal immune-based combinations to overcome intrinsic resistance in this disease. Clinical trial information: NCT02558894.
High neutrophil-to-lymphocyte ratio as an independent adverse prognostic factor in racial minorities with hepatocellular carcinoma.
Authors: Thibaud Santiago , Aparo Santiago , Chuy Jennifer W. , Kaubisch Andreas
Published: January 2019

218

Background: An elevated neutrophil-to-lymphocyte ratio (NLR) has been shown to portend poor prognosis in various types of cancer, including hepatocellular carcinoma (HCC). However, studies that evaluated the prognostic significance of NLR did not include large numbers of Blacks and Hispanics. This single-center, retrospective study conducted on a large, racially diverse cohort explores the utility of NLR in predicting outcomes in minority populations. Methods: We identified patients (pts) diagnosed with HCC at our institution between the years 2000 and 2016. We calculated NLR at the time of diagnosis and divided pts into two groups: high NLR (NLR > 3) and low NLR (NLR ≤3). Demographics, clinical characteristics, MELD/MELD-Na scores, ALBI scores and AFP levels were collected. Survival analysis was conducted using the Kaplan-Meier method. Cox proportional-hazards model was used for multivariate analysis. Results: 751 pts with HCC were included in this study. 542 (72%) were male. Median age was 61 years. 43% were Hispanic, 33% Black, 22% White and 2% Other. NLR was high in 246 pts (32.7%, mean 6.0 ± 3.8) and low in 505 pts (67.2%, mean 1.69 ± 0.7). Overall survival (OS) was significantly lower in the high NLR group (median survival 25.4 vs 49.6 months, HR 1.75, 95% CI 1.41-2.17, P < 0.01). Subgroup analysis showed differences remained significant in the Hispanic group (n = 259, HR 1.93, 95% CI 1.30-2.86, P < 0.01) and the Black group (n = 194, HR 1.99, 95% CI 1.28-3.09, P < 0.01). The high NLR group had significantly higher MELD scores (mean 12.1 ± 5.0 vs 10.1 ± 3.8, P < 0.01), MELD-Na scores (13.9 ± 5.6 vs 11.3 ± 4.4, P < 0.01), ALBI scores (-2.05 ± 0.7 vs -2.28 ± 0.6, P < 0.01) and AFP levels (median 28.9 vs 46.9, P = 0.02). An NLR > 3 on multivariate analysis remained significantly associated with worse OS (HR 1.31; 95% CI 1.03-1.68; P = 0.02) after adjusting for age, gender, AFP and MELD-Na. Conclusions: NLR > 3 at the time of diagnosis had a strong correlation with poor OS in a large, racially diverse cohort of pts with HCC. This correlation held true for both Hispanic and Black patients, who have been previously underrepresented in similar studies. Our findings support the utility of NLR as a prognostic tool in HCC.
SMAD4 mutation acquisition in the metastatic transformation of pancreatic cancer.
Authors: Grewal Amardeep , Ben-Josef Edgar
Published: January 2019

227

Background: SMAD4 mutations have been associated with worse prognosis and metastatic disease in patients with pancreatic cancer. It is unknown whether pancreatic cancers that metastasize acquire this mutation at disease onset or closer to the time of metastatic progression. Methods: Biopsies from 26 patients with known resectable and unresectable pancreatic cancer were analyzed via next generation DNA sequencing for 153 mutations associated with solid tumors, including SMAD4. Imaging and clinical data regarding extent of disease were reviewed at the time of each specimen collection. Results: 46% of patients had metastatic disease at the time of initial biopsy, and of these patients 83% had detectable SMAD4 mutations. Amongst patients with no evidence of metastatic disease, 11 of 14 had intact SMAD4. SMAD4 mutations were associated with metastatic spread of disease, Χ2= 7.46, p = .006. Eight patients with localized, SMAD4 intact pancreatic cancer had repeat biopsies at the time of metastatic progression that showed SMAD4 mutations not previously identified at the time of diagnosis. 2 of 3 patients with SMAD4 mutations and localized disease at diagnosis, developed metastatic disease within 7 months of biopsy. Mean time to metastatic disease development in localized disease patients with mutated and intact SMAD4 were 3.15 and 17 months, respectively, p = .01. Mean CA 19-9 levels in patients with mutated and intact SMAD4 were 10172 and 4117 U/mL, respectively, p = .04. Non-metastatic patients with SMAD4 mutations who developed metastatic disease shortly after initial biopsy only developed rising CA 19-9 levels once radiographic metastases were visible. Conclusions: SMAD4 mutations were ultimately acquired by each patient who presented with localized disease and then developed metastases, and are likely involved in the transformation from localized to metastatic disease. SMAD4 mutations are statistically associated with an earlier time to metastatic disease development in patients with localized disease at diagnosis. SMAD4 mutations precede CA 19-9 elevations in patients that develop metastatic disease and may represent a more sensitive biomarker to identify patients at greater risk for developing metastatic disease.
Discovery and validation of a quantitative, stromal-associated imaging biomarker of pancreatic ductal adenocarcinoma (PDAC).
Authors: Zaid Mohamed , Chaudhury Baishali , Varadhachary Gauri R. , Katz Matthew H. G. , Herman Joseph M. , Tamm Eric P. , Koay Eugene Jon
Published: January 2019

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Background: As pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, biomarkers are needed to identify patients who may benefit from specific therapeutic strategies. We previously described a qualitative computed tomography (CT) based biomarker - delta classification, whereby high delta tumors showed lower stromal content, more aggressive biology and poorer outcomes, than their counterparts. Here, we describe a quantitative method to differentiate these patients and predict outcomes. Methods: We retrospectively identified 101 treatment naïve patients who underwent pancreatectomy as a discovery cohort and 90 patients who underwent preoperative gemcitabine-based chemoradiation for validation. All patients underwent a pre-therapy pancreatic protocol CT and were classified as high or low delta, as described before. We semi-automatically segmented the tumors, chose normal pancreatic (NP) tissue and abdominal fat as references, then measured relative enhancement values using Philips IntelliSpace8 multimodality tumor tracking. We then analyzed the arterial and portal-venous phases separately using ROC and cox proportional hazards. Results: Delta class significantly associated with normalized enhancement values (NEV) in the arterial phase referenced to NP (P<0.0001, AUC =90%). A cutoff of 0.72 was identified that also distinguished high and low delta groups in the validation cohort (P<0.0001). As a continuous variable, the NEV was associated with distant metastasis free survival (DMFS) and overall survival (OS) on uni and multivariate analyses, accounting for traditional survival covariates. Using cutoff of 0.72, patients with high NEV had longer median OS (39 and 35.9 months) compared to those with low NEV (17.5 and 17.6 months, P=<0.0001) in discovery and validation cohorts, respectively. Similarly, patients with high NEV had longer median DMFS (46.6 and 62.2 months) compared to those with low NEV (15.6 and 13.1 months, P=0.005) in discovery and validation cohorts, respectively. Conclusions: The NEV measurement on baseline CT scans may serve as a quantitative imaging biomarker that can objectively reflect tumor biology and provide prognostic insight.
Clinical prognostic impact of depth and pattern of CA19-9 response at 8 weeks of 1st line gemcitabine based chemotherapy in metastatic/unresectable pancreatic adenocarcinoma.
Authors: Kim In-Ho , Jeong Eun-gyo , Jeong Jae kyun , Lee Myung Ah
Published: January 2019

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Background: To evaluate the prognostic impact of depth and pattern of carbohydrate antigen (CA19-9) response at 8 weeks of first-line gemcitabine based chemotherapy in metastatic/unresectable pancreatic adenocarcinoma. Methods: We retrospectively analysed 183 patients who received first-line palliative gemcitabine based chemotherapy. The patients were stratified into 4 groups according to CA19-9 response: group A was defined as above 50% decrease, group B was below 50% decrease, group C was below<50% increase, and group D was above 50% increase in CA19-9 levels. Overall survival (OS) and progression-free survival (PFS) were compared according to CA19-9 response. Results: The CA19-9 response at 8 weeks after gemcitabine based chemotherapy was significantly associated with OS and PFS (median OS and PFS: 13.2 and 6.7[group A], 10.2 and 5.4[B], 6.5 and 3.8[C], and 3.5 and 1.8[D] months, respectively; all P<0.001). For responding group (A&B), group A showed better OS and PFS than group B (all P<0.001). For non-responding group (C&D), group D showed poorer OS and PFS than group C (all P<0.001). In radiologic responding group, complete and partial response by RECIST, group A&B showed better OS and PFS than group C&D (OS,P=0.001; PFS,P=0.003). Moreover, group A had better survival outcome than group B (OS, 14.5[A] vs 11.6[B] months,P=0.011; PFS, 8.6[A] vs 5.6[B] months,P=0.025). In stable or progressive disease by RECIST, OS was significantly prolonged in group A&B than group C&D (OS, 6.5 vs 3.7 months,P=0.038). Group D showed poorer OS than group C (OS, 4.2 vs 2.3 months,P=0.027). The CA19-9 response was a powerful prognostic factor for all patients in responding and non-responding by RECIST. Conclusions: The depth of CA19-9 response at 8 weeks of 1st line gemcitabine based chemotherapy can be a powerful prognostic factor in pancreatic cancer. It also can be a prognostic factor in patients with same response on imaging study by RECIST.
Prospective evaluation of slow-pull with fanning technique in EUS-guided fine needle aspiration on pancreatic masses.
Authors: Lee Jae Min , Lee Hong Sik , Choi Seong ji , Min Geeho , Kim Woojung , Lee Jung Min , Kim Seung Han , Choi Hyuk Soon , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Chun Hoon Jai , Kim Chang Duck
Published: January 2019

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Background: Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) is useful in obtaining pancreatic mass samples. Combination of modified techniques (slow-pull technique and fanning technique) may improve the sample quality obtained by EUS-FNA. We investigated the effectiveness of a slow-pull with fanning technique in EUS-FNA for pancreatic mass. Methods: This prospective comparative study investigated EUS-FNA for pancreatic solid masses from August 2015-July 2016. The pairwise specimens were alternately obtained using two techniques: standard suction or slow-pull with fanning for target pancreatic lesions. We compared the specimen quality, blood contamination, and diagnostic yield of these techniques. Results: Forty-eight consecutive patients were enrolled (29 men; mean age, 68.1±11.9 years), and 96 pancreatic mass specimens were obtained. The slow-pull with fanning technique had significantly superior diagnostic accuracy than the suction technique (88% vs. 71%, p = 0.044). Further, blood contamination significantly reduced when the slow-pull with fanning technique was used (ratio of no or few contamination, 77% vs. 56%, p = 0.041). In the subgroup analysis, tumor size and sampling technique were related to EUS-FNA diagnostic accuracy. Conclusions: The slow-pull with needle fanning technique showed a good diagnostic yield for EUS-FNA for pancreatic mass. It can be useful in performing EUS-guided sampling for diagnosing pancreatic disease.
A sensitive biomarker panel to distinguish pancreaticobiliary malignancies from benign disease.
Authors: Burnett Atuhani S. , Ajibade Dare , Peters Stephen , Ahlawat Sushil , Mahmoud Omar , Chokshi Ravi
Published: January 2019

238

Background: Biliary strictures present a diagnostic challenge to differentiate benign disease from hepatopancreaticobiliary (HPB) malignancies. Cytology from Endoscopic retrograde cholangiopancreatography (ERCP) or Endoscopic ultrasound with fine needle aspiration (EUS-FNA) have both been plagued by poor sensitivity and high false negative rates. In a review of over 80 adjunct molecular biology tests that have been attempted on ERCP and EUS-FNA samples, four immunohistochemistry biomarkers with sensitivities ranging 74-80% were identified; von Hippel Lindau loss of expression (VHL), over-expression of insulin-like growth factor 2 mRNA-binding Protein 3 (IMP3), and EF-hand Calcium 2+ binding S100 subfamily members A4 (S100A4) and P (S100P). We sought to determine if these results could be validated in a tumor explant model and furthermore if combining these tests into a biomarker panel could boost overall diagnostic sensitivity to 100%. Methods: Tumor tissue and normal surrounding pancreas from 27 pancreaticoduodenectomy specimens were selected by an experienced pathologist, subjected to immunohistochemistry staining with VHL, IMP3, S100A4, S100P, and the intensity and percent of cells staining was graded. Using ROC curve analysis, threshold criteria were chosen for each biomarker to differentiate between tumor and normal pancreas. Biomarkers were then evaluated as a panel for their ability to discriminate malignant from benign specimens. Results: Individual sensitivity of VHL, IMP3, S100A4, and S100P were found to be 75.0%, 79.2%, 45.8%, and 0%. When VHL, IMP3, and S100A4 were grouped into a panel, they were able to distinguish cancer from normal tissue with a sensitivity of 100% and a specificity of 96%. S100P was dispensable in our assay and only VHL, IMP3, and S100A4 staining were required to achieve 100% sensitivity. Conclusions: A panel of three biomarkers, VHL, IMP3, and S100A4, were able to distinguish pancreatic cancer from surrounding normal tissue with 100% sensitivity in our tumor explant model. Prospective studies on patient biopsy specimens are required to further validate the clinical use of this biomarker panel.
Introduction of #PancChat: A novel Twitter platform to inform and engage the pancreatic cancer community.
Authors: Ocean Allyson J. , Gusani Niraj Jaysukh , Beg Muhammad Shaalan , Maitra Anirban , Viana Julissa , Rosenzweig Allison , Zelada-Arenas Fatima , Whiteley Andrew , Huneke Cassie , Gavin Cindy Price , Randel Susan , Frame Lisa M
Published: January 2019

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Background: Twitter provides a platform for health care stakeholders to disseminate information about diseases to patients, caregivers, and doctors. Chats are especially effective because participants can interact directly with experts. Pancreatic cancer (PC) conversations on Twitter previously were sporadic and inconsistent. The authors report the creation of #PancChat, a first-of-its-kind Tweet Chat developed to provide relevant, credible, and timely information to the PC community. A collaboration between leading PC organizations, a pharmaceutical company, and an academic oncologist, PancChat is an example of successful outreach using an accessible communications tool. Methods: Launched in April 2016, the hour-long monthly chat is a live event publicized and promoted through multiple social media channels and major news outlets. It is moderated and focused around a pre-selected topic. The hashtag #PancChat is used to filter specific chatter into a single conversation. Participants include patients, caregivers, physicians, researchers, top ASCO social media influencers, AACR members, and advocacy organizations. Moderators and participants are drawn from 23 academic institutions. The PancChat team corresponds with participants and replies to tweets that are not addressed during the chat. Results: Since its inception, PancChat has had a total of 28 million impressions (the total number of times each tweet is seen) from 16 chats, averaging 1.75 million per chat. Popular topics include clinical trials (1.4 million), familial/hereditary PC (2.9 million), and early detection (2.2 million). The average engagement rate is 72% which measures how much people interact with a tweet by clicking or sharing links. From April 2016-August 2017 there were 8,502 tweets using #PancChat. Conclusions: Impression and engagement numbers show that this novel PancChat platform fulfills a need for the PC community. The narrow focus of each chat provides an opportunity to learn about the disease, research, and clinical trials. Participants return knowing that they will interact with PC experts. The popularity of PancChat among patients and doctors confirms the power of social media to reach a specific community.
Skeletal metastases in advanced pancreatic ductal adenocarcinoma (PDAC): A retrospective analysis.
Authors: Puri Akshjot , Chang John , Dragovich Tomislav , Lucente Patricia , Kundranda Madappa N.
Published: January 2019

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Background: Skeletal metastasis (SM) in advanced PDAC is an infrequent occurrence and has been previously reported to be < 2.5%. However; pathological fractures in these patients can result in intractable pain, immobilization and a significant deterioration in quality of life. Methods: A retrospective analysis was conducted of patients (pts) with advanced PDAC receiving palliative chemotherapy. Data collection included age, gender, ECOG, sites of disease, and overall survival (OS). Statistical analysis included Kaplan Meier survival analysis. Results: The 135 pts included had a median age of 65.8 years (range: 53.7–91.3); 5 (31.2%) were women and 11 (68.7%) had an ECOG performance status of 0 or 1. A majority of patients received combination therapy that was either gemcitabine or 5-flurouracil based. Sixteen pts (11.8%) had skeletal metastasis with the primary tumor located in the pancreatic body/tail (11 pts - 68.7%).The sites of SM included thoracic vertebrae (8), lumbar vertebrae (5), pelvis (5), ribs (4), sacrum (4), scapula (3), acetabulum (2), cervical vertebrae (2), femoral head (2), sternum (1) and humerus head (1). A majority of the lesions were osteolytic (62.5%) with a median time of diagnosis of SM from initial diagnosis being 1.25 months (range 0-33). Bone pain was observed as the initial symptom in 5 pts (32%), 1 pt (6.2%) had a pathological fracture. The mOS for patients with SM was 6.5 months (range 0-38) when compared to 8 months (range 0-147) without SM.The mOS for pts treated with gemcitabine based regimen was 5.75 months (range 2.5-14), and patients who received multiple lines of therapy including gemcitabine and 5-FU based regimens was 15 months (range 5-38). Survival from onset of skeletal metastases ranged from 0-14 months (mOS: 4 months). Conclusions: More effective systemic therapies which improve mOS are likely to result in increased incidence of SM. The most common sites observed were the thoracic and lumbar vertebrae and pathological fractures in these sites can be catastrophic. Therefore careful evaluation of skeletal signs and symptoms, early detection and intervention will be important to prevent morbidity and mortality from pathological fractures.
Relationship between ethnicity and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib (S).
Authors: Meyers Daniel E. , Lee-Ying Richard M. , Alghamdi Mohammed Abdullah , Cheung Winson Y. , Samawi Haider , Tam Vincent C.
Published: January 2019

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Background: The SHARP and Asia Pacific (AP) trials showed that S improves OS compared to placebo in advanced HCC. However, OS was worse in the AP trial which included predominantly Asian patients. It is unclear if ethnicity, or perhaps Hepatitis B (HBV) infection, is a poor prognostic factor for these patients. The purpose of this study was to determine whether ethnicity affects OS in patients with advanced HCC being treated with S. Methods: All patients treated with S for HCC in Alberta, Canada from 01/2008 to 07/2016 were included. Patient demographics and clinical/pathological variables were retrospectively collected. Patients were dichotomized by ethnicity as either East Asian or not according to a validated list of surnames. Survival outcomes were assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox-proportional hazard model was constructed with ethnicity and relevant clinical/pathological characteristics to assess their impact on survival. Results: A total of 175 patients were included. Mean age was 64 years. 78% were men, 28% were East Asian, and 79% were Child-Pugh A at initiation of S. The most common etiologies of underlying liver disease were Hepatitis C (HCV) (31%), HBV (29%) and alcohol (21%). 42% had distant metastatic disease. The majority of patients had an ECOG performance status of 0 (26%) or 1 (64%). Median OS was 9.0 months in Asians and 9.5 months in non-Asians (p = 0.68). On multivariate analysis, ethnicity (HR 0.76, 95% CI 0.39 – 1.32, p = 0.33) was not a significant prognostic factor for OS. However, lack of distant metastases (HR 0.57 95% CI 0.40 - 0.82, p < 0.01), initial AFP < 400 (HR 0.54 95%CI 0.38 - 0.78, p < 0.01) and 3+ localized treatments (HR 0.60 95% CI 0.39 - 0.92, p = 0.02) were associated with better OS. Further, HBV was associated with inferior OS when compared to HCV (HR 2.12, 95% CI 1.08 - 4.17, p = 0.03). Conclusions: When treated with S in one Canadian province, ethnicity does not appear to be a prognostic factor for OS. However, HCV infection, lack of distant metastases, initial AFP < 400, and 3+ previous localized treatments were significant prognosticators of OS. We are validating these findings in a larger multi-centre Canadian dataset.
Gauging public awareness and interest related to pancreatic cancer: An analysis of Google search volumes.
Authors: Mukhija Dhruvika , Khorana Alok A. , Sohal Davendra
Published: January 2019

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Background: Over the last 2 decades, the internet has become a major source of medical information. Infoveillance, i.e., public health surveillance using online content analysis has become a powerful tool and internet search activity has been used as a surrogate to gauge public awareness and interest for particular diseases. We aimed to evaluate the search volume for pancreatic cancer (PC), using colon cancer (CC), as a comparator, using data from a popular search engine. Methods: Using Google Trends, a public web facility of Google Inc., based on Google Search, we compared the relative frequency of search terms ‘pancreatic cancer’ and ‘colon cancer’ between 1st January 2004 and 31st August 2017 (n = 164 months). The program assigns a reference value of 100 for the point of maximum popularity from among all the search terms during the search period and provides comparative monthly scores, which we termed relative interest scores (RIS). The RIS for each cancer was then adjusted for incidence (i.e., 53,070 for PC and 95,270 for CC, based on 2016 data), calculated per 10,000 patients and termed ‘i-RIS’. A p-value of < 0.05 was considered significant. Results: For the entire duration, the maximum popularity (RIS = 100) corresponded to a point in March 2008 for PC, likely related to the diagnosis of a famous celebrity during that month. Similar but smaller surges in RIS were observed for other significant news events related to PC during other months (January 2009, October 2009 and October 2011). Overall, the mean (±S.D) RIS for PC and CC were 32.52±8.98 and 50.18±6.44, respectively (p < 0.001). However, the i-RIS was somewhat higher for PC (6.12±1.69) as compared with CC (5.26±0.67) (p < 0.001). Conclusions: Internet search data can provide estimates of public awareness and interest related to cancer. For PC, incidence-adjusted search volumes show spikes in search volumes related to major news events, providing internal validation of these results. Generating news items and promotion by celebrities may play a significant role in the success of cancer awareness campaigns.
Prognostic value of neutrophil-lymphocyte ratio during palliative chemotherapy in patients with unresectable gallbladder adenocarcinoma.
Authors: Lee Jae Woo , Lee Sang Hyub , Son Jun Hyuk , Kang Jinwoo , Paik Woo Hyun , Ryu Ji Kon , Kim Yong-Tae
Published: January 2019

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Background: Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) is a valuable prognostic marker in several kinds of solid tumors. This study aimed to evaluate the NLR, PLR and change of NLR and PLR over time as a prognostic marker in unresectable gallbladder cancer (GBC) which is treated with palliative chemotherapy. Methods: A total of 163 patients with pathologically confirmed unresectable GBC were enrolled. Baseline and post 1-cycle chemotherapy NLR and PLR were used in analysis. The changes in NLR and PLR were defined as the ratio of post chemotherapy value to baseline value. The relation between survival time and NLR and PLR changes were analyzed. Results: NLR and PLR had AUC value of 0.679, 0.660 in predicting 1-year overall survival (OS) and NLR 1.96 and PLR 111 were the optimal cutoff value with the highest sum of sensitivity and specificity. NLR change and PLR change had AUC value of 0.517, 0.519 in predicting 1-year OS and NLR change 0.4, PLR change 0.6 were the optimal cutoff value. Patients with NLR lower than 1.96 had better OS (16.1 months vs. 9.5 months, p < 0.001) and similarly patients with PLR lower than 111 had better OS (17.3 months vs. 9.5 months, p < 0.001). However, NLR change lower than 0.4 didn’t show better OS (9.2 months vs. 11.6 months, p = 0.178), and the same with PLR change lower than 0.6 (8.5 months vs. 11.3 months, p = 0.138). Conclusions: Baseline NLR and PLR is a valuable predictor of overall survival in unresectable GBC undergoing palliative chemotherapy, whereas NLR and PLR change over time is not.
Effect of surgical resection on survival following neoadjuvant chemotherapy in patients with stage I-II pancreatic adenocarcinoma.
Authors: Henrix Ryan James , Rouanet Eva , Schultz Kurt , Ali Tasneem , Switzer Bradley Alan , Bathini Venu Gopal , Whalen Giles Francis , Lafemina Jennifer
Published: January 2019

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Background: Pancreatic adenocarcinoma (PDAC) is a lethal malignancy, representing the 4th leading cause of cancer deaths. Our 2011 institutional protocol guides that patients with Stage I/II PDAC receive neoadjuvant chemotherapy (FOLFIRINOX or gemcitabine- nab-paclitaxel); a similar protocol is followed with patients with Stage III disease. The aim of the study is to determine if potentially curative surgery provides added survival benefit, compared to neoadjuvant chemotherapy alone. Methods: Patients who received neoadjuvant chemotherapy and who were diagnosed with stage I-III PDAC from 2011-2017 at a tertiary medical center were included in this prospectively-collected, retrospective analysis. The primary endpoint was overall survival (OS). Kaplan-Meier curves are compared using Log-rank. Cox proportional hazards were used to adjust for confounders. Results: 105 patients met inclusion criteria: 38 (36%) had Stage I disease (n = 18 had neoadjuvant chemotherapy and surgery [N+S], n = 20 had neoadjuvant chemotherapy [N] alone), 44 (42%) had stage II (N+S n = 20, N n = 24), 23 (22%) had stage III (N+S n = 4, N n = 19). There was no difference in 5-year OS regardless of treatment regimen in patients with Stage I (median OS N+S 22.5 mo vs N 27.9 mo; p = 0.99, HR 1.00, 95%CI 0.74-1.35) or Stage II disease (median OS N+S 28.7 mo vs N 27.6 mo; p = 0.69; HR 1.06, 95%CI 0.79-1.41). There is a trend towards improved OS with N+S in those with Stage III disease (median OS N+S 46.0 mo vs N 14.5 mo, p = 0.08), but the number who underwent resection is low (17%), limiting this analysis. Conclusions: In patients with Stage I-II PDAC, potentially curative surgery may not provide additional survival benefit beyond that afforded by modern day neoadjuvant chemotherapy. Stage III outcomes are limited by small numbers, and the impact of surgery is unclear. It may be possible that the locally unresectable tumor that is rendered resectable with neoadjuvant chemotherapy may be associated with a more favorable biology, such that surgery offers added survival benefit. Additional large-scale trials are needed to confirm whether newer therapies may obviate the need for resection in select patients.
Protease/protease inhibitor balance in blood plasma to predict postoperative complications in operated patients with pancreatic head cancer.
Authors: Kit Oleg Ivanovich , Frantsiyants Elena , Kozlova Larisa S. , Bandovkina Valeria A. , Kolesnikov Evgeniy N. , Kozhushko Mikhail Anatolievich , Kazieva Tanzila Beksultanovna , Averkin Michail , Trifanov Vladimir
Published: January 2019

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Background: Our purpose was to study the protease/protease inhibitor (P/PI) balance in the blood plasma of patients with cancer of the head of the pancreas before and after pancreatoduodenal resection (PDR) with postoperative complications. Methods: The study was performed using clinical observation, biochemical examinations and statistical analysis in Microsoft Office Excel 2010. The blood plasma of 92 patients with pancreatic head cancer (53 men and 39 women aged 45-76 years, Т2-4N0M0) was studied before the surgery (b/s) and on days 1, 7, 14 and 17 after PDR. The patients were divided into two groups: g1 – 69 patients without postoperative (p/o) complications and g2 – 23 patients with p/o complications: generalization – 7, thrombosis - 8, acute postoperative pancreatitis - 2, gastrostasis - 2, anastomotic leakage - 4 patients. Kinetics of trypsin-like proteases (TLP) and α-1-proteinase inhibitor (α1PI) was studied by spectrophotometry. The data were compared with the blood plasma of 39 healthy donors (N). Results: TLP activity b/s exceeded N in g1 and g2 by 4.1 and 10.6 times; TLP in g2 was 2.6 times higher than in g1. The α1PI activity b/s was higher than N by 1.2 times (p < 0.05) in g1 and lower than N by 2.0 times in g2; α1PI in g2 was 2.4 times lower than in g1. After PDR, activity of TLP increased in all patients on day 1 but decreased on days 7-14 in g1 remaining 2.7 times higher than N by the discharge. The TLP activity in g2 by the discharge was similar to levels b/s and exceeded g1 by 4.4 and N by 12.1 times. The α1PI activity after PDR increased in all patients on days 1-17, but in g1 by the discharge it was similar to N and in g2 it was 1.5 times lower than N. The TLP/α1PI ratio was higher in g2 than in g1 at all times. Conclusions: A high TLP activity and a low α1PI activity, compared to N, were maintained in the blood plasma of all patients with p/o complications, despite their types. The P/PI balance in g2 was shifted to the left being 5.5-9.0 times higher than in g1 at all times which allowed the prognosis of postoperative complications before the surgery, perioperatively or on day 1 after the surgery.
Effect of outside referrals to a tertiary care liver tumor board on diagnostic testing and initial curative therapy.
Authors: Zhang Yapei , Arango Jennifer , Weinreb Jeffrey , Taddei Tamar Hamosh
Published: January 2019

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Background: Hepatocellular carcinoma (HCC) is a complex and unique cancer. Arriving at the optimal treatment plan is best accomplished by a multidisciplinary tumor board (MDTB). We hypothesized that patients referred from outside institutions to our tertiary care center for MDTB review may face disparities in diagnosis and treatment. Methods: We performed chart review of incident HCC cases presented from 2/1/13-2/1/16 at an American College of Surgeons accredited MDTB that convenes weekly at a tertiary care, university-affiliated hospital. We examined variables such as demographics, originating institution, liver disease etiology, location of index imaging, date of first tumor board presentation, diagnostic method (imaging, biopsy, tumor board consensus), BCLC stage at diagnosis, initial treatment, and time to treatment. Results: 167 cases of HCC were referred from 37 outside institutions (outside cases); 127 cases originated from our institution (internal cases). The two groups were comparable in gender distribution, liver disease etiology, and BCLC stage at tumor board presentation. Compared to internal cases, outside cases were diagnosed less often by imaging (47% vs. 77%, p < 0.000001) and more often by biopsy (38% vs. 17%, p < 0.001) or MDTB consensus (16% vs. 6%, p < 0.05). When stratified by BCLC stage, this difference in diagnostic method persisted in early and mid-staged patients (Stages 0, A, B), but not in advanced staged patients. Outside cases were also more likely to receive tumor biopsy (33% vs. 9%, p < 0.05) and less likely to receive initial curative therapy (resection, ablation, transplantation) (22% vs. 32%, p < 0.05). There was no significant difference in time to treatment. Conclusions: Despite similar demographics and disease profiles compared to patients from our tertiary care center, patients referred from outside facilities for MDTB review more often required biopsies or MDTB consensus to diagnose HCC, and were less likely to receive curative therapy. Differences in HCC diagnostic imaging protocols across institutions may help explain these results. Further study will help identify disparities in receipt of curative therapy.
Defining the number of lymph nodes needed to accurately stage small bowel neuroendocrine tumors: An 8-institution study from the US neuroendocrine tumor study group.
Authors: Zaidi Mohammad , Lopez-Aguiar Alexandra G , Dillhoff Mary , Beal Eliza W , Poultsides George A. , Makris Eleftherios , Rocha Flavio G. , Crown Angelena , Idrees Kamran , Marincola Smith Paula , Nathan Hari , Beems Megan , Abbott Daniel , Barrett James , Fields Ryan C , Davidson Jesse T , Cardona Kenneth , Maithel Shishir
Published: January 2019

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Background: Small bowel neuroendocrine tumors (SB-NETs) frequently involve regional lymph nodes (LNs). The prognostic value of LN positivity on recurrence of disease is not well defined. The number of LNs needed to accurately stage patients is unknown. Methods: All patients with primary SB-NETs who underwent curative-intent resection at 8 institutions in the US Neuroendocrine Tumor Study Group between 2000 and 2016 were identified. Patients with distant metastatic disease were excluded. The association of LN positivity with recurrence of disease and the extent of lymphadenectomy required were analyzed. Results: Of 2182 patients with resected NETs, 203 had SB-NETs. Median age was 60 yrs, 56% were male, and median follow-up was 39 months. 83.5% of patients (n = 157) had LN positive disease. There was no difference in 3-year recurrence free survival (3-yr RFS) among patients with 1 or 2 positive LNs compared to patients with negative LNs (p = 0.63). Patients who had 3 or more positive LNs had a worse 3-yr RFS compared to those with 0, 1, or 2 positive LNs (n = 92 vs n = 73; 3-yr RFS 82% vs 92%; p < 0.001). Retrieval of 8 or more LNs was associated with a higher positive LN count compared to less than 8 LNs (4.6 vs. 1.6; p = 0.002). However, an increasing LN ratio was not associated with 3-yr RFS. When examining patients who had less than 8 lymph nodes retrieved, there was no difference in 3-yr RFS in those patients with 3 or more positive LNs compared to those with 0, 1, or 2 positive LNs (3-yr RFS: 100% vs 91%; p = 0.37). Retrieval of more than 8 lymph nodes, however, accurately discriminated patients with 3 or more positive LNs compared to those with 0, 1, or 2 positive LNs (3-yr RFS: 79.7% vs 93.5%; p = 0.005). Conclusions: For patients undergoing curative-intent resection of small bowel NETs, accurate lymph node staging requires a minimum of 8 lymph nodes for examination. 3 or more positive LNs is associated with decreased 3-yr RFS compared to 0, 1, or 2 positive lymph nodes. A thorough regional lymphadenectomy is critical for accurate staging and management of patients with small bowel neuroendocrine tumors.