bluuebunny/crossref_metadata_2025 huggingface dataset:
A closer look at the number of lymph nodes examined in colorectal cancer: A VAMC experience
Authors: Kovar J. M. , Bui H. X. , Reynolds J. P. , Al-Ghawi H. , Luo G. , Abdel Karim N. , Samaan S. , Mehta A. , Molloy M.
Published: August 2020

e15117

Background: Retrieval of 12 lymph nodes (LN) is a current benchmark in colorectal cancer (CRC) resections according to the National Quality Forum (NQF). Series of multiple institutions contain variability in surgical and pathologic techniques for lymph node retrieval. To ensure consistency in retrieving lymph nodes for satisfactory staging, we present a 12 year experience by a single surgeon and single pathology lab at one VAMC on 157 patients (mean age 67) undergoing CRC resection. Furthermore, the use of chemotherapy for Stage II patients <12 LN retrieved is controversial and yields only a small survival benefit. Methods: The records of 157 patients from one surgeon's case log from 1994–2007 were reviewed. Strict guidelines were applied to remove the same distribution of pericolonic fat. The lab followed a two step approach to LN dissection: Step 1 search for grossly identifiable LN; Step 2 overnight Carnoy's immersion to find smaller LN. Statview and SAS software analyzed 1)Overall survival (OS) and association with finding >12LN; 2)Number of LN identified and impact on AJCC tumor stage (TS) and overall survival; 3)Number of LN and WHO tumor grade (TG) with OS; 4)The impact of number of positive LN on OS. Results: Our mean LN found (14.75) is higher than the 12 recommended by the NQF and is not significantly associated with OS regardless of AJCC TS(p=0.06). The mean LN per TS was I=13.4(N=41)/II=16.3(N=56)/ III=14.3(N=38)/IV 14.2(N=22). Number of LN identified was not statistically significant in predicting TS(p=0.42) or OS(p=0.24). WHO TG is significantly associated to decreased OS, but only in AJCC TS II/III/IV and not stage I (Ip>0.05/IIp=0.008/ IIIp=0.01/IVp=0.025). Higher number of positive LN was associated with lower OS (per each +LN, survival decreases by 0.15 months p=0.001) Conclusions: Contrary to multicenter studies, total number of LN identified does not impact AJCC TS or OS. Higher WHO TG and higher number of positive LN is associated with worse OS. This suggests that the tumor biology is more indicative of OS rather than host response (reactive lymphoid tissue) to the tumor. Stage II patients <12 LN may not be ‘high risk’ and adjuvant chemotherapy based on this factor alone should be reconsidered. Further studies would be warranted.

No significant financial relationships to disclose.
Randomized phase II trial of capecitabine versus capecitabine, low molecular weight heparin, and prednisone in refractory colorectal carcinoma
Authors: Mak E. , Townsley C. , Buckman R. , Chen E. , Lopez L. , Wang L. , Moore M. , Oza A. M.
Published: August 2020

e15126

Background: Capecitabine is widely used in the treatment of advanced colorectal cancer. Continuous low dose chemotherapy has been postulated to have anti-angiogenic effects discrete from its anti-proliferative effects on tumors (metronomic therapy). Dalteparin and prednisone have also been implicated in inhibiting tumour angiogenesis and hypothesized to have additive benefit to chemotherapy. This randomized phase II study examined the additive effect of dalteparin and prednisone with capecitabine in metastatic colorectal cancer. Methods: Patients with metastatic colorectal cancer were randomized to either capecitabine (C) 2,500 mg/m2 in divided doses from days 1–14 in a 3-week cycle or capecitabine with dalteparin and prednisone (CDP). There was no restriction on previous treatment, other than no prior capecitabine. Dalteparin was given at 5,000 units once daily subcutaneously, and prednisone orally 10 mg daily, both on a continuous basis. Thirty patients were planned for accrual in each arm with interim analysis when accrual reached fifteen in each arm. The primary end-point was disease control defined as treatment response or stable disease >4 months. Radiological evaluation was performed every 6 weeks. Treatment was discontinued if patients had progressive disease or intolerable toxicity. Results: Thirty patients were recruited. Fourteen patients had received ≥3 previous regimens (median 3 (C), 2 (CDP)). Median performance statuses were ECOG 1 (C) and 0 (CDP). Nine patients achieved stable disease greater than 6 months (5 (C)/4 (CDP)). There was no statistical difference in the median survival time and time-to- progression for the two groups (11.1 mth (C)/15.8 mth (CDP); 3.2 mth (C)/2.8 mth (CDP)). The commonest toxicities overall were myelosuppression and hand-foot syndrome (HFS). The most common Grade 3+ adverse events were HFS (6 patients) and diarrhea (4 patients). Conclusions: The combination of dalteparin, prednisone and capecitabine did not improve disease control over that seen with capecitabine in refractory metastatic colorectal cancer.

No significant financial relationships to disclose.
Protective role of silibinin on matrix metalloproteinase-2 and activator protein-1 on LoVo cells
Authors: Lin C. , Chen Y.
Published: August 2020

e15136

Background: Silibinin, a flavonoid and the major active component of milk thistle, has been as a safe diet supplement for several decades. It has been proved with anti-hepatotoxic properties and pleiotropic anticancer capabilities. Current study aimed to investigate the role of silibinin as potential therapeutic target of colon cancer through antiangiogenesis and its related molecular mechanisms with matrix metalloproteinase- 2 (MMP-2) and activator protein-1 (AP-1). Colon cancer cell line, LoVo cells, treated with a major prognostic factor, interleukin-6 (IL-6), was studied. Methods and Results: By western blot analysis, silibinin suppressed MMP- 2 protein expression in time- and concentration-dependent manners. Furthermore, the inhibitors of JNK/AP-1 binding activity abolished the expression of MMP-2 in IL-6-stimulated LoVo cells, but not PI3K pathways. We also demonstrated that silibinin inhibited IL-6- stimulated LoVo cell migration and further tumor angiogenesis, which similar to the effects from addition with AP-1 inhibitor. By EMSA, the binding activity of AP-1 in LoVo cells was also decreased with silibinin treatment. In addition, the imaging of confocal microscopy revealed that AP-1 presentation was attenuated on IL-6-stimulated LoVo cells plus silibinin treatment. Conclusions: Taken together, these data indicated that silibinin inhibits angiogenesis through the suppression of MMP-2 expression and AP-1 binding activity in colon cancer cells. It suggests a novel anti-metastatic application of silibinin in colon cancer chemoprevention.

No significant financial relationships to disclose.
Phase I study of preoperative (pre-op) short course chemoradiation (CRT) with proton beam therapy (PBT) and capecitabine (cape) for resectable pancreatic ductal adenocarcinoma (PDAC) of the head
Authors: Hong T. , Ryan D. P. , Blaszkowsky L. S. , Mamon H. J. , Mino-Kenudson M. , Adams J. , Yeap B. , Winrich B. , DeLaney T. F. , Fernandez-del Castillo C.
Published: August 2020

e15536

Background: Standard adjuvant 6 week CRT may delay and reduce tolerability of adjuvant gemcitabine-based chemotherapy. We explore the feasibility of a one-week course of pre-op CRT with PBT and cape followed by pancreaticoduodenectomy (PD). Methods: 15 pts with radiographically resectable, biopsy-proven PDAC of the head were enrolled from May 2007- September 2008. Eligibility included no CT involvement of SMA or celiac artery; adequate renal, hepatic and hematopoetic function; and ECOG PS 0/1. Dose level 1 consisted of PBT delivered 3 Gy x 10 Monday to Friday. Pts in subsequent dose levels received 5 Gy x 5 in progressively shortened schedules: level 2 (wk 1 M W F, wk 2 T Th), level 3 (wk 1 M T Th F, wk 2 M), level 4 (wk 1 M-F). Radiation was targeted at pancreatic mass with elective nodal coverage. Pts received Cape 825 mg/m2 BID wk 1 and 2 M-F. PD was performed 1–6 wks after completion of chemotherapy. Results: 15 pts were enrolled on study. 3 pts were treated at each of dose levels 1–3. 6 pts were at dose level 4, which was selected as MTD. No dose limiting toxicities were observed. Gr 3 toxicity was noted in 4 pts (pain-1, GI-1, stent obstruction/infxn- 2). 11 pts underwent resection. Reasons for no resections were: metastatic disease-3 and unresectable tumor- 1. Mean time from last therapy to surgery was 28 d (10–44). Mean post-PD length of stay was 6 days (range 5–10). No unexpected 30-d post-op complications, including leak or infection, were noted in comparison to historical controls. 9/11 resected pts had R0 resection. 9/11 had positive nodes. Mean resected tumor diameter was 2.9 cm (2.2–4.3). Average percentage of fibrosis in tumor mass was 74%. Conclusions: Pre-op CRT with 1 wk of PBT and capecitabine followed by early surgery is feasible. A phase II study is underway.

No significant financial relationships to disclose.
A phase I pharmacokinetic (PK) study of vorinostat (V) in combination with irinotecan (I), 5-fluorouracil (5FU), and leucovorin (FOLFIRI) in advanced upper gastrointestinal cancers (AGC)
Authors: Fetterly G. J. , Brady W. E. , LeVea C. M. , Litwin A. M. , Zagst P. D. , Prey J. D. , Tarquini M. , Giardina M. K. , Iyer R. V. , Khushalani N. I.
Published: August 2020

e15540

Background: Currently, advanced AGC has no clear standard regimen. The loss of transforming growth factor-β (TGFβ) response contributes to oncogenesis and has been described in gastric cancer. V, an inhibitor of histone deacetylase (HDAC) can restore TGFβ activity. We hypothesize that the addition of V to a standard chemotherapy regimen, FOLFIRI will result in improved therapeutic efficacy. Methods: AGC (esophagus, gastric, hepatocellular) patients (pts) with adequate organ function, performance status (ECOG 0–1), and 0–1 prior chemotherapy regimens are eligible for this phase 1 study to determine the MTD of V. Treatment consists of standard FOLFIRI (I 180mg/m2, leucovorin 400mg/m2, 5FU 400mg/m2 followed by 46-hr infusion 5FU 2400 mg/m2 q2w) with escalating doses of V given orally daily starting on day 2 (doses 200mg, 300mg, 400mg) in part 1 of the study. Per pre-specified design, initial intra- and inter-patient dose escalation was permitted, but then changed to a standard 3+3 design after observed toxicities. Tumor biopsy pre-Rx and at D13 are being done for TGFβ and survivin expression. PKs for I, SN-38 & SN-38G are being evaluated in part 1. Part 2 examines PK of V at the highest V dose tolerated. Results: 10 pts (7 M, 3 F), with a median age of 52 yr have been treated at 3 dose levels of V in part 1 (2 at 200mg, 5 at 300mg, 3 at 400mg). 2 pts have been given 400mg V in part 2. Major toxicities included neutropenia, leukopenia, fatigue, diarrhea, anemia, and hypoalbunemia. No DLT was noted at any dose level. Of the 8 pts evaluable for response, 2 pts experienced a partial response and 5 pts had stable disease. SN-38 exposure was similar prior to (316–395 ng-hr/mL) and in combination with escalating doses of V (426–469 ng-hr/mL), with a terminal half-life ranging from 7.5–14 hr. Conclusions: V continuously at 400mg/d with FOLFIRI was tolerable in AGC pts. Drug exposure of SN-38 is not affected by V coadministration. The expansion cohort will determine the recommended phase 2 dose. Correlative studies of survivin and TGFβ expression are ongoing. Part 3 will examine intermittent V dosing. This study is supported by an IISP research grant from Merck & Co., Inc.

[Table: see text]
Phase II study of efficacy of bevacizumab and erlotinib in inoperable previously untreated hepatocellular carcinoma (HCC)
Authors: Govindarajan R. , Siegel E. , Makhoul I. , Williamson S.
Published: August 2020

e15557

Background: New treatment options are needed for patients with inoperable and metastatic HCC. Sorafenib, a RAF kinase inhibitor, prolongs the time to progression and overall survival compared to best supportive care (5.5 and 10.7 months respectively). Angiogenesis plays important role in the development and progression of HCC. Erlotinib, an EGFR tyrosine kinase inhibitor that down-regulates expression of Vascular Endothelial Growth Factor (VEGF), and bevacizumab, a monoclonal anti-VEGF antibody, have synergistic activity in arresting angiogenesis. The objective of the study was designed to evaluate the efficacy of the combination of bevacizumab and erlotinib. The pre-determined endpoint for a positive result is a 27 week PFS of > 20%. Methods: A phase II study was conducted for newly diagnosed unresectable or metastatic HCC, Child-Pugh class A or B cirrhosis with bilirubin <2.0 mg/dL, transaminases < 5 x ULN, Platelet count >75,000 K/UL and ECOG PS 0–2 who had no prior systemic therapy and were not candidates for liver transplantation. Erlotinib was administered continuously at a daily dose of 150 mg, and bevacizumab was administered at a dose of 15 mg/kg intravenously every three weeks. Subjects were evaluated for disease progression by RECIST criteria. Results: At the time of analysis, 21 subjects were enrolled (16 Child- Pugh class A, 5 class B). 16 were evaluable. The median age was 60 Yrs.(range 33–81). Four subjects (27%) were progression-free at 27 weeks of enrollment (95% CI 8%- 55%). Median (quartiles) time to progression was 10.3 (9.0–57.1) weeks. The median (quartiles) overall survival (OS) was 59.7 (range 24.6- 92.6) weeks. Grade-3 events observed were (no.): fatigue (4), dehydration (2), hematemesis (1), diarrhea (1), nausea (1), and dyspnea (1). Grade-4 events (no.) observed were: myocardial infarction (1), atrial fibrillation (1), and ventricular tachycardia (1); pulmonary edema (1). Conclusions: The results met the predetermined study end point of progression free survival at 27 weeks of > 20%. The combination of bevacizumab and erlotinib should be further evauated as treatment option for patients with HCC.

[Table: see text]
Phase II study of intrabuccally-administered amplitude-modulated electromagnetic fields in patients with advanced hepatocellular carcinoma
Authors: Costa F. P. , de Oliveira A. C. , Meirelles R. , Machado M. M. , Surjan R. , Chammas M. , Bottger B. , Morgan D. , Barbault A. , Pasche B.
Published: August 2020

e15573

Background: Over the past few years we have identified tumor-specific frequencies for several common forms of cancer. The goal of this study was to assess the tolerability and effectiveness of electromagnetic fields amplitude-modulated at tumor-specific frequencies and administered by means of an intrabuccal spoon-shaped probe in patients with advanced hepatocellular carcinoma (HCC). Methods: From October 2005 to July 2007, patients with advanced HCC and Child-Pugh A or B were recruited in a phase II study. Three daily 60 min outpatient treatments were administered until disease progression or death. Imaging studies were performed every eight weeks. The primary efficacy end point was progression-free survival ≥ 6 months. Secondary efficacy end points were progression-free survival and overall survival. Results: A total of 41 patients were enrolled, 17 had Child-Pugh A, 20 Child-Pugh B disease. The median age was 64.0 years. Seventeen patients (34.1%) were progression-free for more than 6 months. Median progression-free and overall survivals were 4.8 months (95% CI 2.3–6.0) and 6.9 months (95 CI 4.8–11.1). As of December 2008, four patients are alive and two patients, who are still undergoing therapy, remain progression-free for 30.4 and 30.7 months, respectively. Four patients had partial response (9.8%) and sixteen had stable disease for at least 12 weeks (39.0%) according to the RECIST criteria resulting in 48.8% disease control. All responses were confirmed by independent review. There were no NCI grade 2, 3 or 4 toxicities. One patient developed grade 1 mucositis and one patient grade 1 fatigue. Conclusions: In patients with advanced HCC and impaired hepatic function, treatment with amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of anti-tumor effects, which are long-lasting in some patients.

No significant financial relationships to disclose.
A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma
Authors: O'Neil B. H. , Williams-Goff L. W. , Kauh J. , Bekaii-Saab T. , Strosberg J. R. , Lee R. , Deal A. M. , Sullivan D. , Sebti S. M.
Published: August 2020

e15574

Background: HCC is a deadly disease with few effective treatments. It is characterized by frequent MEK/ERK activation in the absence of RAS or RAF mutation. AZD6244 is a specific inhibitor of MEK that can be administered orally. Methods: Multi-center, single-arm study with a two-stage design utilizing RR as primary endpoint. Patients had advanced or metastatic HCC not amenable to surgical therapy or who failed locoregional therapy. Pts with Childs-Pugh A and compensated B were eligible. No prior systemic therapy was allowed. A pre-treatment biopsy was performed for p-ERK analysis. AZD6244 was administered orally at a dose of 100 mg bid. Results: 19 patients were enrolled, completing the first planned stage. One patient withdrew during cycle 1 with grade 2 AEs and is not evaluable. One patient is too early for evaluation. Another was removed from study for toxicity prior to evaluation. Two patients exhibited clinical progression and were removed from study without imaging (both assigned response of PD). Of 16 evaluable patients, PR + CR was 0%, SD 37.5%, PD 62.5%. Toxicities were generally low grade and included nausea (75%), transaminitis (63%), Alkaline phosphatase (50%), vomiting (50%), fatigue (44%), diarrhea (44%) and skin rash (44%). Grade 3–4 toxicity included transaminitis (38%), hyperbilirubinema (25%), and hypokalemia (13%). Median TTP was 8 weeks (95% CI: 6.6, 11.1). Conclusions: The study has been stopped at the interim analysis due to lack of radiographic response. Time to progression is not suggestive of significant prolonged stable disease. AZD6244 is well tolerated, but appears to have minimal activity in advanced HCC. Analysis of ERK phosphorylation status in biopsy samples is ongoing.

No significant financial relationships to disclose.
BRSK2 expression as a prognosis marker in pancreatic cancer patients
Authors: Lou Dr. W. , Niu G.
Published: August 2020

e15603

Background: The prognosis of pancreatic cancer remains dismal because of difficult early diagnosis, low resection rate and aggressive biological behavior. The research of factors related to oncogenesis, tumor infiltration and metastasis is valuable. AMPK(AMP-activated protein kinase)family is a group of regulators on the cellular energy metabolism which are sensitive to the cytoplasmic change of AMP/ATP ratio. As a member of AMPK, BRSK2 is found to be expressed in human pancreatic cell line and facilitate the tumor cell survival on glucose starving. In order to examine the expression of BRSK2 in human pancreatic cancer and explore the underline clinical implication, human pancreatic tissue was examined immunohistochemically Correlation of tumor biological behavior, prognosis and BRSK2 expression was examined. Methods: Seventy nine resected tumor specimens were collected. Immunochemical staining method was used to examine the expression pattern of BRSK2 translated protein. Semi-quantitative analysis was employed to compare the expression intensity and content of BRSK2 in tumor issues, peri-tumorous tissue and normal pancreatic tissue. Possible relationship of tumors differentiation, TNM stage, presence or absence of vessel and neural infiltration were explored with BRSK2 expression. The correlation of BRSK2 expression profile and patients survival was explored. Results: BRSK2 was weakly expressed in normal pancreatic tissues and peri-tumor tissues, including the islet and minor ducts. BRSK2 was strongly expressed in pancreatic cancer tissues, the expression intensity was correlated with extent of lymphatic metastasis, distant metastasis, TNM staging and neural invasion. Tumors with lymphatic metastasis, distant metastasis, neural invasion and later TNM stages showed stronger expression of BRSK2. The expression of BRSK2 in pancreatic cancer was closely correlated to the prognosis of patients, those with higher expression pattern showed bad prognosis. Conclusions: BRSK2 is up-regulated in pancreatic cancer; the expression of BRSK2 is correlated with tumor biological behavior and patient's prognosis.

No significant financial relationships to disclose.
Phase I study of docetaxel, oxaliplatin, and capecitabine as first-line therapy to patients with advanced gastroesophageal cancer
Authors: Schønnemann K. R. , Andersen M. , Yilmaz M. , Jensen H. A. , Vestermark L. W. , Pfeiffer P.
Published: August 2020

e15613

Background: Previously, epirubicin, cisplatin, and 5-FU (ECF) were often recommended as first line therapy to patients (pts) with advanced gastro-esophageal cancer (GE). If cisplatin is substituted by oxaliplatin (E) and 5-FU by capecitabine (X) this regimen can easily be administered with comparable efficacy and lower toxicity. In addition, recent studies have shown that efficacy can be improved by adding docetaxel (T) to CF. We therefore initiated a phase I trial of docetaxel, short-time infusion of oxaliplatin and continuously capecitabine (TEX) as first line therapy to establish the recommended dose for further therapy. Methods: Pts were enrolled in cohorts of 3 at each dose level ( Table ). All pts had non resectable histologically GE adenocarcinoma. No pts had received prior chemotherapy. Therapy was given day 1 with escalating doses of docetaxel (60 mg/m2to 75 mg/m2, as a 60 minutes infusion), capecitabine (1000 to1250 mg/m2/day continuously) and oxaliplatin (85 to 130 mg/m2 as a 30 minutes infusion). Cycles were repeated every 3 weeks for a maximum of 8 cycles. Toxicity was evaluated according to NCIC-CTC 3.0. DLT was evaluated after the first TEX cycle and defined as non-hematological toxicity grade ≥ 3, neutropenia grade 4 or febrile neutropenia more than 7 days. Results: From June 2007 to July 2008, 16 consecutive pts were treated with escalating doses of TEX. Median age was 59 years (43–74), median performance status was 1 (0–1). At dose level 5, two of 4 pts had DTL (1 pt had grade 3 vomiting and nausea and 1 pt had grade 3 nausea, vomiting and diarrhea). In addition 3 of 4 pts had neutropenia grade 4 without fever at dose level 5. Presently, 12 pts are still alive. Conclusions: First line taxotere, oxaliplatin and capecitabine every 3 weeks is easily administered in an out-patient setting but with substantial GI and haematological toxicity at dose level 5. An additional 6 pts will be included at dose level 4 to confirm tolerability at dose level 4. [Table: see text]

No significant financial relationships to disclose.
Primary gastroenteropancreatic poorly differentiated neuroendocrine carcinoma: Clinico-pathologic analysis of 68 cases
Authors: Bukhari M. H. , Byron E. , Strosberg J. R. , Nasir N. A. , Henderson-Jackson E. , Bui M. , Hakam A. , Domenico C. , Kvols L. , Nasir A.
Published: August 2020

e15616

Background: Primary gastro-entero-pancreatic poorly differentiated neuroendocrine carcinomas (GEP-PDNECAs) are highly aggressive neoplasms with a very poor prognosis. This study was conducted to evaluate the immuno-morphological spectrum of GEP-PDNECA, and patient survival with systemic platinum and etoposide therapy. Methods: Under an IRB-approved protocol, clinico-pathologic data were collected on 68 adult patients with GEP-PDNECA who had undergone biopsy / resection at MCC or outside institution. Data sources: Pathology archives, consultation files, tumor registry and social security index. All available slides were reviewed and tumors were histologically sub-typed. Subsequently, clinico-pathologic data and patient survival were analyzed. Results: Patients: 41 M/27 F. Age: 25–76 yrs (mean 42 yrs). Sites: Colo-rectum 39, pancreas 19, small intestine (SI) 4, stomach 3, colon/SI/pancreas 3. 63 of 68 (93%) patients presented with lymph node/distant metastases. Of 68 tumors 37 (54%) were classified as small cell carcinoma (SCCA), 16 (24%) large cell carcinoma (LCCA), 5 (7%) mixed small and large cell (MSLCCA) and 10 (15%) poorly differentiated carcinoma with neuroendocrine features (PDCA-NEF). Tumors were positive for chromogranin in 38/65 (55%), synaptophysin in 62/67 (92%), and CD56 in 17/21 (81%) cases. One marker was positive in 22/68 (32%), 2 in 40/68 (59%) and all 3 were positive in 9/68 (13%) cases. Fifty eight of 68 (85%) patients were treated with platinum and etoposide. Overall survival at 1, 3 and 5 years was 85%, 40% and 24% respectively. Patient survival was independent of age (r= -0.1022), sex (r= -0.909) and histologic subtype (r= - 0.1028) (p= 0.128) but was related to distant metastases (r=0.306; p=0.0383). Conclusions: Diagnosis of GEP-PDNECA can be based on histo-morphologic features and expression of neuroendocrine markers. Synaptophysin was the most sensitive marker; however, a panel of 2 or 3 neuroendocrine markers (Syn, Cg and CD56) may be more useful to avoid under-diagnosis of GEP-PDNECA, especially in the metastatic setting. Although survival of GEP-PDNECA patients following platinum and etoposide in our series was relatively favorable, there is need for novel therapies to improve patient survival.

No significant financial relationships to disclose.
Serum lactate dehydrogenase (LDH) level as a prognostic factor for the patients with advanced gastric cancer
Authors: Lee H. , Yuh Y. , Kim S.
Published: August 2020

e15621

Background: Though serum LDH level is frequently elevated in the patients with advanced gastric cancer, its clinical significance is still elusive. Moreover, the relationship between the change of serum LDH level after chemotherapy and the response to the treatment has not been studied, yet. We analyzed serum LDH level as a prognostic factor for the patients with advanced stomach cancer. Methods: We assessed serum LDH level before chemotherapy for the patients who were planned to receive palliative chemotherapy. We re-assessed their serum LDH level at the time when the response to chemotherapy was evaluated after 2–4 cycles of treatment. The survival duration and the response to chemotherapy for the patients with low serum LDH level were compared to the survival duration and the response to chemotherapy for the patients with high serum LDH level. The relationship between the change of serum LDH level and the response to the treatment was evaluated, too. Results: Total 118 patients were entered into this study and 114 patients were evaluable for their response to chemotherapy. Pre-treatment serum LDH level was normal in 88 patients and elevated in 30 patients. The response rate in the patients with high serum LDH level was significantly higher than the response rate in the patients with normal serum LDH level (34.5% versus 15.3%, p < 0.05). However, the patients with normal serum LDH level lived longer than the patients with high serum LDH level (median: 378 days versus 206 days, p < 0.001). The normalizing of the elevated serum LDH level after chemotherapy was related to the good response to treatment (response rate 50.0% versus 18.8%, p < 0.05). Conclusions: For the patients with advanced gastric cancer, high serum LDH level was related to better response to chemotherapy but shorter survival duration. The normalization of elevated serum LDH level after chemotherapy was related to good response to treatment.

No significant financial relationships to disclose.
Analysis of association between carcinoid heart disease and mesenteric fibrosis in patients with midgut carcinoid tumour
Authors: Desai K. , Bhattacharya S. , Srirajaskanthan R. , Morgan-Rowe L. , Toumpanakis C. , Meyer T. , Caplin M.
Published: August 2020

e15650

Background: Valvular heart disease in patients with carcinoid syndrome is due to development of fibrosis and endocardial thickening in the heart. The most accepted theory relating to development of heart disease is secretion of serotonin (5- hydroxy tryptamine) by the tumour or metastases. Mesenteric fibrosis develops as a result of peptides e.g.TGF beta released by local metastases. Both complications cause significant morbidity and mortality in patients with carcinoid syndrome. Aim: to evaluate the relationship of carcinoid heart disease and mesenteric fibrosis. Methods: We analysed retrospectively all patients (n=200) who had metastatic (liver metatstasis) neuroendocrine tumour and carcinoid syndrome with the primary clearly identified within the small bowel or caecum. We aimed to evaluate clinically symptoms of mesenteric ischemia and small bowel obstruction and also radiological presence of desmoplasia and small bowel dilatation. All patients underwent clinical and echocardiographic cardiovascular assessment to determine the presence of carcinoid heart disease. Results: Of 200 patients 42 had echocardiographic evidence of carcinoid heart disease. 4 patients had evidence of both mesenteric desmoplasia and carcinoid heart disease. 38 patients had carcinoid heart disease alone. Of the remaining 158 patients who had no evidence of carcinoid heart disease, 24 of them had evidence of desmoplasia and/or clinical evidence of sub-acute bowel obstruction where no other cause could be found. The remaining 134 patients had none of these complications. Comparing the relationship of Carcinoid heart disease and mesenteric fibrosis using two tailed exact Fisher's test, p value is 0.45, demonstrating they are statistically independent. We are currently assessing the effect on mortality. Conclusions: Carcinoid heart disease and mesenteric fibrosis (and its effects) are important determinants in morbidity and mortality of patients with midgut neuroendocrine tumour. Although carcinoid heart disease and mesenteric fibrosis are part of the same patho-physiologic process affecting patients with midgut neuroendocrine tumour, the results suggest that progression of these complications is independent of each other.

No significant financial relationships to disclose.
Use of fermented mistletoe (viscum album L.) extract from oak tree (quercus) as supportive treatment for patients with pancreatic cancer
Authors: Stauder G. M. , Matthes H. , Friedel W. E. , Bock P. R.
Published: August 2020

e15656

Background: To evaluate safety and efficacy of supportive treatment with fermented mistletoe extract Iscador Qu (from oak tree, quercus) (ISC-Qu) in a cohort of patients that received conventional adjuvant chemo- and/or radiotherapy (conv-th) alone (control) or additionally ISC-Qu (test group). Methods: Multicenter, comparative, non- interventional cohort study with parallel groups. Unselected, standardized, anonymized data from medical records meeting the eligibility criteria were followed until last visit or death. All endpoints were adjusted to baseline imbalance, therapy regimen and other confounders. Results: 270 patients (75 ISC-Qu/195 control) from 17 oncological centers. The treatment with ISC-Qu started before (16.7%), during (75.0%), or after (8.3%) the conv-th (mainly with gemcitabine) and usually lasted until last visit or death. The period of aftercare was median 20.3 (test group) and 10.1 months (control). Isc-Qu was applied by sequential dose escalation from 0.01 mg up to 20 mg, 2–3 injections per week (s.c.). Safety: Only 14.7% of the patients developed local ADR to ISC-Qu, there was no life- threatening ADR. Efficacy: There was a significant and relevant prolongation of overall survival: hazard ratio, HR (95% CI) = 0.35 (0.21- 0.58), p < 0.001; estimated relative risk reduction = 65%. The number of ADR to conv-th (odds ratio, OR = 0.20, p = 0.006, risk reduction 80%) and the estimated risk for disease or therapy related symptom persistence were significantly reduced in the test group with ISC-Qu. Conclusions: The results show reliable safety and an important effect of supportive ISC-Qu treatment on overall survival in patients with pancreatic cancer of any stage.

[Table: see text]
Eligibility of patients with hepatocellular carcinoma for systemic treatment with sorafenib
Authors: Zimmermann L. C. , Schuette K. , Borschein J. , Csepregi A. , Malfertheiner P.
Published: August 2020

e15673

Background: Sorafenib is the first systemic drug that effects prolonged overall survival in patients with advanced hepatocellular carcinoma (HCC) by almost three months with moderate toxicity. This study aims to evaluate how many patients diagnosed with HCC are candidates for systemic treatment and possibly benefit from it. Methods: All patients diagnosed with HCC in our hospital in between January 2006 and June 2008 were analysed regarding the presence and stage of liver cirrhosis, tumor stage and the treatment applied. Results: In a period of 30 months 182 patients were diagnosed with HCC (female n = 42, male n = 140, median age 66 (16–84)). 169 suffered from liver cirrhosis, 96 in Child A, 46 in Child B and 27 in Child C stage. 36 patients (19.8 %) were diagnosed with uninodular disease, in 17 patients (9.3%) 2 or 3 nodules were detected and 129 (70.9%) patients suffered from multinodular HCC. 79 patients received local ablative therapy or transarterial chemoembolisation, 15 underwent surgical resection, 29 patients were treated with best supportive care and 59 patients were candidates for systemic treatment. Out of these 25 either had no liver cirrhosis or were in stage Child A and 17 were in Child B stage and would therefore fit for therapy with sorafenib (23.1%). 17 pts with advanced disease and Child C cirrhosis did not fit for this treatment. Conclusions: Assuming that patients with advanced HCC and good or moderate liver function are candidates for systemic treatment with sorafenib every fifth patient is likely to benefit from the introduction of this treatment option.

[Table: see text]
Adjuvant chemoradiotherapy with carboplatin and a fluoropyrimidine for resectable gastric and gastroesophageal junction cancer: A retrospective review of the Stanford experience
Authors: de Bruin M. A. , Kunz P. L. , Sharma V. B. , Norton J. A. , Bastidas J. , Chang D. T. , Koong A. C. , Koong A. C. , Balise R. R. , Ford J. M. , Fisher G. A.
Published: August 2020

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Background: The standard of care for the adjuvant treatment of resected gastric or gastroesophageal junction (GEJ) adenocarcinoma in the U.S. is post-operative 5FU and radiotherapy per the MacDonald regimen. At Stanford Cancer Center (SCC) we have adopted a modified regimen of chemoradiotherapy using carboplatin and a fluoropyrimidine. Methods: A retrospective review was performed of patients at SCC with T2-T4 or node positive gastric or GEJ cancer who underwent surgery with curative intent, and then received the following treatment. Carboplatin (AUC 6) was administered on days 1 and 22. Patients also received either 5FU at 200 mg/m2/day (via continuous infusion) plus leucovorin for six weeks, or capecitabine at 1,000 mg/po BID for 14 days, repeated every 21 days for 2 cycles. At week 8, infusional 5FU or capecitabine was combined with external beam radiotherapy to the gastric bed for five weeks (total 4,500 cGy). At week 14, patients repeated an additional 2 cycles of carboplatin and fluoropyrimidine as tolerated. Results: Forty-nine patients were identified. The majority (76%) were male. Median age at diagnosis was 57 years. Thirty-nine had gastric and 10 had GEJ cancers. With a mean follow up of 35 months, twenty-one patients (43%) have died; median disease free and overall survival have not been reached. Eighteen patients (37%) have recurred. The percentage of patients alive by stage was 100% (4/4) for stage IB, 62% (8/13) for stage 2, 53% (9/17) for stage IIIA, 33% (2/6) for stage IIIB and 22% (2/9) for stage IV. Grade 3 or 4 toxicities occurred in 27 patients (55%); most common were neutropenia (16), thrombocytopenia (11) and gastrointestinal toxicity in (8). Conclusions: Adjuvant chemoradiotherapy with carboplatin and a fluoropyrimidine after curative resection of gastric and GEJ cancer was well tolerated and yielded survival results similar to historical data.

No significant financial relationships to disclose.
Predictive factors of outcome and clinical management of adjuvant S-1 chemotherapy for gastric cancer
Authors: Iwasa S. , Yamada Y. , Nakajima T. E. , Kato K. , Hamaguchi T. , Morita S. , Saka M. , Fukagawa T. , Katai H. , Shimada Y.
Published: August 2020

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Background: Adjuvant S-1 chemotherapy has become a standard treatment for stage II and III gastric cancer, following the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC). This study was designed to identify factors that can be used for predicting the outcome and clinical management of adjuvant S-1 chemotherapy in patients with stage II and III gastric cancer. Methods: We retrospectively examined 97 consecutive patients with stage II or III gastric cancer who received S-1 chemotherapy after gastrectomy to investigate factors associated with outcome and clinical management. S-1 (80 mg/m2/day) was orally administered twice daily for 28 consecutive days, followed by a 14-day rest period. As a rule, this protocol was continued for one year after gastrectomy. According to toxicity profiles, dose reduction or dose schedule modification was performed. Results: Patients consisted of 63 males and 34 females (median age, 59 years; range, 35–80 years), and those undergoing total gastrectomy/subtotal gastrectomy = 40/57. The median follow-up period after gastrectomy was 43.0 months (range, 5.3–73.4 months). As for adjuvant S-1 chemotherapy, dose reduction and dose schedule modification were conducted in 59% and 40% of the patients, respectively. Of the patients needing dose reduction, 79% underwent reduction within three months of treatment. The most common reason for dose reduction during the treatment period was anorexia (47%), followed by diarrhea (32%), leukopenia (24%) and rash (16%) with overlapping reasons. The duration period of the treatment was at least 3 months in 88%, at least 6 months in 82%, and scheduled 12 months in 73%. Twenty six patients discontinued treatment due to adverse event (20 patients), recurrent disease (2 patients) and other reasons (4 patients). The median duration until treatment discontinuation was 4.0 months. To date, 15 patients have recurrent disease. Significant predictive factors for recurrence were not statistically identified. Conclusions: Most patients (73%) could complete the scheduled treatment duration by dose reduction and dose schedule modification.

No significant financial relationships to disclose.
Preoperative gemcitabine based chemoradiotherapy in locally advanced nonmetastatic pancreatic adenocarcinoma
Authors: Maximous D. , Abdel-Wanis M. E. , Aboziada M. A. , El-Sayed M. I. , Abd-Elsayed A. A.
Published: August 2020

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Background: Almost 30% of patients with pancreatic cancer present with locally advanced tumours in absence of distant metastasis. Because surgical resection is often contraindicated by vascular invasion, this disease has a dismal prognosis. The combination of gemcitabine with concurrent radiation therapy is a promising approach that is being investigated in patients’ unresectable pancreatic cancer. Aim of the work: The efficacy of preoperative gemcitabine based chemo-radiotherapy in increasing the resectability rate for patients locally advanced, non metastatic pancreatic cancer was assessed. Methods: 25 patients were treated by preoperative gemcitabine based chemo-radiotherapy. Approximately 6 weeks after completion of chemo radiation, evaluation was performed regarding tumour response and resectability. Pancreatico-duodenectomy was done for operable patients with surgical reconstruction. Results: Patients who achieved complete remission (CR) were 2 out of 25 patients while those achieved partial remission (PR) were 11 out of 25, 6 of them were considered operable. Thus Pancreatico- duodenectomy was done for 8 patients with surgical reconstruction. The postoperative 30 day mortality occurred only in one patient. The postoperative morbidity occurred in the form of minor biliary leakage occurred only in 1 patient & leakage from gastrointestinal anaestomosis in 1 patient. Out of 8 patients who underwent radical surgical resection, only one patient developed local recurrence and simultaneous liver metastasis during the follow up period. The median survival was 12 months. Conclusions: preoperative gemcitabine based chemoradiation might benefit patients with locally advanced non metastatic pancreatic cancer by increasing the resectability without significant acute toxicity.

No significant financial relationships to disclose.
Comorbidity and survival of hepatocellular carcinoma patients at a VA medical canter
Authors: Zhong F. , Oliphant T. , Chang V. T. , Crump B. , Gonzalez M. L. , McPherson M. , Morales E. , Duque L. , Einhorn J. , Kasimis B.
Published: August 2020

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Background: To determine whether comorbidity indices predict survival in hepatocellular carcinoma (HCC) pts. Methods: In an IRB approved protocol, we reviewed the records of pts with tissue diagnosis of HCC seen at a VA Medical Center between 1/1/1999 to 12/31/2008. Comorbidity was assessed with four comorbidity indices, the Charlson Comorbidity Index (CMI), the Kaplan- Feinstein Index (KFI), the Cumulative Illness Rating Scale (CIRS), and VA Comorbidity Scale (VACS). Demographics, ECOG PS, stage, alpha-fetoprotein (AFP) at diagnosis, hepatitis B (HBV) and C (HCV) status, alcohol use, and iron overload were also reviewed. Cox survival regression analysis was performed. Results: There were 44 pts. All pts were men. The median (M) age at diagnosis was 60.5 years (range 35–86). The overall M survival was 230 days (4–2784). There were Stage I 12 (27%) pts, Stage II 7 (16%) pts, Stage III 14 (32%) pts, and Stage IV 11 (25%) pts. The M ECOG PS was 1.0 (0–4), stage 3 (1–4), CMI 5.75 (1–16), CIRS15 3.0 (1–5), CIRS16 6.0 (1–14), CIRS17 2.0 (0.83–5.0), CIRS18 0 (0–2), CIRS19 0 (0–1), KFI 3.0 (1–3), VACS 6.0 (2–9), and AFP 56.35 (1.1–379567). HBV was positive in 10 pts (23%), HCV 26 (59%) pts, alcohol use 37 (84%) pts, and iron overload 11 (25%) pts. In univariate survival analysis, stage (p<.038), ECOG PS (p<.001), AFP (p<.009), presence of iron overload (p<.006), and CMI (p<.019) were significant in predicting survival. However, age, HBV, HCV, alcohol use, CIRS15, CIRS16, CIRS17, CIRS18, KFI, and VACS were not significant for survival. In multivariate survival analyses that included stage and a comorbidity index, the CMI approaches significance (p<.077). Conclusions: In this sample, the CMI was a predictor for survival in pts with HCC. Further analysis in a larger sample is needed to provide a more definitive conclusion. This was supported by the New Jersey Commission for Cancer Research 09–1133-CCR-EO.

No significant financial relationships to disclose.
Predicting renal functional outcomes after surgery for renal cortical tumors: A multifactorial retrospective analysis
Authors: Korets R. , Barlow L. , Laudano M. , Benson M. , McKiernan J.
Published: August 2020

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Background: Nephrectomy (Nx) is the standard of care for localized renal tumors. The risk of developing chronic renal insufficiency (CRI) increases after renal surgery. This study examines the functional outcomes for radical and partial Nx stratified by pre- and perioperative variables using estimated GFR. Methods: Using the Columbia Urologic Oncology Database, a retrospective analysis of patients treated with partial or radical Nx for renal cancer from 1988 to 2008 was conducted. Postoperative chronic renal function was measured using GFR as estimated by the MDRD study equation. Three primary outcomes were measured: 1) presence of new onset postoperative CRI (defined as GFR lower than 60 mL/min per 1.73 m2), 2) percent change in postoperative GFR from preoperative value, and 3) change in CRI stage postoperatively. Regression models were used to determine the effect of surgical procedure (radical vs partial Nx), approach, and multiple preoperative characteristics on functional outcomes. Results: 174 patients met the criteria for analysis after radical Nx and 102 after partial Nx for a total of 276 patients. 209 patients had preoperative GFR > 60, 67 had preoperative GFR < 60, and 6 had preoperative GFR < 30. After a minimum of 3 months postoperatively, 108/209 (52%) and 2/209 (1%) patients developed new-onset GFR <60 and <30, respectively. On multivariate analysis controlling for age, sex, race, diabetes and hypertension, preoperative CKD stage (p<0.001) and procedure (p<0.001) were both independent predictors of GFR progression to <60; similarly, preoperative CKD stage (p<0.001) and procedure (p<0.01) were independent predictors of percent change in postoperative GFR. Patient with worsened preoperative CRI stage were less likely to have further progression of CRI postoperatively (p<0.001) independent of the surgical procedure. Surgical approach was not an independent predictor of any renal functional outcomes measured. Conclusions: Patients undergoing renal surgery have a high rate of new-onset postoperative renal failure. After controlling for preoperative risk factors, patients undergoing radical Nx are at higher risk for decline in renal function. Surgical approach, however, was not a significant predictor for the development of CRI.

No significant financial relationships to disclose.
Correlation of N-telopeptide of type I collagen (NTX) with survival and fractures in patients (pts) with bone metastases from renal cell carcinoma (RCC)
Authors: Brown J. E. , Lipton A. , Cook R. J. , Michaelson D. , Coleman R. E. , Saad F.
Published: August 2020

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Background: The osteolysis marker NTX has shown prognostic significance in pts with bone metastases from a broad range of solid tumors, but its potential in pts with RCC has not been investigated. Methods: This was an exploratory correlative analysis of NTX levels and outcomes in the RCC subset of pts treated with zoledronic acid (ZOL) in a 21-month phase III trial (Rosen et al. J Clin Oncol. 2002). In North American pts in this study, urinary NTX was measured approximately every 3 mo and was expressed per mmol creatinine (CR). Endpoints included overall survival (OS), disease progression in bone, and pathologic fractures. Relative risks and 95% confidence intervals for pts with elevated NTX (NTX ≥ 64 nmol/mmol CR) versus normal NTX (< 64 nmol/mmol CR) were calculated by Cox regression for baseline and most recent (≤ 6 mo prior) NTX assessments. Results: Among 55 ZOL-treated RCC pts, 29 had baseline NTX data (median = 60 nmol/mmol CR). Whereas baseline NTX levels showed trends for outcomes, recent NTX levels profoundly correlated with outcomes ( Table ). An elevated recent NTX measurement correlated with a > 13-fold increased risk of death and a > 11-fold increased risk of progression in bone. Correlations were also significant for first and all on-study fractures. Conclusions: In pts with RCC receiving ZOL, serial NTX assessments may provide important prognostic insight. Although based on a small sample size, correlations between recent NTX levels and outcomes in RCC pts are more profound than those previously reported in pts with other solid tumors (Brown et al. J Natl Cancer Inst. 2005). Elevated NTX could alert physicians to the need to more closely monitor bone lesions and intervene to prevent fractures in RCC pts. This may be especially important in the context of new systemic therapies that are improving the outlook in the advanced RCC setting. [Table: see text]

[Table: see text]