bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preoperative chemoradiation and cetuximab for resectable, locally advanced esophageal cancer: Preliminary results of a prospective phase Ib/II trial.
Authors: Brenner Baruch , Kundel Yulia , Purim Ofer , Medalia Gal , Olshinka Liran , Kashtan Hanoch , Menasherov Nikolai , Fenig Eyal , Sulkes Aaron , Idelevich Efraim 
Published: March 2020

e14571 Background: This prospective phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative chemoradiation (CRT) in locally advanced esophageal cancer (LAEC). We hereby report its preliminary results. Methods: Patients (pts) with potentially resectable LAEC, defined as T2-4N0-1M0, T1-4N1M0 or T1-4N0-1M1A tumors, received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-FU 1000 mg/m2/day as a continuous infusion (CI), days 1–5, followed 4 weeks later by 50.4 Gy radiotherapy (RT) given concurrently with 2 cycles of cisplatin 75 mg/m2 and escalating doses of CI 5-FU, days 1–4 and 29-32. Pts received also 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose of 400 mg/m2, starting from the induction. The phase II part of the study started when the 5-FU dose during CRT was defined. Surgery was planned 6-8 weeks after CRT. Results: Thirty-six pts have been enrolled to date and 32 completed CRT. The median age was 65 years and 60% were males. The ratio of squamous/adeno histologies was 53%/47%. Pts had very advanced tumors: 95% T3-T4, 63% N1 and 28% M1A. In the absence of dose limiting toxicity, 31 pts received the phase II dose of 5-FU, defined as 1000 mg/m2/day. The most common grade >3 toxicities were leucopenia (51% of pts) and neutropenia (48%). There was one toxic death, due to neutropenic sepsis. Among the 27 operated pts, R0 resection was achieved in 24 (89%). There were 4 cases (15%) of postoperative mortality, due to infection (3 pts) or respiratory failure (1). Downstaging was noted in 83% of pts and pathological complete response (pCR) in 32%. Pts with squamous histology had a higher pCR rate (53% vs 7%, p=0.007). At the time of the analysis, 14 pts (40%) remain free of disease and the local control rate is 92%. Updated results will be presented at the meeting. Conclusions: Preliminary results from this prospective study suggest that the addition of cetuximab to standard CRT is safe. The R0, pCR and local control rates are encouraging. Squamous cell tumors may gain more benefit from the addition of cetuximab.
The features and outcome of HIV-associated anal cancer in screened and unscreened populations.
Authors: Newsom-Davis Thomas , Fox Paul , Bradley Victoria , Dalla Pria Alessia , Nelson Mark , Bower Mark 
Published: March 2020

e14574 Background: The aims of screening for anal cancer are to prevent invasive anal cancer and/or to detect it at an early and hence more curable stage. We sought to evaluate differences in clinicopathological features and outcomes of HIV associated anal cancer between patients who were enrolled on a programme of high resolution anoscopy (HRA) surveillance and those who were not. Methods: A retrospective study of patients diagnosed with anal cancer was undertaken based on our HIV cancer registry. Results: Since 1989, 74 patients (73 male) have been diagnosed and treated for HIV-associated invasive anal cancer, including 7 patients who had been enrolled onto an HRA screening programme. The surveillance patients had undergone a total of 26 examinations starting a median of 3.8 years (range: 0.3-8.7) prior to cancer diagnosis. At anal cancer diagnosis, the screened patients were older (median age: 50 years, range: 45-61 vs 44, range: 28-75, p=0.04), had higher CD4 cell counts (median CD4: 575 /mm3, range: 390-842 vs 321, range: 16-1250, p=0.02), more had undetectable plasma HIV viral loads (100% vs 56%, p=0.04) and more were on HAART (100% vs 70% p=0.09). However, there were no differences in cancer stage (p=0.64), local tumour (T) stage (p=0.4), lymph node status (N) stage (p=0.47) or metastatic (M) disease (p=0.51). Similarly, there was no difference in tumour grade between screen and unscreened patients (p=0.19). Finally, there is no difference in the actuarial overall survival between the two groups (Log rank p=0.63). Conclusions: Despite enrolment onto an HRA screening programme and better immunological status at diagnosis, tumours detected in screened patients were neither earlier stage nor better differentiated and there was no improvement in survival. These findings in a relatively small number of patients may cast doubt on the validity of screening by HRA for anal cancer.
Effect of inhibition of protein kinase C delta (PKCδ) on pancreatic cancer cells.
Authors: Sorescu George P. , Forman Lora W. , Faller Douglas V. 
Published: March 2020

e14591 Background: 93% of pancreatic cancers have activating mutations in the K-Ras gene. We have previously shown that mutated, constitutively-activated Ras is lethal to cells if an essential Ras-driven survival pathway is disrupted by suppression of PKCδ. PKCδ has various cellular functions, but is not required for the survival of normal cells and its inhibition in vitro or in vivo has no known adverse effects. Signal transducer and activator of transcription 3 (STAT3) is constitutive driver of many solid cancers, including pancreatic cancers. STAT3 requires phosphorylation of Tyr 705 for activation and, once activated translocates to the nucleus, where it controls genes involved in cell survival or death. Methods: Human pancreatic cancer cell lines PancI, MIAPACA and primary human pancreatic cancer stem cells were studied. shRNA-mediated knockdown of PKCδ, with scrambled shRNA as a control, was used to validate PKCδ as a target. Rottlerin and KAM1 were used as relatively specific PKCδ inhibitors. For inhibition of STAT3, specific shRNA against STAT3 versus scrambled shRNA were employed for knock-downs. For cytotoxicity analyses, MTS assays were used to assess cell growth. Z-vad-FMK was used as a pan-caspase inhibitor. Immunoblotting was used to verify knock-down of PKCδ or STAT3 and to quantify the phosphorylation status of STAT3 phospho-Tyr 705. Results: PKCδ inhibition by either shRNA knock-down or inhibitor led to dephosphorylation of STAT3 at Tyr 705, extensive cytotoxicity of pancreatic cancer cells and dramatic reductions in tumor clonogenic capacity. Knock down of STAT3 was equally cytotoxic to pancreatic cancer cells. Cytotoxicity following PKCδ inhibition was not prevented by a pan-caspase inhibitor. Conclusions: Activated STAT3 and survival in pancreatic cancer cells requires PKCδ. Inhibition of PKCδ, and subsequent suppression of STAT3 activation, is cytotoxic for pancreatic cancer cells through a mechanism independent of caspase activation or apoptosis. Small molecule inhibitors of PKCδ have potential as targeted therapeutic agents against pancreatic tumors, pancreatic cancer stem cells, and other human tumors with mutational activation of Ras.
Phase II trial of combination therapy using S-1, cisplatin, and radiation for distant metastatic esophageal cancer (stage IVb).
Authors: Iwase Hiroaki , Shimada Masaaki , Tsuzuki Tomoyuki , Goto Hidemi 
Published: March 2020

e14596 Background: S-1 is an orally active fluoropyrimidine that enhances the efficacy of radiotherapy (RT) and has low gastrointestinal toxicity. Our previous phase II study demonstrated that definitive chemoradiotherapy (CRT) with S-1 and cisplatin was well-tolerated and had favorable activity for locally advanced esophageal cancer (Iwase H et al, Proc. ASCO 2011, Abst 4034). The present study was a phase II trial of combination therapy using S-1, cisplatin, and RT for distant metastatic esophageal cancer (DMEC). Methods: S-1 (80 mg/m2/day) was given orally for 14 consecutive days from Day 1 and cisplatin (70 mg/m2) was administered on Day 14, both with 3 weeks of RT (2.0 Gy per traction) 5 times per week for the primary lesion and metastases in the neck, which initiated on Day 1. One Cycle equals 5 weeks, 2 weeks of chemotherapy concurrent with 3 weeks of RT followed by 2 weeks of complete rest. After 2 cycles, only chemotherapy with S-1 and cisplatin were administered. Results: Forty-one patients with DMEC (Stage IVb) were enrolled between March 2002 and February 2011. 37/male7/female, median age 67.5 years (48-82). The median survival follow-up time was 16.6 months and 37 patients (90.2%) completed the combination treatment. The most common adverse event was neutropenia. Grades 3 and 4 neutropenia were observed in 29.2% and 12.2%, respectively. In general, non-hematological adverse events were mild and the most common were Grade 2 nausea (34.1%), esophageal pain and oral mucositis (17.1% each), and renal dysfunction (9.8%). The overall response rate was 65.9% comprising 93.2% in the primary lesion, 60% in the liver metastasis, 64.3.% in the lung, 54.5% in the distant lymph node, 83.3% in the regional lymph node metastasis, and 50% in the other distant metastases. Thirty-nine patients (88.6%) showed improvement in their dysphagia score. The median progression-free and overall survival durations were 5.3 [95% confidence interval (CI), 4.1 to 6.0] and 13.1 months (95% CI, 9.8 to 15.6), respectively. Conclusions: Combination therapy using S-1, cisplatin, and RT has a promising safety and efficacy profile. Potentially, this regimen could become the baseline treatment for patients with DMEC.
No role for infection with human papillomavirus in upper aerodisgestive tract cancers in smokers and alcoholics.
Authors: Antunes Luis Carlos Moreira , Lopes Antonio de Barros , Pacheco Luisa Silva , Brites Patricia Chaves , Muller Leandro Bizarro , Fagundes Renato Borges 
Published: March 2020

e14597 Background: The highest rates of esophageal cancer in Brazil occur in Rio Grande do Sul (18/100,000/year for men and 6/100,000/year for women). Furthermore, the incidence of head and neck squamous cell carcinoma (HNSCC) is significant in this region (11/100,000/year for cancer of the oral cavity and 10/100,000/year for laryngeal cancer in men). Tobacco smoking and alcohol consumption are the major risk factors for esophageal squamous cell carcinoma (ESCC) and HNSCC. The role of HPV in the development of ESCC remains controversial. Otherwise, there are some evidence that HPV-related HNSCC is a distinct entity compared with HNSCC associated with smoking and alcohol consumption. Methods: In order to investigate the association of HPV infection with ESCC and HNSCC in smokers/alcoholics in southern Brazil, we evaluated, prospectively, samples from three groups. Group 1 was formed by patients with ESCC where we evaluated esophageal samples from tumor and from non-tumoral areas. Group 2 was formed by HNSCC patients. We assessed biopsies from primary tumor and esophageal biopsies from either iodine negative or positive areas. Group 3 was formed by dyspeptic patients, no smokers/non alcoholics, with normal appearing esophageal mucosa in Upper GI Endoscopy. Biopsies were taken from middle esophagus. With extreme care to prevent DNA contamination, we used nested PCR with the general primer sets MY09/11 and GP5/GP6 for HPV L1 in formalin fixed paraffin-embedded tissue. We planned to genotype the final PCR product for 73 HPV types. Results: Group 1 included 48 samples from ESCC and 48 samples of esophageal non-tumoral areas. In Group 2, there were 37 patients with 35 biopsies taken from primary tumor, 32 from iodine positive esophageal areas and 17 from unstained esophageal areas (15 normal and 2 esophagitis). In this group, 1 patient had synchronous tumors of HNSCC and ESCC. Group 3 included 37 patients, 35 with normal esophageal mucosa and 2 with mild esophagitis. HPV DNA was negative in all samples. Therefore, we did not carry out the genotyping. Conclusions: In smokers/alcoholics patients from Southern Brazil, there is no evidence that HPV is involved in upper aerodigestive carcinogenesis.
Phase I/II trial of sorafenib combined with FOLFOX4 in untreated patients with advanced gastric adenocarcinoma: Phase I results.
Authors: Chi Yihebali , Yang Jianliang , Du Feng , Yang Sheng , Sun Yongkun , Shi Yuankai 
Published: March 2020

e14606 Background: Sorafenib (Sor) is a potent inhibitor of multiple intracellular and cell surface kinases. FOLFOX4 was demonstrated to be an active and well-tolerated chemotherapy for advanced gastric adenocarcinoma (AGA). The phase I portion of the phase I/II study is designed to assess the maximum tolerated dose (MTD) of Sor combined with standard dose FOLFOX4, as well as safety, tolerance, and activity of the combination in patients (pts) with AGA. Methods: Pts with AGA with ECOG 0-1 and without prior chemotherapy or radiotherapy were eligible. Three patients per cohort were treated with FOLFOX4 [Oxaliplatin (85 mg/m2), LV (200mg/m2) and 5-FU (400 mg/m2), followed by 5-FU continuously infusion (1200mg/ m2) for 44h every 2 weeks, up to 8 cycles, along with escalating doses of Sor (200, 400, 600mg) PO BID, continuously. If one patient experienced DLT, three additional patients were entered at the same dose level. Dose escalation continued until DLTs were experienced in two or more out of six patients, which was then defined as the MTD. Radiographic responses were assessed every 6 weeks per RECIST v1.0. Results: Nine pts were enrolled. Median age was 59.3 yr (range 42.6-71.6). M/F: 6/3; ECOG PS 0/1: 2/7. One out of 6 pts experienced DLT (G3 HFSR) in dose level 1 (200 mg BID), and 2 out of 3pts experienced DLT in dose level 2 (400 mg BID). The Sor 200mg BID was therefore identified as the MTD when combined with FOLFOX4. Major toxicity of this combination include neutropenia (G3/4: 7/3), leucopenia (G3/4: 2/0), HFSR (G3/4: 2/0) and incomplete bowel obstruction (G3/4: 1/0). One patient experienced G4 ALT/AST elevation accompanied with G3 GGT/bilirubin elevation, which led to treatment discontinuation. Preliminary efficacy data in 9 evaluable pts included 1 complete response (CR), 6 partial responses (PR) and 1 stable disease (SD) as best response. Median time to progression was 6.6 months. Median overall survival was 12.2 months. Conclusions: The MTD of Sor when used in combination of FOLFOX4 in AGA is 200mg PO BID, and this combination regimen has a manageable toxicity profile and promising activity in AGA. This efficacy and safety profiles need to be confirmed in further phase II studies.
Phase Ib dose-escalation study of a phase II randomized trial to assess the safety and tolerability of tigatuzumab (CS-1008) in combination with sorafenib in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Cheng Ann-Lii , Kang Yoon-Koo , Ryoo Baek-Yeol , Yen Chia-Jui , Lim Ho Yeong , Oh Do-Youn , Austin TaShara , Wang Qiang , Greenberg Jonathan , Beckman Robert A. , Kudo Masatoshi 
Published: March 2020

e14617 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist and exerts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-like activity, is currently undergoing a phase Ib/II study in advanced HCC. Preclinical studies showed that sorafenib (S) can overcome TRAIL resistance in HCC cells and enhances T-induced apoptosis. In this phase Ib dose-escalation portion of a phase 2 study, safety/tolerability of T + S was evaluated in advanced HCC pts. Methods: Adult pts (≥ 18 years) with advanced HCC and measurable disease (RECIST v1.1), ECOG=0/1, and Child-Pugh A, were administered sequentially-escalating doses of T (2, 4, 6 mg/kg/week IV) in combination with S (400 mg PO BID) over 4 weeks (n = 3/cohort). If no pt had a dose-limiting toxicity (DLT), dose escalation proceeded. If 1/3 pts had DLT, the cohort was to be expanded to 6; if 2/3 or 2/6 pts had DLT, the cohort was to be expanded to 9. Dose escalation was to be stopped when ≥ 3 pts experienced DLTs in a cohort with the prior dose designated as the maximum tolerated dose (MTD). Pts received treatment until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. Results: Nine pts (3 at each dose level of T + S) were treated in this phase Ib portion. Grade 3/4 treatment-emergent AEs (> 20% incidence) were increased AST, blood amylase, and lipase and hand-foot syndrome. Serious AEs were reported in 5 pts (upper GI hemorrhage, esophageal varices hemorrhage [EVH], tumor progression, increased serum amylase, fever, and lumbar spine compression), which were considered unrelated to study medication except for EVH (T + S), increased serum amylase (T + S), and fever (S). No DLTs were observed and the MTD of T was not reached. 2 pts had a partial response, and 4 pts had disease stabilization. The trial is ongoing. Conclusions: Phase Ib data show that T in combination with S was safely administered with no DLT and demonstrated clinical activity in advanced HCC pts. T and S constitute a promising rational combination treatment for HCC.
Clinical outcomes and predictive value of chromogranin A (CgA) and pancreastatin (PcSt) in liver-directed therapies (LDTs) for well-differentiated metastatic neuroendocrine tumors.
Authors: Engelman Eric Steven , Leon-Ferre Roberto , Naraev Boris G. , Sharma Nancy , Button Anna M , Zamba Gideon , Sun Shiliang , O'Dorisio Thomas M. , Halfdanarson Thorvardur Ragnar 
Published: March 2020

e14620 Background: LDTs have been shown to improve time to tumor progression and morbidity in metastatic neuroendocrine tumors (mNETs). CgA and PcSt are being used to predict and evaluate response to LDTs. Methods: Medical records of 42 mNET patients (pts) with hepatic metastases treated with either bland hepatic artery embolization (HAE), chemoembolization (HACE), or hepatic radioembolization (HRE) at the University of Iowa from 2001 to 2011 were analyzed. Time to progression (TTP) and overall survival (OS) were calculated using Kaplan-Meier analysis. PcSt and CgA were compared using a standardized mean Results: The tumors were located in the small bowel in 21 pts (50%), pancreas in 8 (19%), lung in 2 (5%), and other locations in 11 pts (26%). 13 pts had HAE, 17 had HACE and 12 had HRE. 20 pts had a second procedure with 6 receiving HRE, 9 HAE and 5 HACE. There was no significant difference in initial radiographic response among the three treatments (p = 0.082). TTP was similar between HRE (15.1 months) and HAE or HACE (HA(C)E) (19.6 months) (p= 0.968). There was a trend towards an increased TTP in pts receiving HACE (33.4 months), compared to HAE (12.1 months) or HRE (15.1 months) (p = 0.512). The overall survival for all pts from the first intervention was 41.9 months. There was no significant difference in symptom improvement among the treatment groups (p = 0.265). HRE and HA(C)E had no difference in post-therapy fever (p=0.236), vomiting (p=0.470), or abdominal pain (p=0.139). There was no difference between HA(C)E and HRE in pre-therapy CgA (p= 0.1913) or PcSt (p=0.983) nor was there a difference in post-therapy change of CgA (p=0.233) and PcSt (p=0.158). TTP did not correlate with the pre-therapy CgA (p=0.131) or PcSt (p=0.630) nor the change in the post-therapy CgA (p=0.299) or PcSt (p=0.208). Conclusions: There was no significant difference in TTP in patients treated with HRE compared to patients treated with HAE or HACE in this cohort. No single therapy was better than another in reducing symptoms. Baseline CgA and PcSt and post-therapy marker changes did not predict TTP and there was no difference in post-therapy marker changes based on treatment type.
Positron emission tomography for the assessment of survival after subsequent surgery in multimodality treatment for patients with locally advanced esophageal squamous cell carcinoma.
Authors: Emi Manabu 
Published: March 2020

e14636 Background: Recent studies imply that positron emission tomography with fludeoxyglucose F 18(FDG-PET) correlates with histopathologic response and survival in patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy (CRT) followed by surgical resection. To evaluate the rating system of FDG-PET after the completion of neoadjuvant CRT for the assessment of histopathologic response and prognosis inthe multimodality treatment of patients with esophageal cancer. Methods: Seventy patients (58 men, 12 women; median age, 61 years) with locally advanced esophageal squamous cell carcinoma who received neoadjuvant CRT underwent FDG-PET before chemoradiotherapy and transthoracic en bloc esophagectomy in evaluation of pathologic response to CRT and postoperative survival. Lack of FDG uptake was defined as primary tumors with SUVmax at least 2.5, and FDG-PET complete response after CRT (PET-CR) was defined as SUVmax<2.5 or SUVmax<3 with mild hyper metabolic activity around the primary tumor. Results: After CRT, lack of FDG uptake was noted 34 patients, PET-CR was noted 49 patients and pathological CR was noted 31 patients. PET-CR indicated stronger correlation with postoperative survival than lack of FDG uptake and rate of decrease in SUV. PET-CR and pathologic CR predicted for improved outcomes (3-year disease free survival 70.3% vs 42.6% P=0.0032; log-rank test, 76.4% vs 37.6% P=0.0008; log-lank test). But on multivariate analysis using the Cox proportional hazards model, only pathologic CR was found to be correlated with post-CRT disease free survival (HR 0.190, 95%CI 0.049-0.73, P=0.017). Conclusions: To evaluate the value of FDG-PET for the assessment of prognosis in the multimodality treatment for patients with locally advanced esophageal squamous cell carcinoma, we tried different rating system of FDG-PET but no recommendation was made for the use of FDG-PET.
Comparison of S-1 and cisplatin combination versus S-1 adjuvant chemotherapy for advanced gastric cancer.
Authors: Kim Hyo Song , Jeung Hei-Cheul , Jung Minkyu , Kim Hye Ryun , Ahn Ji Yeong , Kim Hyoung-Il , Cheong Jae-Ho , Hyung Woo Jin , Noh Sung Hoon , Chung Hyun Cheol , Rha Sun Young 
Published: March 2020

e14652 Background: Adjuvant chemotherapy demonstrated the efficacy for stage II-III gastric cancer patients in the ACT-GC and CLASSIC trial. However, in the subgroup analysis, stage III patients receiving S-1 monotherapy didn’t report survival benefit unlike the capecitabine/oxaliplatin combination regimen in CLASSIC trial. With the assumption that doublet adjuvant chemotherapy may be more effective for advanced stages of patients, we compared the efficacy of S-1/cisplatin (SP) and S-1 adjuvant chemotherapy. Methods: After curative D2 resection, 274 patients were treated with S-1 monotherapy (98 patients, 80 mg/m2 for 4 weeks, every 6 weeks) or S-1 plus cisplatin (176 patients, S-1 80 mg/m2 day 1-14 and cisplatin 60 mg/m2 day 1, every 3 weeks). Treatment was continued for 12 months in S-1 arm and 6 months in SP arm or until unacceptable toxic effects or disease progression. Results: A total of 65 (66.3%) patients in SP and 118 (67%) in S-1 group completed all the treatment. The relative dose intensity of S-1 was 82% for S-1 and 88% for SP group, respectively. During the early times after the operation, more patients in SP group completed adjuvant treatment. More patients in SP discontinued treatment during the 1st cycle (12.5% S-1 vs 8.5 % SP group) and this trend was consisted thereafter. The progression free survival (PFS) was not reached for both groups. For the stage III patients, 2 year PFS was better for SP group (89%) than S-1 group (80.8%). Among the 23 recurrence, S-1 group (19.8%) demonstrated more frequent recurrence than SP group (12%). In terms of tolerance, hematologic toxicities was more frequent in SP group, therefore, 21% of SP group and 3.4% of S-1 monotherapy had grade 3-4 neutropenia. However, for the non-hematologic toxicity, grade 3-4 anorexia was similar and grade 3-4 stomatitis was more common in S-1 group (2.8% vs 7%) Conclusions: S-1 plus cisplatin adjuvant chemotherapy is effective and tolerable. For the high risk patients, considering favorable compliance and slightly better efficacy, combination treatment may be a good therapeutic option. Further studies for optimal drugs and schedule are warranted.