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Background: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA., Methods: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5., Results: Ten patients were included; eight were female, and the median age was 75.5 years (54-87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m 2 ), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40-100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4-50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%)., Conclusions: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials.

Background and Objectives: Pancreaticoduodenectomy (PD), the only surgical option for right-sided pancreatic ductal adenocarcinoma (PDAC), carries significant morbidity. Not all patients may be deriving a survival benefit from this operation. We sought to identify the rate of futile PD and its associated factors in a large national cohort., Methods: We performed a retrospective analysis using the National Cancer Database (2004-2020), including all patients who underwent PD for non-metastatic PDAC. The primary outcome was operative futility, which was defined as death within 12 months of diagnosis despite PD. Multivariable regression was used to identify factors associated with futility. We performed a subgroup analysis on patients who received neoadjuvant systemic therapy., Results: Data from 66 326 patients were analyzed, and 16 772 (25.3%) underwent PD that met criteria for futility. Macroscopically positive margins (odds ratio [OR]: 2.87; 95% confidence interval [CI]: 2.36-3.48), poor tumor differentiation (OR: 2.44; 95% CI: 2.25-2.65), and N2 nodal stage (OR: 2.09; 95% CI: 1.98-2.20) were associated with the greatest odds of futility. Meanwhile, receipt of any systemic therapy (OR: 0.33; 95% CI: 0.31-0.34), receipt of any radiation (OR: 0.60; 95% CI: 0.57-0.63), and receipt of neoadjuvant systemic therapy (OR: 0.62; 95% CI: 0.57-0.66) were associated with the lowest odds of futility. In the neoadjuvant subgroup, a longer diagnosis-to-surgery interval was associated with lower odds of futility., Conclusion: PD was futile in about one quarter of patients. Futility was associated with higher age and worse tumor biology. Receipt of neoadjuvant therapy resulted in fewer futile operations., (© 2024 Wiley Periodicals LLC.)

Background: The percentage of physicians identifying as Latina has not improved despite improvements in recruitment of Latina medical students, suggesting barriers to retention and career advancement. Discriminatory experiences and mental health inflictions throughout training may contribute to difficulties in recruitment, retainment, and advancement of Hispanic/Latinx trainees, a notably understudied population., Methods: An anonymous, online survey was distributed to Latinas in the continental U.S. between June 22 to August 12, 2022. Eligibility criteria included: self-identifying as Hispanic/Latina, female/woman, and completing or have completed medical school, residency, or fellowship in the continental U.S. in the past 10 years. Recruitment was done via the Twitter account @LatinasInMed and outreach to Latino Medical Student Association chapters. Descriptive statistics summarized the self-reported experiences., Results: The survey included 230 Hispanic/Latinx women, mostly medical students (46.9%). A majority (54.5%) reported negative ethnicity-based interactions from patients and/or patients' families; 71.8%, from others in the medical field. High rates of depression (76.2%) and anxiety (92.6%) during training were reported by Latinas, especially medical students. Feelings of imposter syndrome and burnout were high at 90.7% and 87.4%, respectively., Conclusions: This is the first study evaluating the unique experiences of Latinas in medicine, who reported discrimination and mental health struggles, specifically during medical school, at alarmingly high rates. Our findings could aid in creating the needed interventions to support Latinas in medical training to reduce the existing exodus of Latinas from medicine., (© 2023. The Author(s).)

Background: Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers., Methods: The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated., Results: Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56., Conclusion: The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388)., (© The Author(s) 2023. Published by Oxford University Press.)

Immunotherapy (IO) agents have led to significant improvements in patient outcomes across many tumor types. There have been great efforts to introduce immune checkpoint inhibitors into the treatment paradigm of esophagogastric cancers as well. A number of randomized phase III trials, which will be reviewed here, established the role of these agents in both early-stage and advanced-stage disease. Adjuvant nivolumab is US Food and Drug Administration-approved after neoadjuvant chemoradiation and resection of esophageal and gastroesophageal junction cancers on the basis of the phase III CheckMate 577 trial. In the advanced setting, patients with programmed death receptor ligand-1-positive tumors should be recommended IO in combination with chemotherapy in the first-line setting on the basis of the results from KEYNOTE 590, CheckMate 649, and CheckMate 648. Across trials, chemotherapy continues to play a critical role in the first-line setting and should be offered to all patients who are eligible for systemic therapy, including those with biomarker select tumors. In the later lines of treatment, IO has modest activity, and prior studies have grown largely irrelevant because of the enrollment of IO-naive patients. Similar to other disease types, patients with microsatellite unstable (microsatellite instability high) tumors represent a unique cohort that is more sensitive to IO. However, there are no randomized studies evaluating how best to apply IO in early or advanced stages specifically for the treatment of patients with microsatellite instability high upper GI tumors. Questions remain how to best select patients who benefit from IO treatments, how to augment IO activity in programmed death receptor ligand-1-negative tumors, and how to incorporate IO in late-line settings or for recurrent disease that has been treated with IO-containing regimens during early stages.

Purpose: To evaluate the efficacy of percutaneous biopsy for diagnosing intrahepatic cholangiocarcinoma (IHCCA)., Methods: Retrospective review of biopsy and pathology databases from 2006 to 2019 yielded 112 patients (54F/58 M; mean age, 62.9 years; 27 cirrhotic) with IHCCA who underwent percutaneous biopsy. Data regarding the lesion, biopsy procedure technique, and diagnostic yield were collected. If biopsy was non-diagnostic or discordant with imaging, details of repeat biopsy or resection/explant were gathered. A control group of 100 consecutive patients (56F/44 M; mean age, 63 years, 5 cirrhotic) with focal liver lesions > 1 cm was similarly assessed., Results: Mean IHCCA lesion size was 6.1 ± 3.6 cm, with dominant lesion sampled in 78% (vs. satellite in 22%). 95% (n = 106) were US guided and 96% were core biopsies (n = 108), typically 18G (n = 102, 91%), median 2 passes. 18 patients (16%) had discordant/ambiguous pathology results requiring repeat biopsy, with two patients requiring 3-4 total attempts. A 4.4% minor complication rate was seen. Mean time from initial biopsy to final diagnosis was 60 ± 120 days. Control group had mean lesion size of 2.9 ± 2.5 cm and showed a non-diagnostic rate of 3.3%, both significantly lower than that seen with CCA, with average time to diagnosis of 21 ± 28.8 days (p = 0.002, p = 0.001)., Conclusion: IHCCA is associated with lower diagnostic yield at initial percutaneous biopsy, despite larger target lesion size. If a suspicious lesion yields a biopsy result discordant with imaging, the radiologist should recommend prompt repeat biopsy to prevent delay in diagnosis., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In 1848, Rudolf Ludwig Karl Virchow described an association of left supraclavicular lymphadenopathy with abdominal malignancy. The left supraclavicular lymph node later became commonly referred to as Virchow's node. Charles-Emile Troisier went on to describe the physical exam finding of an enlarged left supraclavicular lymph node, later termed Troisier's sign. Subsequent studies confirmed a predilection of abdominal and pelvic malignancies to preferentially metastasize to the left supraclavicular node. Identification of a pathologically enlarged left supraclavicular node raises the suspicion for abdominopelvic malignancy, particularly in the absence of right supraclavicular lymphadenopathy, and provides a safe and easy target for biopsy. Supraclavicular lymph nodes also represent a great target for diagnosis of metastatic thoracic malignancies, although thoracic malignancies can involve either right or left supraclavicular nodes and do not show a predilection for either. This article presents a review of the history, anatomy, pathophysiology, clinical significance, radiological appearance, and biopsy of Virchow's node. Key points are illustrated with relevant cases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo., Objective: To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation., Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy., Interventions: Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings., Main Outcomes and Measures: The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life., Results: Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo., Conclusions and Relevance: This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation., Trial Registration: ClinicalTrials.gov Identifier: NCT02989857.

Background: The purpose of this study is to evaluate the safety and intermediate-term efficacy of percutaneous microwave (MW) ablation for the treatment of colorectal liver metastases (CRLM) at a single institution., Methods: A retrospective review was performed of all CRLM treated with MW ablation from 3/2011 to 7/2020 (102 tumors; 72 procedures; 57 patients). Mean age was 60 years (range, 36-88) and mean tumor size was 1.8 cm (range, 0.5-5.0 cm). The patient population included 19 patients with extra-hepatic disease. Chemotherapy (pre- and/or post-ablation) was given in 98% of patients. Forty-five sessions were preceded by other focal CRLM treatments including resection, ablation, radiation, and radioembolization. Kaplan-Meier curves were used to estimate local tumor progression-free survival (LTPFS), disease-free survival (DFS), and overall survival (OS) and multivariate analysis (Cox Proportional Hazards model) was used to test predictors of OS., Results: Technical success (complete ablation) was 100% and median follow-up was 42 months (range, 1-112). There was a 4% major complication rate and an overall complication rate of 8%. Local tumor progression (LTP) rate during the entire study period was 4/98 (4%), in which 2 were retreated with MW ablation for a secondary LTP-rate of 2%. LTP-free survival at 1, 3, and 5 years was 93%, 58%, and 39% and median LTP-free survival was 48 months. OS at 1, 3, and 5 years was 96%, 66%, 47% and median OS was 52 months. There were no statistically significant predictors of OS., Conclusions: MW ablation of hepatic colorectal liver metastases appears safe with excellent local tumor control and prolonged survival compared to historical controls in selected patients. Further comparative studies with other local treatment strategies appear indicated., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-159). TJZ receives research funding from HistoSonics Inc. and Ethicon Inc., is a shareholder of HistoSonics Inc., and is a consultant of Ethicon Inc.. SJL receives research funding from Incyte and Agios. JLH is a shareholder of Elucent Medical, Accure, HistoSonics Inc., and Cellectar and is a consultant of Ethicon Inc.. MGL received research funding previously from Philips and Ethicon Inc.. DA is a consultant of PatientPort. DD is a consultant of Array, Pfizer, Acrotech, MEI Pharma, Taiho, Bristol Myers Squibb, Promega, and Bayer and receives research funding from Merck, Revolution Medicine, Bayer, Promega, Genentech, and EMD Serono. NU is a consultant of QED, Ipsen, Taiho Inc., Incyte, and AstraZeneca, receives research funding from Taiho Inc., Eli Lilly, Ipsen, and EMD Serono, and has long position holdings in Natera and Exact Sciences. SAW is a consultant of Ethicon Inc.. PFL is a consultant of HistoSonics Inc. and Ethicon Inc., is a shareholder of HistoSonics Inc., and receives research funding from HistoSonics Inc.. MA is a consultant of Ethicon Inc.. FTL is a board member of HistoSonics Inc., is a consultant of HistoSonics Inc.. and Ethicon Inc., is a shareholder of HistoSonics Inc., receives research funding from HistoSonics Inc. and Ethicon Inc., and has patents/royalties from Medtronic. The other authors have no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

Purpose: The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach., Methods and Materials: Patients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT., Results: A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume., Conclusions: SBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neuroendocrine tumors (NETs) are understudied and have limited systemic treatment options. Prior studies for patients with advanced NETs have demonstrated promising results when antimetabolite agents, including fluoropyrimidines, were combined with temozolomide TMZ. TAS-102 (trifluridine/tipiracil) is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. This study evaluated the safety of TAS-102 in combination with TMZ in patients in neuroendocrine tumors. Escalating doses of TMZ (100, 150 and 200 mg/m 2 ) on days 8-12 were given in combination with TAS-102 (35 mg/m 2 twice a day) on days 1-5 and 8-12 of a 28 day cycle in subjects with advanced NETs. Primary endpoints were safety and determination of maximum tolerated dose (MTD). Growth factor support was mandated starting with level 2 to avoid treatment delays. Fifteen evaluable subjects were enrolled in the phase 1 study. No dose limiting toxicities (DLTs) were observed on level 1. One DLT was observed on level 2 (grade 3 fatigue and inability to resume treatment), and 1 on level 3 (grade 4 thrombocytopenia). The most common grade ≥ 3 adverse events included neutropenia (33%), lymphopenia (27%), and thrombocytopenia (27%). Disease control rate of 92% and partial response rate of 8% were observed in 13 evaluable subjects. This study established MTD of TAS-102 (35 mg/m 2 twice daily) and TMZ (200 mg/m 2 daily). This regimen was well tolerated. Early signs of clinically meaningful activity were observed. Further evaluation of the efficacy of this regimen is warranted.

Background: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma., Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857., Findings: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths., Interpretation: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma., Funding: Agios Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of the study was to determine if patients undergoing percutaneous biopsy for genetic profiling are undergoing more biopsies (procedures, passes per procedure), or experiencing more procedure-related complications., Methods: 60 patients undergoing biopsy procedures for genetic profiling were retrospectively compared with 60 consecutive control patients undergoing routine biopsies. Procedural details and related complications were collected. Results were analyzed using t-tests and logistic regression., Results: Biopsied organs included mainly lung (n = 31), liver (n = 50), and lymph nodes (n = 18). The average number of core biopsy passes was 3.45 in the study group and 2.18 in the control group (0.73, 1.81; p = 0.0001). The average study patient underwent 1.44 biopsy procedures by radiology from 2016 to 2017, whereas the average control patient underwent 1.08 (0.1657, 0.5010, p = 0.0002). Results were similar when looking at the subset of patients undergoing liver biopsies. In our cohort of 120 patients total, only 6 complications were noted. There were 4 complications in the control patients and 2 complications in the study patients, all of which were pneumothoraces in patients undergoing lung biopsy; only 2 of these required treatment. The odds ratio for a complication occurring from an increase in one core biopsy is 1.07 (0.601, 1.573; p = 0.775), suggesting no significant relationship among the number of biopsies taken and the probability of complication in this cohort., Conclusions: Patients being biopsied for genetic profiling or clinical study enrollment are undergoing more biopsy procedures and more biopsy passes per procedure, but are not experiencing a detectable increased rate of complications in this small cohort, single-center study.

Background: Molecular profiles guide the clinical management of metastatic colorectal cancer (mCRC), particularly related to the use of anti-epidermal growth factor receptor (EGFR) antibodies. Tumor sidedness has also been implicated in resistance to these therapies, but has largely been studied in the first-line setting. We examined the role of tumor sidedness and disease bulk in predicting clinical outcomes to anti-EGFR therapy in the treatment-refractory setting. Methods: We identified a retrospective cohort of 62 patients with KRAS wild-type mCRC who received anti-EGFR therapy in the late-line setting. Response was assessed per RECIST 1.1, with bulky disease defined as any single lesion >35 mm in longest cross-sectional diameter or nodal short axis. Primary sidedness was defined in relation to the splenic flexure. Results: Patients with right-sided primary tumors at time of late-line EGFR therapy presented with increased tumor bulk and worsened overall survival (OS) relative to left-sided primary tumors. Tumor bulk, defined as either a categorical or continuous variable, predicted worsened progression-free survival (PFS) and OS, which persisted when controlling for differences in the primary tumor location. Within the right-sided cohort, no objective responses were observed for bulky disease or during treatment with anti-EGFR monotherapy. The nonbulky cohort experienced clinical benefit with anti-EGFR monotherapy, showing similar PFS and an improved response rate compared with sequential chemotherapy. Conclusions: In an effort to expand understanding of the role of primary sidedness in clinical response to anti-EGFR therapy, we identified sidedness and tumor bulk as potential predictive biomarkers of clinical response in late-line mCRC. Future prospective studies of EGFR targeting should consider tumor bulk in addition to molecular profiling in the identification of populations most likely to achieve meaningful clinical benefit., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Importance: Gemcitabine with platinum has limited efficacy for treatment of advanced cholangiocarcinoma, necessitating an evaluation of alternative drug combinations. Recent evidence suggests that paclitaxel may potentiate gemcitabine activity., Objective: To evaluate whether gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel is safe and effective for treatment of advanced cholangiocarcinoma., Design, Setting, and Participants: This single-arm, 2-stage, phase 2 clinical trial was conducted at 23 community and academic centers across the United States and Europe. Patients aged 18 years or older enrolled between September 2014 and March 2016 had confirmed advanced or metastatic cholangiocarcinoma without prior systemic therapy, and had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 and a Child-Pugh score less than 8. Previous surgery, radiation, or liver-directed therapies were permitted., Interventions: Patients received intravenous nab-paclitaxel, 125 mg/m2, followed by gemcitabine, 1000 mg/m2, on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxic effects., Main Outcomes and Measures: The primary outcome was improvement in 6-month progression-free survival (PFS) rate (null and alternative hypotheses of 55% and 70%, respectively) in the evaluable population. Secondary outcomes included median overall survival (OS), PFS, time to progression, best overall response rate, disease control rate, safety and toxicity, and association of change in carbohydrate antigen 19-9 with survival., Results: Seventy-four patients with a median age of 62 (range, 36-87) years, including 44 women (60%), were enrolled. Patients received a median of 6 (range, 1-18) treatment cycles, and the median follow-up was 10.2 (range, 0.6-27.3) months. The observed 6-month PFS rate of 61% (95% CI, 48%-73%) did not favor the alternative hypothesis. Median PFS was 7.7 (95% CI, 5.4-13.1) months, median OS was 12.4 (95% CI, 9.2-15.9) months, and median time to progression was 7.7 (95% CI, 6.1-13.1) months. The confirmed best overall response rate and disease control rate were 30% and 66%, respectively. Hazard ratios for an association between a change in serum carbohydrate antigen 19-9 and median PFS as well as median OS were 2.02 (95% CI, 0.86-4.75) (P = .10) and 1.54 (95% CI, 0.64-3.71) (P = .34), respectively. The most common treatment-related hematologic and nonhematologic adverse events at grade 3 or higher were neutropenia (43%) and fatigue (14%), respectively., Conclusions and Relevance: Although the trial did not meet its primary efficacy end point, the results indicate that a nab-paclitaxel plus gemcitabine regimen was well tolerated and may be an alternative option to current therapeutic approaches for advanced cholangiocarcinoma., Trial Registration: ClinicalTrials.gov identifier: NCT02181634.

Background & Aims: Recommendations for surveillance after curative surgery for colorectal cancer (CRC) include a 1-year post-resection abdominal-pelvic computed tomography (CT) scan and optical colonoscopy (OC). CT colonography (CTC), when used in CRC screening, effectively identifies colorectal polyps ≥10 mm and cancers. We performed a prospective study to determine whether CTC, concurrent with CT, could substitute for OC in CRC surveillance., Methods: Our study enrolled 231 patients with resected stage 0-III CRC, identified at 5 tertiary care academic centers. Approximately 1 year after surgery, participants underwent outpatient CTC plus CT, followed by same-day OC. CTC results were revealed after endoscopic visualization of sequential colonic segments, which were re-examined for discordant findings. The primary outcome was performance of CTC in the detection of colorectal adenomas and cancers using endoscopy as the reference standard., Results: Of the 231 participants, 116 (50.2%) had polyps of any size or histology identified by OC, and 15.6% had conventional adenomas and/or serrated polyps ≥6 mm. No intra-luminal cancers were detected. CTC detected patients with polyps of ≥6 mm with 44.0% sensitivity (95% CI, 30.2-57.8) and 93.4% specificity (95% CI, 89.7-97.0). CTC detected polyps ≥10 mm with 76.9% sensitivity (95% CI, 54.0-99.8) and 89.0% specificity (95% CI, 84.8-93.1). Similar values were found when only adenomatous polyps were considered. The negative predictive value of CTC for adenomas ≥6 mm was 90.7% (95% CI, 86.7-94.5) and for adenomas ≥10 mm the negative predictive value was 98.6% (95% CI, 97.0-100)., Conclusions: In a CRC surveillance population 1 year following resection, CTC was inferior to OC for detecting patients with polyps ≥6 mm. Clinical Trials.gov Registration Number: NCT02143115., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to compare unidimensional (1D/linear) and volumetric (3D) measures of metastatic colorectal cancer (mCRC) at computed tomography (CT) for predicting clinical outcome., Patients and Methods: Analysis of CT images in 105 patients (mean age, 59 years; range, 25-81 years; 45 women, 60 men) receiving treatment for mCRC was performed. Both unidimensional and volumetric measures were obtained on index lesions at 3 time points (baseline/midpoint/post-therapy; mean interval, 4.1 months; median, 3.7 months) by 3 readers using a semi-automated technique. Measurements were summed and compared using best overall response across the 3 time points. Patient response was categorized based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 thresholds for unidimensional and volume measures (CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease). Survival data was correlated (mean follow-up, 19.9 ± 17.1 months; median, 14.7 months). Intra/interobserver variability and reproducibility of 1D and 3D measures was assessed. Cox survival and Kaplan-Meier models were constructed and compared., Results: Cox models and Kaplan-Meier curves for unidimensional versus volumetric assessment were very similar in appearance. Both 1D and 3D measurements effectively separated PD from the SD/PR groups, but neither separated SD from PR well. Volumetric measures showed comparable intra/interobserver variability on Bland-Altman analysis to unidimensional measures across readers using a semi-automated measurement technique. Metastatic site (lung, liver, node, other) did not seem to impact measurement reproducibility., Conclusions: Although CT volumetric assessment of metastatic colorectal cancer is fairly reproducible by reader and site using a semi-automated technique, the ability to stratify progressive disease from other disease response categories in terms of survival was similar to unidimensional measurement., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to compare the accuracy of CT colonography versus optical colonoscopy for neoplastic involvement at the surgical anastomosis 1 year after curative-intent colorectal cancer resection., Design, Setting, Patients, and Interventions: Two hundred one patients (mean age, 58.6 years; 117 men, 84 women) underwent same-day contrast-enhanced CT colonography and colonoscopy approximately 1 year (mean, 12.1 months; median, 11.9 months) after colorectal cancer resection as part of a prospective, multicenter trial. All patients enrolled were without clinical evidence of disease and considered low risk for recurrence (stage I-III)., Main Outcome Measures: Suspected neoplastic lesions within 5 cm of the colonic anastomosis were recorded at CT colonography, with subsequent colonoscopy performed for the same, with segmental unblinding of colonography findings. Anastomotic region biopsy or polypectomy was performed at the endoscopist's discretion., Results: None of the 201 patients had intraluminal anastomotic cancer recurrence or advanced neoplasia (or metachronous cancers). CT colonography detected extramural perianastomotic recurrence in 2 patients (1.0%); neither was detected at colonoscopy. Only 2 patients (1.0%; 2/201) were called positive at CT colonography for intraluminal anastomotic nondiminutive lesions (7- to 8-mm polyps), which were confirmed at colonoscopy but nonneoplastic at histopathology. At optical colonoscopy, the anastomosis was deemed abnormal and/or biopsied in 10.0% (20/201), yielding only 1 nondiminutive benign neoplasm (7-mm tubular adenoma)., Limitations: The lack of luminal cancer recurrence in our lower-risk cohort precludes assessment of sensitivity for detection, rendering the study underpowered in this regard. Potential cost savings of combined CT/CT colonography over the standard CT/colonoscopy approach were not assessed., Conclusions: Relevant intraluminal anastomotic pathology appears to be very uncommon 1 year after colorectal cancer resection in lower-risk cohorts. Unlike colonoscopy, diagnostic contrast-enhanced CT colonography effectively evaluates both the intra- and extraluminal aspects of the anastomosis. See Video Abstract at http://links.lww.com/DCR/A471.

Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds. Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Improvements in surgical technique and perioperative care have resulted in increased long-term survival for patients with congenital heart disease. As these patients begin to reach their later years, clinicians are challenged with determining optimal management of noncardiac diseases in this complex patient population, including surgically treatable malignancies. We present a case of esophageal cancer in a patient with previously repaired tetralogy of Fallot and right-sided aortic arch, treated with neoadjuvant therapy followed by laparoscopic and left thoracoscopic esophagectomy., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

As treatment strategies for patients with colorectal cancer advance, there has now become an ever-increasing need for multidisciplinary teams to care for these patients. Recent investigations into the timing and duration of perioperative therapy, as well as, the rise of molecular profiling have led to more systemic chemotherapeutic options. The most efficacious use, in terms of timing and patient selection, of these therapies in the setting of modern operative and radiotherapy techniques requires the generation of care teams discussing cases at multidisciplinary conferences. This review highlights the role of multidisciplinary team conferences, advances in perioperative chemotherapy, current clinical biomarkers, and emerging therapeutic agents for molecular subtypes of metastatic colon cancer. As our understanding of relevant molecular subtypes increases and as data becomes available on treatment response, the treatment of colorectal cancer will become more precise and effective.

Lessons Learned: Pancreatic neuroendocrine tumors versus carcinoid tumors should be examined separately in clinical trials.Progression-free survival is more clinically relevant as the primary endpoint (rather than response rate) in phase II trials for low-grade neuroendocrine tumors., Background: The most common subtypes of neuroendocrine tumors (NETs) are pancreatic islet cell tumors and carcinoids, which represent only 2% of all gastrointestinal malignancies. Histone deacetylase (HDAC) inhibitors have already been shown to suppress tumor growth and induce apoptosis in various malignancies. In NET cells, HDAC inhibitors have resulted in increased Notch1 expression and subsequent inhibition of growth. We present here a phase II study of the novel HDAC inhibitor panobinostat in patients with low-grade NET., Methods: Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design., Results: Fifteen patients were accrued, and 13 were evaluable for response. No responses were seen, but the stable disease rate was 100%. The median progression-free survival (PFS) was 9.9 months, and the median overall survival was 47.3 months. Fatigue (27%), thrombocytopenia (20%), diarrhea (13%), and nausea (13%) were the most common related grade 3 toxicities. There was one grade 4 thrombocytopenia (7%). These results did not meet the prespecified criteria to open the study to full accrual., Conclusion: The HDAC inhibitor panobinostat has a high stable disease rate and reasonable PFS in low-grade NET, but has a low response rate., (©AlphaMed Press; the data published online to support this summary is the property of the authors.)

Background: KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC., Methods: A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC., Results: 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease., Conclusions: The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

Purpose: The purpose of the study was to determine if CT texture features of untreated hepatic metastatic colorectal cancer (CRC) relate to pathologic features and clinical outcomes., Methods: Tumor texture analysis was performed on single hepatic metastatic lesions on pre-treatment contrast-enhanced CT scans in 77 pts (mean age 58, 34F/43M) using a novel tool. Measures of heterogeneity, including entropy, kurtosis, skewness, mean, mean positive pixels (MPP), and standard deviation (SD) of pixel distribution histogram were derived with filter values corresponding to fine (spatial scaling factor (ssf) 2), medium (ssf 3, 4), and coarse textures (ssf 5, 6). Texture parameters were correlated with tumor grade, baseline serum CEA, and KRAS mutation status. Overall survival was also correlated using Cox proportional hazards models. Single-slice 2D vs. whole-tumor volumetric 3D texture analysis was compared in a subcohort of 20 patients., Results: Entropy, MPP, and SD at medium filtration levels were significantly associated with tumor grade (MPP ssf 3 P = 0.002, SD ssf 3 P = 0.004, entropy ssf 4 P = 0.007). Skewness was negatively associated KRAS mutation (P = 0.02). Entropy at coarse filtration levels was associated with survival (Hazard ratio (HR) for death 0.65, 95% CI 0.44-0.95, P = 0.03). Texture results for 2D and 3D analysis were similar., Conclusions: CT texture features, particularly entropy, MPP, and SD, are significantly associated with tumor grade in untreated CRC liver metastases. Tumor entropy at coarse filters correlates with overall survival. Single-slice 2D texture analysis appears to be adequate.

When considering treatment options for patients with metastatic colorectal cancer (mCRC), molecular profiling has become a pivotal component in guiding clinical decisions. FOLFOX and FOLFIRI (fluorouracuil, leucovorin plus oxaliplatin or ininotecan, respectively) are the standard base regimens used for the treatment of mCRC. Biologic agents, such as the epidermal growth factor receptor (EGFR) targeted therapies, cetuximab and panitumumab and the vascular endothelial growth factor monoclonal antibody, bevacizumab, are safe and effective in the first-line setting. The most efficacious use of these agents in terms of timing and selection of the right patient population continues to be debated. Here we review multiple investigations into the effectiveness of treatment options as a function of the mutations present in colon cancers. Early studies have reported that KRAS mutations at exon 2 predict resistance to EGFR targeted therapies. More recently the data have expanded to include KRAS mutations at exons 3 and 4 and NRAS mutations at exons 2, 3 and 4 as well as other biomarkers including BRAF and PIK3CA , leading to the evolution of the treatment of mCRC to a more precision-based approach. As our understanding of relevant biomarkers increases, and data from both molecular profiling and treatment response become more readily available, treatment options will become more precise and their outcomes more effective., Competing Interests: The authors declare no conflicts of interest in preparing this article., (© The Author(s), 2015.)

Purpose: Fluoropyrimidines and oxaliplatin have demonstrated some efficacy against pancreatic adenocarcinoma, but survival remains brief. Sorafenib is an oral multikinase inhibitor which we sought to combine with a unique capecitabine and oxaliplatin regimen for pancreatic adenocarcinoma., Methods: We performed a multicenter phase II study of sorafenib 200 mg orally twice daily along with oxaliplatin 85 mg/m(2) IV on days 1 and 15, followed by capecitabine 2250 mg/m(2) orally every 8 h for six doses starting on days 1 and 15 of a 28-day cycle in patients who had no more than one previous chemotherapy regimen for their pancreatic adenocarcinoma. The primary objective was response rate; secondary objectives were progression-free survival (PFS), overall survival (OS), and safety., Results: Twenty-four patients were enrolled; median age was 63 years (range 48-83). The most common related toxicities were fatigue, neuropathy, anemia, thrombocytopenia, diarrhea, nausea, leukopenia, and hand-foot syndrome. Grade 3 hand-foot syndrome was rare (4 %). Other grade 4 toxicities included abdominal pain (8 %), pulmonary embolism (4 %), and anemia (4 %). Three partial responses were seen (13 %), and 11 patients had stable disease (46 %) as their best response. Median PFS was 6.0 months (range 1.5-13 months). Median OS was 8.1 months (range 1.5-13.6 months)., Conclusions: Sorafenib, oxaliplatin, and capecitabine produced partial responses in patients with advanced pancreatic cancer including previously treated patients and demonstrated a PFS of 6 months with few grade 3/4 toxicities.

Background: RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors., Methods: Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle., Results: Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration., Conclusions: The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.

This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, (131)I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of-concept of phospholipid ether analogues' retention within tumors. A total of 10 patients received (131)I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m(2) and greater, DLTs were thrombocytopenia and neutropenia. Disease-specific studies are underway to identify cancers most likely to benefit from (131)I-CLR1404 monotherapy.

The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10) vs 3.27×10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease.

Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2,250 mg/m2 PO every 8 h x 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.

Purpose: We evaluated the cost-effectiveness of adjuvant chemotherapy using 5-fluorouracil, leucovorin (5FU/LV), and oxaliplatin (FOLFOX) compared with 5FU/LV alone and 5FU/LV compared with observation alone for patients who had resected stage II colon cancer., Methods: We developed 2 Markov models to represent the adjuvant chemotherapy and follow-up periods and a single Markov model to represent the observation group. We used calibration to estimate the transition probabilities among different toxicity levels. The base case considered 60-year-old patients who had undergone an uncomplicated hemicolectomy for stage II colon cancer and were medically fit to receive 6 months of adjuvant chemotherapy. We measured health outcomes in quality-adjusted life-years (QALYs) and estimated costs using 2007 US dollars., Results: In the base case, adjuvant chemotherapy of the FOLFOX regimen had an incremental cost-effectiveness ratio (ICER) of $54,359/QALY compared with the 5FU/LV regimen, and the 5FU/LV regimen had an ICER of $14,584/QALY compared with the observation group from the third-party payer perspective. The ICER values were most sensitive to 5-year relapse probability, cost of adjuvant chemotherapy, and the discount rate for the FOLFOX arm, whereas the ICER value of 5FU/LV was most sensitive to the 5-year relapse probability, 5-year survival probability, and the relapse cost. The probabilistic sensitivity analysis indicates that the ICER of 5FU/LV is less than $50,000/QALY with a probability of 99.62%, and the ICER of FOLFOX as compared with 5FU/LV is less than $50,000/QALY and $100,000/QALY with a probability of 44.48% and 97.24%, respectively., Conclusion: Although adjuvant chemotherapy with 5FU/LV is cost-effective at all ages for patients who have undergone an uncomplicated hemicolectomy for stage II colon cancer, FOLFOX is not likely to be cost-effective as compared with 5FU/LV.

Background: Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3β has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs., Design: Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8-1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3β phosphorylation, and toxicity., Results: Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies., Conclusions: Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3β at serum levels used to treat bipolar disorders.

Introduction: Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for NETs. Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo., Patients and Methods: Eight patients with low-grade NETs (carcinoid and pancreatic) were treated with 500 mg of oral VPA twice a day with dosing adjusted to maintain a goal VPA level between 50 and 100 μg/mL. All patients were followed for 12 months or until disease progression., Results: Notch1 signaling was absent in all tumors prior to treatment and was upregulated with VPA. One patient had an unconfirmed partial response and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5 out of 7 patients. Overall, treatment with VPA was well tolerated., Conclusion: . VPA activates Notch1 signaling in vivo and may have a role in treating low-grade NETs.

Purpose: Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras., Patients and Methods: Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction., Results: Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes., Conclusion: Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

Purpose: Capecitabine has shown similar efficacy to 5-fluorouracil (5-FU); a regimen containing 2 weeks of capecitabine/oxaliplatin (CapOx) has demonstrated noninferiority to infusional 5-FU/oxaliplatin/leucovorin (FOLFOX) for the treatment of metastatic colorectal cancer (mCRC). This phase II study explores the efficacy and safety of a 2-day course of oxaliplatin/capecitabine (2DOC), with oxaliplatin given on day 1 and capecitabine given orally every 8 hours in high doses over 6 doses, mimicking FOLFOX6., Patients and Methods: This phase II study was conducted by the University of Wisconsin Carbone Cancer Center. Eligible patients with mCRC received oxaliplatin 100 mg/m2 intravenously (I.V.) over 2 hours followed by leucovorin 20 mg/m2 I.V. bolus and 5-FU 400 mg/m2 I.V. bolus on day 1 and day 15. Capecitabine was administered at 1500 mg/m2 orally every 8 hours over 6 doses starting on day 1 and day 15., Results: A total of 45 patients were enrolled; 44 were evaluated for response. Seventeen patients (39%) had objective responses. Median time to progression was 6.8 months, and median overall survival (OS) was 17.5 months. The most common side effects were grade 1/2 neuropathy, fatigue, and nausea. Severe hand-foot syndrome (HFS) was rare., Conclusion: The overall response rate with the 2DOC regimen is similar to published CapOx regimens, and time to progression and OS are similar. The incidence of HFS, diarrhea, and mucositis were lower compared with published results of 2-week schedules of capecitabine. The 2DOC regimen merits further study as a more convenient regimen than infusional 5-FU with less HFS when compared with a 2-week administration of capecitabine.

Paragonimiasis (human infections with the lung fluke Paragonimus westermani) is an important public health problem in parts of Southeast Asia and China. Paragonamiasis has rarely been reported from North America as a zoonosis caused by Paragonimus kellicotti. Paragonimus species have complex life cycles that require 2 intermediate hosts, namely, snails and crustaceans (ie, crabs or crayfish). Humans acquire P. kellicotti when they consume infected raw crayfish. Humans with paragonimiasis usually present with fever and cough, which, together with the presentation of hemoptysis, can be misdiagnosed as tuberculosis. Only 7 autochthonous cases of paragonimiasis have been previously reported from North America. Our study describes 3 patients with proven or probable paragonimiasis with unusual clinical features who were seen at a single medical center during an 18-month period. These patients acquired their infections after consuming raw crayfish from rivers in Missouri. It is likely that other patients with paragonimiasis have been misdiagnosed and improperly treated. Physicians should consider the possibility that patients who present with cough, fever, hemoptysis, and eosinophilia may have paragonimiasis.