bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Assessment of radioembolization among patients who met the inclusion criteria for Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP).
Authors: Sangro Bruno , Carpanese Livio , Cianni Roberto , Gasparini Daniele , Golfieri Rita , Ezziddin Samer , Kolligs Frank T , Izzo Francesco
Published: March 2020

e14654

Background: SHARP was pivotal in determining the safety and efficacy of sorafenib in advanced hepatocellular carcinoma (HCC) in patients with predominately good liver function. In practice, many patients with advanced HCC receive radioembolization (RE). Investigators from the European Network on RE with yttrium-90 resin microspheres (ENRY) group conducted an analysis of safety and survival among consecutive patients who met the SHARP inclusion criteria. Methods: 58% of patients (189 of 325) who had received RE between 09/2003 and 12/2009 were considered SHARP-equivalents. Of these, 11.6% received sorafenib 4.7 months (median) after RE for a median duration of 2.8 months. Safety and tolerability analyses were conducted up to day 90 post RE; changes from baseline were recorded and transitions in CTCAE grades >3 tested. Statistical analyses used SAS (SAS, Cary NC) version 9.2 XP Pro. Results: Like the SHARP sorafenib cohort, most patients had advanced HCC (BCLC stage C: 72.5%), good liver function (Child–Pugh class A: 100%) and ECOG performance status (0–1: 90.5%). Macroscopic vascular invasion (MVI), extrahepatic spread (EHD) or both was present in 33.9%. 20.1% had received prior surgical procedures, 8.5% prior ablative procedures and 33.3% prior vascular [chemo]embolization. RE was predominantly a single whole-liver procedure (median activity 1.7 GBq). Median overall survival was 10.8 months (95% CI: 8.8–12.8) in the SHARP-equivalent cohort, 10.2 months (8.3–11.8) in patients with MVI/EHD, 9.7 months (7.6–10.9) in advanced HCC (BCLC stage C) and 16.6 months (11.2–22.8) in intermediate HCC (BCLC stage B). Treatment-related adverse events (all grades; grade >3) were: fatigue (50.3%; 2.1%), abdominal pain (25.9%; 2.1%), nausea/vomiting (31.2%; 0.5%) and GI ulcer (3.2%; 1.0%). At baseline, raised bilirubin (all grades) was present in 20.3%, increasing to 49.4% of patients evaluated up to day 90. Bilirubin grade was unchanged in 58.1% and increased in 37.8%; 4.0% had ≥grade 3 events. Conclusions: In patients matching the inclusion criteria for SHARP, RE was well tolerated with a median overall survival which compares favorably with sorafenib.
Activation of hedgehog pathway in neuroendocrine tumors.
Authors: Dong Mei , Sangai Takafumi , Zhao Qiang , Rashid Asif , Meric-Bernstam Funda , Yao James C.
Published: March 2020

e14662

Background: Neuroendocrine tumors (NETs) are rare tumors and often follow an indolent course, especially the tumors of low-to-intermediate grade. Nonetheless, they are incurable and lethal when advanced. The genetic etiology of sporadic NET is largely unknown. Numerous established oncogenes and tumor suppressor genes have been studied, but no mutations have been consistently identified, indicating tumorigenesis of NET may follow distinct mechanisms. It is well known that significant amount of patients with NETs may have harbored the slow-growing lesions since very young age, suggesting it could result from alterations of pathways involved in development. Hedgehog (Hh) signaling has been found to be important in embryonic patterning, stem cell maintenance and tissue repair; and is normally silenced in most mature adult tissue. However, it frequently undergoes gain-of-function mutations or reactivation due to ligand overproduction and has been linked to the etiology of a variety of tumors. Specific inhibitors of Hh pathway have been developed and tested in clinical trials with very promising results. Methods: In this study, the functional status of Hh pathway was examined in archival tissue specimmen using immunohistochemistry and its role in tumorigenesis was tested using an xenograft mouse model. Results: we have found that Hh ligand is overproduced in 48% (27/52) of small bowel NETs, 28% (9/32) of pancreatic NETs, and 28.6% of lung carcinoids. Hh signaling blockade led to decreased survival of NET cells in vitro, and tumor shrinkage in vivo using a xenograft mouse model. Conclusions: we conclude that Hh pathway is involved in the tumorigenesis of NETs, and can be used as a potential therapeutic target for NETs.
Relationship between treatment duration and outcomes in patients receiving concurrent chemoradiotherapy (CCRT) and surgery for locoregionally advanced (LRA) esophageal and gastroesophageal junction (E/GEJ) adenocarcinoma (ACA).
Authors: McNamara Michael J. , Rybicki Lisa A. , Rice Thomas W. , Rodriguez Cristina P. , Videtic Gregory M.M. , Saxton Jerrold P. , Bodmann Joanna , Ives Denise I. , Adelstein David J.
Published: March 2020

e14665

Background: Retrospective studies in breast, colon, and head and neck cancer have suggested that delays in administration of adjuvant chemotherapy result in inferior outcomes. We explore this question in patients with LRA E/GEJ ACA. Methods: From 11/99 to 7/06, 152 patients with cT3, N1, or M1a disease were enrolled on one of two clinical trials at the Cleveland Clinic. Two courses of CCRT consisting of 30Gy radiation (@1.5Gy BID) with continuous infusion cisplatin (20mg/m2/day x 4 days) and 5Fu (1000mg/m2/d x 4 days) were given both before and after surgical resection. In the second trial, 75 patients also received gefitinib during the 4 week induction and for a total of two years postoperatively. Using recursive partitioning analysis (RPA), we retrospectively explored the relationship between treatment duration and loco-regional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR), and overall survival (OS) in the 115 patients (76%) who completed all treatment. Outcomes were estimated using the Kaplan-Meier method and compared among groups using the log-rank test. Results: RPA analysis identified three groups of patients: 19 patients in whom resection occurred ≤45 days from the start of CCRT to resection (short treatment), 63 patients who underwent resection >45 days from the start of CCRT and required <50 days to complete treatment after surgery (intermediate treatment), and 33 patients who underwent resection >45 days from the start of CCRT but required ≥50 days to complete treatment after surgery (prolonged treatment). With a median follow-up of 90 (range 57-126) months, we found that patients with shorter treatment times had better 5 year DMC [64% (short) v 26% (intermediate) v 16% (prolonged); p=0.004], FFR [57% (short) v 23% (intermediate) v 16% (prolonged); p=0.015)], and OS [42% (short) v 30% (intermediate) v 12% (prolonged); p=0.08]. LRC was not different between the groups. Conclusions: Treatment delays in patients receiving multimodality therapy for LRA E/GEJ ACA may result in a greater risk of recurrence and decreased survival.
Randomized, single-centered, phase II clinical trial of nimotuzumab plus cisplatin and S-1 as first-line therapy in patients with advanced gastric cancer.
Authors: Wang Jin-Wan , Chi Yihebali , Zheng Zhao-xu , Qu Tao , Zhou Ai-Ping , Yang Lin , Jiang Wen-chang , Shi Shu-zhen , Sun Yong-kun , Song Yan , Kang Su-yi
Published: March 2020

e14668

Background: Nimotuzumab, a humanized IgG1 anti-EGFR monoclonal antibody, has demonstrated efficacy associated with an absence of severe skin toxicity in many phase I/II cancer trials. Methods: This is a single-center, parallel assignment and open-label study randomized to receive a infusion Cisplatin (30mg/m2/d, on day 1 and 2) and oral S-1 (80mg/m2/d, twice daily on day 1-14) every 3 weeks, either alone or together with Nimotuzumab (200 mg as a infusion on day 1, 8 and 15) (CS or NCS) as 1st line in patients with advanced or metastatic gastric cancer. The observation points were ORR, TTP, PFS, 1-year survival rates and safety. Results: 62 patients, 43 men and 19 women, median age 57 years (22-76 years), on good performance status (ECOG PS 0-2, one prior regimen) were treated with NCS (n = 31) or CS (n = 31). Up to 2012-01-16, 57 patients (NCS 30 cases compared with CS 27 cases) have undergone efficacy assessment. The objective response rate (ORR: PR 15) was 50% (15/30) in NCS group compared with (ORR: pCR 2+ PR 15) 63.0% (17/27) in CS group. Disease control rate was 96.7% and 96.3%, respectively. Until the same day, 36 patients have achieved progression in both groups (NCS 15: CS 11), median TTP was 5 months in NCS group compared with 3 months in CS group, and average TTP was 4.9 months and 4 months, respectively. The incidence of adverse events was similar between both groups. Adverse events included grade 3/4 hypo-hemoglobin 13.33%/7.41%, grade 3/4 thrombocytopenia 3.33%/0 and grade 3/4 neutropenia 3.33%/0. One patient experienced grade 3/4 digestive side effects 3.33%/0. Conclusions: The results have demonstrated benefit in TTP improvement. Further investigation is ongoing.
A study of activated carbon nanoparticles guided dissection of lymph nodes in radical gastric cancer surgery.
Authors: Keshari Rajiv Prasad , Zhou Zhiwei , Chen Gong , Yuan Shuqiang
Published: March 2020

e14674

Background: Gastric cancer is common and a leading cause of cancer deaths in the world. Lymph node(LN) status is important prognostic factor. As per AJCC, atleast 15 LNs to be dissected for accurate nodal staging and prognosis. More LNs dissections may reduce the possibility of skip metastases, thus, less recurrence and proper staging of the disease. Activated Carbon Nano-particle(AcCNP) can map a large number and even smallest lymph nodes. The objective of this study is to detect and dissect maximum number of LNs during radical gastrectomy by using AcCNP lymphatic mapping. Methods: 40 patients, Gr. A (22) experimental and B (18)control group, pathological diagnosis- Adenocarcinoma of stomach, AJCC staging I-IIIB. Time duration- 2008 to 2009, Institution- SYSUCC, Guangzhou,China, Plan- Radical Gastrectomy with extended lymphadenectomy. Neo-adjuvant given patients were excluded. A 1 ml of AcCNP was injected in the subserosa of the stomach at four different sites of the tumor border. All visible stained/nonstained LNs were dissected. The LN's size and the number were recorded. After pathological reports, descriptive analysis and t-test were performed to calculate the mean, median, ratio, range, frequency and predictive value for the accuracy and viability of the study. Results: Total LNs dissected-1254, Gr.A-772 (mean-35.41) and Gr.B- 482 (26.78). There was difference between total LNs dissected (p-value- 0.046). In Gr. A, 590 blackened and 182 non-blackened LNs resected. The ratio to the total number of LNs was ≥70%. LNs size in Gr. A was 0.03 to 0.5 cm and 0.80 to 1.5 cm in Gr. B, p-value: 0.000. No statistical differences between the two groups in age, sex, pTNM staging and histo-pathological type with p-value - 0.305, 0.369, 0.828 and 0.425 respectively, and in tumor size, Gr. A (5.59 cm) and Gr. B (3.72), p-value of 0.78. Conclusions: Lymph node detection procedure by intra-operative injection of Ac. carbon nanoparticle during radical gastrectomy is feasible in all stages of gastric cancer, with high detection rate and almost nil morbidity or mortality. It is safe, cost-effective and an effective tracer for lymphatic mapping procedure. It can be an appropriate tool for more accurate staging of gastric cancer.
Comparative outcome of sorafenib treatment in central Europe and Russia.
Authors: Bisovskaya Yulia , Pinter Matthias , Scheithauer Werner , Peck-Radosavljevic Markus
Published: March 2020

e14681

Background: Sorafenib is the standard treatment for advanced stage HCC. Here we compare outcomes in 2 cohorts of HCC patients from two large oncologic referral centers in Russia (R) and Austria (A). Methods: 69 pts (19 f/50 m) with HCC (BCLC A/B/C/D 1/30/38/0) in R and 148 pts (27 f/121 m; n. s. between cohorts) with HCC (BCLC A/B/C/D 0/26/104/18) in A were treated with standard dose of sorafenib 400 mg bid until progression or death between 2006 and 01/2012. Dose reductions were due to side effects. Survival was evaluated using Kaplan-Meier analysis and compared by log-rank test. Prognostic factors evaluated were pretreatment BCLC stage, Child-Pugh stage, and etiology of liver disease (viral/non-viral). Results: BCLC-staging distribution was significantly different between R and A centers with more patients in advanced st BCLC-C in A (A 70% vs. R 55%, p<0.0001). Patients also had more advanced stage liver disease in A (Child-Pugh stage A/B/C = 52/37/11%) compared to R (A/B/C = 85/15/0%; p<0.0001). Overall survival in A (median 7.4 mo; 95% CI 5.5 – 9.3) compared to R (median 9 mo; 95% CI 7.6 – 10.4) was not significantly different between the two cohorts (p=0.144). When analyzed according to BCLC-stage (B and C), survival in st B pts (A 11.2 vs. R 11.0; p=0.286) as well as st C pts (A 8.9 vs. R 6.4; p=0.62) was not different between the two cohorts. When evaluated according to severity of liver disease (non-cirrhotics/Child-Pugh A and Child-Pugh B), survival in non-cirrhotics/Child-Pugh A patients (A 11.3 mo vs. R 9.0 mo; p=0.746) and Child-Pugh B patients (A 5.5 mo vs. R 3.3 mo; p=0.481) was again not different between these two cohorts. Patients with viral etiology were more common in R (48%) than in A (34%) but not significantly so (p=0.06). Survival in patients with viral (A 10.2 mo vs. R 8.7 mo; p=0.644 ) or non-viral etiology of chronic liver disease (A 6.7 mo vs. R 9.7 mo; p=0.089) was also not significantly different. Conclusions: Overall survival and survival in various subgroups analyzed was not significantly different between the two cohorts. Sorafenib treatment in Russia compared to European Institutions seems to offer a comparable benefit for patients with intermediate/advanced stage HCC, independent of severity or etiology of the underlying liver disease.
An educational tool as an aid for making decisions about the initial treatment of gastric cancer.
Authors: Ravdin Peter , Peterson Lindsay , Rowe Julie
Published: March 2020

e14684

Background: Tools for making individualized numerical estimates of outcomes and to provide useful information are revolutionizing medicine. We have produced such a tool for decision making for patients with gastric cancer [GC] for whom neo/adjuvant therapy might be an option to be considered. Methods: We widely reviewed the medical literature and meta-analyses about adjuvant and neoadjuvant treatment for potentially resectable [GC]. We also reviewed the guidelines' statements about what is considered appropriate treatment for patients. In addition we used information about individual prognosis based on information from the SEER registry, the AJCC, and also as supplemented from the medical literature. Results: Examination of the medical literature shows the value of adjuvant chemotherapy and radiation for [GC]. For example, and recent GASTRIC meta-analysis of 31 trials found that a benefit for overall survival (hazard ratio [HR], 0.82; 95% CI, 0.76-0.90) and for disease-free survival (HR, 0.82; 95% CI, 0.75-0.90). There is also a substantial literature supporting the use of these regimens in the neoadjuvant setting (such as the MAGIC study with benefit in overall survival (HR for death, 0.75; 95% CI, 0.60 to 0.93). We found however that these HRs were rarely accompanied with estimates of absolute benefit. A typical quote from the GASTIC analysis is "Five-year overall survival increased from 49.6% to 55.3% with chemotherapy," which reflects the outcomes for an average patient. This information is implied as the basis for treatment recommendations for treatment, but numerical estimates of what is gained are not given in such texts as the NCCN guidelines. Our analysis of the SEER data showed disease specific [GC] mortality at 3 years to range from 4% for patients with low grade stage 1a disease to 49 % for patients with high grade stage IIIa disease. Conclusions: Integrating the information about the base line risks for negative outcome with hazard ratio estimates of the effective therapy we can make individualized estimates of outcome. We have also included in the tool substantial additional information about the nature of the disease, past and ongoing trials, and the safety and efficacy of the treatment opinions.
The clinical significance of neutrophil-lymphocyte ratio versus platelet-lymphocyte ratio in patients with metastatic gastric cancer.
Authors: Lee Suee , Oh Sung Yong , Kwon Hyuk-Chan , Kim Sung-Hyun , Lee Ji Hyun , Kim Min Chan , Kim Ki-Han , Kim Hyo-Jin
Published: March 2020

e14686

Background: Several inflammatory response materials could be biomarkers for prediction of prognosis of cancer patients. The neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR) has been introduced for prognostic scoring system in several cancer. The objective of this study was to determine whether the neutrophil-lymphocyte ratio (NLR), or the platelet-lymphocyte ratio (PLR) are significant prognostic marker in metastatic gastric cancer. Methods: We analyzed 150 patients with metastatic gastric cancer who received mFOLFOX regimen as the first-line chemotherapy. The NLR and PLR were calculated from complete blood counts in baseline laboratory test before the first cycle chemotherapy. Results: The overall response rate was 34.7% and stable disease was 38.7%. The median progression-free survival (PFS) was 4.2 months (95% CI, 3.5-4.8 months) and the median overall survival (OS) was 13.1 months (95% CI, 10.6-15.5 months). Kaplan-Meier analysis and log-rank test revealed that higher NLR (≥3) was a good prognostic biomarker of OS (p=0.024), but not associated with PFS (p=0.838). The PLR was not associated with PFS and OS (p=0.373 and p=0.304, respectively). In Cox regression analysis for predicting OS, younger age, good performance status, response of chemotherapy, and lower NLR (<3) were independent prognostic markers (Hazard ratio 2.052, 95% CI 1.370-3.075, p<0.001, hazard ratio 8.467, 95% CI 1.937-37.017, p=0.005, hazard ratio 1.889, 95% CI 1.222-2.921, p=0.004, and hazard ratio 1.616, 95% CI 1.080-2.416, p=0.019, respectively). Conclusions: Although prognosis in metastatic gastric cancer was associated with age and performance status, the NLR might be simple and prognostic index for metastatic gastric cancer.
Prognostic factor analysis of second-line chemotherapy in advanced biliary tract cancer.
Authors: Lee Sang-Cheol , Kim Kyoungha , Kim Hanjo , Kim Hyun Jung , Kim Se Hyung , Bae Sang-Byung , Kim Chan Kyu , Lee Namsu , Lee Kyu Taek , Park Sung Kyu , Won Jong-Ho , Yun Jina , Hong Dae Sik , Park Hee Sook
Published: March 2020

e14688

Background: There is no evidence that second-line chemotherapy in advanced biliary tract cancer (BTC) will result in substantial prolongation of survival. The purpose of this study was to evaluate prognostic factors for the survival of patients with advanced biliary tract cancer who was refractory BTC for first-line chemotherapy. Methods: We reviewed 89 patients retrospecitively with advanced biliary tract cancer who had enrolled in two clinical trials at three branches of Soonchunhyang university hospital. They received palliative chemotherapy with 2 regimens (biweekly GEMOX and modified FOLFOX-6). GEMOX is consist of gemcitabine 1,000 mg/m2 intravenously on day 1 and oxaliplatin 85 mg/m2 intravenously on day 2 every 2 weeks and mFOLFOX-6 is that oxaliplatin 85mg/m2 and folinic acid 400 mg/m2 on day 1 follwed by a 5-FU bolus 400 mg/m2 and 46-h infusion 2400 mg/m2 every 2 weeks. To evaluate the clinicopathologic factors that affected overall survival, univariate and multivariate analyses were performed on the baseline factors. Results: 89 patients were enrolled from Sep 2006 to Aug 2010. Medain age was 62.14 years (range 35-81). Univariate analysis revealed 4 prognostic factors affecting overall survival after first-line chemotherapy. Performance status of 0-1 vs >2 (p=0.014), salvage chemotherapy (p=0.021), locoregional disease vs disseminated disease (p=0.046) and responder of first-line chemotherapy (p=0.025) was revealed. Multivariate analysis found 2 prognostic factors affecting overall survival. They were salvage chemotherapy and initial responder. Conclusions: This results suggest that 2nd-line chemotherapy is needed for patients with good performance and responder of initial chemotherapy.
Imageable orthothopic metastatic mouse models for the identification of the antitumor and antimetastatic efficacy of traditional Chinese medicine (TCM).
Authors: Zhang Lei , Wu Chengyu , Zhang Yong , Wang Xiaoen , Reynoso Jose , Hoffman Robert M. , Zhao Ming
Published: March 2020

e14700

Background: Traditional Chinese Medicine (TCM) is still poorly understood with regard to the types of cancer it is effective against, as well as its mechanism of action. Modernization of TCM evaluation is necessary in order for TCM to be effectively developed. We report here on the use of patient-like orthotopic nude-mouse models of metastatic cancer to obtain proof-of-concept that TCM combinations can have anti-tumor and anti-metastatic activity. Methods: In the present study, human and mouse lung cancer and pancreatic cancer cell lines (H460, Lewis lung carcinoma [LLC] and MIA-PaCa-2, respectively), labeled with red fluorescent protein (RFP) or green fluorescent protein (GFP) were used. The cells were initially implanted subcutaneously or injected in the tail vein in nude mice. Subcutaneous tumors were harvested to obtain tissue fragments which were implanted orthotopically in nude mice. These models were used to evaluate the anti-tumor and anti-metastatic efficacy of the TCM termed Fufang LQ (LQ), which contains a mixture of Chinese herbs. Results: LQ (gavage, 600 mg/kg/day) significantly inhibited pancreatic and lung cancer tumor growth as measured by imaging, tumor and weight in both subcutaneous and orthotopic models. LQ was significantly efficacious against primary and metastatic cancer in the above models without weight loss in contrast to drugs such as doxorubicin and cisplatin, which caused significant weight loss. Survival of tumor-bearing mice was also prolonged by LQ treatment. Conclusions: The results of the present study indicate that TCM can have non-toxic efficacy, in contrast to standard chemotherapy drugys, against metastatic pancreatic and lung cancer in clinically-relevant orthotopic mouse models of cancer, an important step toward the clinical development of TCM.
Does 18-fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT) predict survival in advanced pancreatic cancer? A single-institution experience.
Authors: Ashraf Noman , Razzaque Saqib , Weber Jill M. , Malafa Mokenge Peter , Kim Richard D.
Published: March 2020

e14715

Background: Pancreatic cancer is associated with a poor prognosis. Histological grade, stage and serum tumor markers are well established prognostic factors for survival. Some studies suggest that 18-fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT) correlates with survival in pancreatic cancer. In this study, we aimed to determine whether standardized uptake value (SUV), a measure of FDG uptake by fusion PET/CT, had prognostic significance in patients with advanced pancreatic cancer. Methods: Using a comprehensive pancreatic cancer database at H. Lee Moffitt Cancer Center, we identified patients who underwent PET/CT scan as initial workup for resection but were found to have advanced disease (stages III and IV) when surgery was attempted. Data from January 2006 to December 2010 was retrospectively analyzed and correlated with the maximum SUV determined by PET/CT. Other prognostic factors including stage, age, gender, serum tumor marker CA 19-9 levels and the use of chemotherapy were also evaluated using multivariate analysis. Results: We identified 41 consecutive patients who were deemed resectable by virtue of staging workup with CT, PET/CT and endoscopic ultrasound (EUS), but found to have locally advanced/metastatic disease intra-operatively. At the time of analysis, there were a total of 30 deaths. Twelve patients had metastatic disease and 29 had stage III pancreatic cancer. SUV uptake ranged from 2.9 to 16.2 with a mean of 6.4. Median overall survival for the 28 patients with SUV less than or equal to the mean (≤ 6.4) was 14 months (95% confidence interval 10 – 25 months) vs. 9.1 months for the 13 patients with SUV > 6.4 (95% confidence interval 4-17 months). This difference was not statistically significant (p=0.178). On multivariate analysis, use of chemotherapy was the only independent predictor of survival. Conclusions: Glucose uptake by PET/CT, reflected by SUV, was not found to be a predictor of survival in patients with advanced pancreatic cancer. The retrospective nature and limited sample size are limitations of our study, however further research is warranted.