A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients.

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B. Median overall survival was 7.15 months for Arm A and 7.66 months for Arm B (HR 0.93, 95% CI: 0.58-1.47, P = .75). The Kaplan-Meier rates of progression free survival at 4 months were 32% in Arm A and 26% in Arm B. Common ≥Grade 3 treatment related adverse events in Arm A were neutropenia (42%), anemia (18%), diarrhea (11%), compared to Arm B pts with neutropenia (12%), anemia (12%). Guadecitabine and irinotecan had similar OS compared to standard of care TAS-102 or regorafenib, with evidence of target modulation. Clinical trial information: NCT01896856.

Late-Stage Pancreatic Cancer Detected During High-Risk Individual Surveillance: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Identification and resection of successful targets, that is, T1 N0M0 pancreatic ductal adenocarcinoma (PDAC) and high-grade precursors during surveillance of high-risk individuals (HRIs) confers improved survival. Late-stage PDACs refer to T2-4 N0M0 and nodal or distant metastatic PDAC stages diagnosed during the follow-up phase of HRI surveillance. This study aimed to quantify late-stage PDACs during HRI surveillance and identify associated clinicoradiologic factors. METHODS: A systematic search (PROSPERO:CRD42018117189) from Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science was last performed on April 18, 2021. Only original HRI surveillance manuscripts that specified follow-up strategies were included, and studies with only baseline information were excluded. Cumulative incidences of advanced neoplasia: high-grade precursors and all PDACs, and surveillance-detected/interval late-stage PDACs were calculated through random-effects model. Incidence of late-stage PDACs underwent metaregression to identify association with HRI clinicoradiologic features. Publication bias was assessed through the funnel plot and Egger's regression line. RESULTS: Thirteen original surveillance studies included 2169 HRIs followed over 7302.72 patient-years. Cumulative incidence of advanced neoplasia and late-stage PDACs was 3.3 (95% confidence interval [CI]: 0.6-7.4) and 1.7 (95% CI: 0.2-4.0) per 1000 patient-years, respectively. Late-stage PDACs lacked significant association with surveillance imaging, baseline pancreatic morphology, study location, genetic background, gender, or age. Limited information on diagnostic error, symptoms, timing of presentation, lesion site, and surveillance adherence precluded formal meta-analysis. CONCLUSION: A sizeable proportion of late-stage PDACs were detected during follow-up. Their incidence lacked association with baseline clinicoradiologic features. Further causal investigation of stage-based outcomes is warranted for overall improvement in HRI surveillance.

Benefit of Extended Surveillance of Low-Risk Pancreatic Cysts After 5-Year Stability: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) lacking worrisome features (WF) and high-risk stigmata (HRS) warrant surveillance. However, their optimal duration, especially among cysts with initial 5 years of size stability, warrants further investigation. We systematically reviewed the surveillance of low-risk BD-IPMNs and investigated the incidence of WF/HRS and advanced neoplasia, high-grade dysplasia, and pancreatic cancer during the initial (<5 years) and extended surveillance period (>5-years). METHODS: A systematic search (CRD42020117120) identified studies investigating long-term IPMN surveillance outcomes of low-risk IPMN among the Cochrane Library, Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, from inception until July 9, 2021. The outcomes included the incidence of WF/HRS and advanced neoplasia, disease-specific mortality, and surveillance-related harm (expressed as percentage per patient-years). The meta-analysis relied on time-to-event plots and used a random-effects model. RESULTS: Forty-one eligible studies underwent systematic review, and 18 studies were meta-analyzed. The pooled incidence of WF/HRS among low-risk BD-IPMNs during initial and extended surveillance was 2.2% (95% CI, 1.0%-3.7%) and 2.9% (95% CI, 1.0%-5.7%) patient-years, respectively, whereas the incidence of advanced neoplasia was 0.6% (95% CI, 0.2%-1.00%) and 1.0% (95% CI, 0.6%-1.5%) patient-years, respectively. The pooled incidence of disease-specific mortality during initial and extended surveillance was 0.3% (95% CI, 0.1%-0.6%) and 0.6% (95% CI, 0.0%-1.6%) patient-years, respectively. Among BD-IPMNs with initial size stability, extended surveillance had a WF/HRS and advanced neoplasia incidence of 1.9% (95% CI, 1.2%-2.8%) and 0.2% (95% CI, 0.1%-0.5%) patient-years, respectively. CONCLUSIONS: A lower incidence of advanced neoplasia during extended surveillance among low-risk, stable-sized BD-IPMNs was a key finding of this study. However, the survival benefit of surveillance among this population warrants further exploration through high-quality studies before recommending surveillance cessation with certainty.

Early Detection of Cancers in the Era of Precision Oncology.

PURPOSE OF REVIEW: The increasing global incidence of cancer demands innovative cancer detection modalities. The current population-based early cancer detection approaches focus on several major types of cancers (breast, prostate, cervical, lung and colon) at their early stages, however, they generally do not target high-risk individuals at precancerous stages. RECENT FINDINGS: Some cancers, such as pancreatic cancer, are challenging to detect in their early stages. Therefore, there is a pressing need for improved, accessible, noninvasive, and cost-effective early detection methods. Harnessing cell-free-based biomarker-driven strategies paves a new era of precision diagnosis for multicancer early detection. The majority of these tests are in the early stages and expensive, but these approaches are expected to become cost sensitive in the near future. SUMMARY: This review provides an overview of early cancer detection strategies, highlighting the methods, challenges, and issues to be addressed to revolutionize and improve global early cancer detection.

Role of colectomy in the management of appendiceal tumors: a retrospective cohort study.

BACKGROUND: Appendiceal tumors represent a range of histologies that vary in behavior. Recommendations for treatment with appendectomy versus right hemicolectomy (RHC) for different tumor types are evolving and sometimes conflicting. This study sought to characterize variation in the United States around surgical treatment of major appendiceal tumor types over time and describe differences in outcomes based on procedure. METHODS: Patients diagnosed with appendiceal goblet cell adenocarcinoma (GCA), mucinous adenocarcinoma, neuroendocrine neoplasm (NEN), or non-mucinous adenocarcinoma from 2004-2017 were identified in the National Cancer Database. Trends in RHC over time and predictors of RHC were identified. Surgical outcomes for each histologic type and stage were compared. RESULTS: Of 18,216 patients, 11% had GCAs, 34% mucinous adenocarcinoma, 31% NENs, and 24% non-mucinous adenocarcinoma. Rate of RHC for NEN decreased from 68% in 2004 to 40% in 2017 (p = 0.008) but remained constant around 60-75% for other tumor types. Higher stage was associated with increased odds of RHC for all tumor types. RHC was associated with higher rate of unplanned readmission (5% vs. 3%, p < 0.001) and longer postoperative hospital stay (median 5 days vs. 3 days, p < 0.001). On risk-adjusted analysis, RHC was significantly associated with increased survival versus appendectomy for stage 2 disease of all tumor types (HRs 0.43 to 0.63) and for stage 1 non-mucinous adenocarcinoma (HR = 0.56). CONCLUSIONS: Most patients with appendiceal tumors undergo RHC, which is associated with increased readmission, longer length of stay, and improved survival for stage 2 disease of all types. RHC should be offered selectively for appendiceal tumors.

Colorectal cancer survivorship care plans: Variations in documentation and posttreatment surveillance recommendations.

BACKGROUND: Survivorship care plans (SCP) should outline pertinent information about cancer treatment and follow-up. METHODS: We descriptively analyzed the content of 74 colorectal cancer SCPs completed as part of a randomized, controlled trial of SCPs at an academic and community cancer center. Surveillance recommendations were compared with American Cancer Society, American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines. RESULTS: SCP information provided in >80% of the plans included participant age, cancer diagnosis, details, and side-effects of treatment (surgery, chemotherapy, radiation) and health promotion recommendations. SCP content documented less frequently included predisposing conditions, genetic counseling/testing information and staging. Posttreatment surveillance recommendations were documented in >90% SCPs. For stage 2-3 cancer, rates of guideline concordant recommendations were 100% for colonoscopy surveillance (Year 1 only), 87% for imaging surveillance, 65% for carcinoembryonic antigen surveillance, and 33% for follow-up visits. Excluding colonoscopy, >15 unique recommendations were listed for each modality across stages and sites, with more variation at the academic site. CONCLUSIONS: SCPs consistently recorded information about cancer diagnosis and treatment but omitted critical information about cancer-specific details denoting risk. Surveillance recommendations varied considerably between cancer centers. Future work to improve the consistency of surveillance recommendations documented in SCPs may be needed.

Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance.

Advances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1-4 merkel cell carcinoma5, urological cancers6-8, non-small cell lung cancer9-11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma with response rates ranging from 25 to 60% in the first and second line settings13,14. FDA approval has also been given for treatment for hepatocellular carcinoma, gastric cancer, triple negative breast cancer, cervical and head and neck cancers with response rates closer to 15 %15. Additionally, some clinical efficacy has been observed in ovarian cancer, mesothelioma, prostate cancer, diffuse large B cell lymphoma, follicular lymphoma, and both cutaneous and peripheral T-cell lymphoma. However, despite these successes, most patients will initially fail to respond to treatment and almost half of initial responders will develop secondary resistance to immunotherapy and progress. Moreover, many prevalent solid organ tumors remain resistant to immunotherapy including colorectal, pancreatic and hepatobiliary cancers. Therefore, new therapies are needed to increase both initial and durable response rates and to develop new mechanistic insights into pathways of immune resistance so that immunotherapy may become more widely available as a therapeutic option in common malignancies.

Management of Low-Grade Appendiceal Mucinous Neoplasms (LAMN): An International Survey of Surgeons Performing CRS and HIPEC.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are commonly managed by community surgeons at diagnosis. There is variability in the treatment of LAMN, both by community and specialist providers. We assessed current management practices for LAMN across surgeons with expertise in peritoneal surface malignancies (PSM). METHODS: An online survey was sent to 106 international surgeons specializing in PSM. The survey assessed demographics, favored pre-referral management, and definitive management practices for LAMN. RESULTS: The response rate was 40% (67% USA, 33% international). Respondents had performed a median of 18 (interquartile range [IQR] 7.75-29) HIPEC cases in the last year, of which 10 (IQR 4-20) were for LAMN. Ninety-three percent reported more than half of LAMN referrals had already undergone surgery-an estimated 50% appendectomy and 20% right hemicolectomy (RH). No surgeon respondents supported performing right hemicolectomy before referral. For LAMN confined to the appendix, 86% of respondents would definitively treat with appendectomy. In the presence of mucinous implants, 24% would observe after appendectomy and 76% would proceed with HIPEC. All would perform HIPEC if implants contained tumor cells. When LAMN involved the appendiceal base, 67% of respondents would proceed with partial cecectomy, while 33% favored RH. CONCLUSIONS: Pre-referral management of LAMN is not standardized and 20% of patients were referred to a surgeon who performs CRS/HIPEC after a right hemicolectomy that would not have been recommended. Management of LAMN by surgeons who treat PSM is also variable. Long-term data and identification of prognostic features are necessary to generate consensus on the optimal management of these complex patients.

Postoperative Morbidity After Resection of Recurrent Retroperitoneal Sarcoma: A Report from the Transatlantic Australasian RPS Working Group (TARPSWG).

BACKGROUND: This study aimed to evaluate perioperative morbidity after surgery for first locally recurrent (LR1) retroperitoneal sarcoma (RPS). Data concerning the safety of resecting recurrent RPS are lacking. METHODS: Data were collected on all patients undergoing resection of RPS-LR1 at 22 Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) centers from 2002 to 2011. Uni- and multivariable logistic models were fitted to study the association between major (Clavien-Dindo grade ≥ 3) complications and patient/surgery characteristics as well as outcome. The resected organ score, a method of standardizing the number of organs resected, as previously described by the TARPSWG, was used. RESULTS: The 681 patients in this study had a median age of 59 years, and 51.8% were female. The most common histologic subtype was de-differentiated liposarcoma (43%), the median resected organ score was 1, and 83.3% of the patients achieved an R0 or R1 resection. Major complications occurred for 16% of the patients, and the 90-day mortality rate was 0.4%. In the multivariable analysis, a transfusion requirement was found to be a significant predictor of major complications (p < 0.001) and worse overall survival (OS) (p = 0.010). However, having a major complication was not associated with a worse OS or a higher incidence of local recurrence or distant metastasis. CONCLUSIONS: A surgical approach to recurrent RPS is relatively safe and comparable with primary RPS in terms of complications and postoperative mortality when performed at specialized sarcoma centers. Because alternative effective therapies still are lacking, when indicated, resection of a recurrent RPS is a reasonable option. Every effort should be made to minimize the need for blood transfusions.

Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

BACKGROUND: Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes. METHODS: Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis. RESULTS: A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32-48%), 73% (58-92%), 76% (68-85%), and 56% (43-73%) (p < 0.001), respectively. The 6-year second local recurrence incidence was 66% (59-73%), 63% (48-82%), 66% (57-76%), and 77% (66-90%), respectively. The 6-year distant metastasis incidence was 13% (9-19%), 3% (0.4-22%), 5% (2-11%), and 4% (1-16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p < 0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) CONCLUSION: A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.

Morbidity and Outcomes After Distal Pancreatectomy for Primary Retroperitoneal Sarcoma: An Analysis by the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Multi-visceral resection often is used in the treatment of retroperitoneal sarcoma (RPS). The morbidity after distal pancreatectomy for primary pancreatic cancer is well-documented, but the outcomes after distal pancreatectomy for primary RPS are not. This study aimed to evaluate morbidity and oncologic outcomes after distal pancreatectomy for primary RPS. METHODS: In this study, 26 sarcoma centers that are members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) retrospectively identified consecutive patients who underwent distal pancreatectomy for primary RPS from 2008 to 2017. The outcomes measured were 90-day severe complications (Clavien-Dindo ≥ 3), postoperative pancreatic fistula (POPF) rate, and oncologic outcomes. RESULTS: Between 2008 and 2017, 280 patients underwent distal pancreatectomy for primary RPS. The median tumor size was 25 cm, and the median number of organs resected, including the pancreas, was three. In 96% of the operations, R0/R1 resection was achieved. The 90-day severe complication rate was 40 %. The grades B and C POPF complication rates were respectively 19% and 5% and not associated with worse overall survival. Administration of preoperative radiation and factors to mitigate POPF did not have an impact on the risk for the development of a POPF. The RPS invaded the pancreas in 38% of the patients, and local recurrence was doubled for the patients who had a microscopic, positive pancreas margin (hazard ratio, 2.0; p = 0.042). CONCLUSION: Distal pancreatectomy for primary RPS has acceptable morbidity and oncologic outcomes and is a reasonable approach to facilitate complete tumor resection.

Patterns of recurrence and survival probability after second recurrence of retroperitoneal sarcoma: A study from TARPSWG.

BACKGROUND: In this series from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the authors examined longitudinal outcomes of patients with a second recurrence of retroperitoneal sarcoma (RPS) after complete resection of a first local recurrence (LR). METHODS: Data from patients undergoing resection of a first LR from January 2002 to December 2011were collected from 22 sarcoma centers. The primary outcome was overall survival (OS) after second recurrence. RESULTS: Second recurrences occurred in 400 of 567 patients (70.5%) after an R0/R1 resection of a first locally recurrent RPS. Patterns of disease recurrence were LR in 323 patients (80.75%), distant metastases (DM) in 55 patients (13.75%), and both LR and DM in 22 patients (5.5%). The main subtype among the LR group was liposarcoma (77%), whereas DM mainly were leiomyosarcomas (43.6%). In patients with a second LR only, a total of 200 patients underwent re-resection (61.9%). The 5-year OS rate varied significantly based on the pattern of failure (P < .001): 45.6% for the LR group, 25.5% for the DM group, and 0% for the group with LR and DM. The only factors found to be associated with improved OS on multivariable analysis were both time between second surgery and the development of the second recurrence (32 months vs 8 months: hazard ratio, 0.44 [P < .001]) and surgery for second recurrence (yes vs no: hazard ratio, 3.25 [P < .001]). The 5-year OS rate for patients undergoing surgery for a second LR was 59% versus 18% in the patients not deemed suitable for surgical resection. CONCLUSIONS: Survival rates after second recurrence of RPS varied based on patterns of disease recurrence and treatment. Durable disease-free survivors were identified after surgery for second LR in patients selected for this intervention.

Postoperative Onset and Detection of SARS-CoV-2 in Surgically Resected Specimens From Gastrointestinal Cancer Patients With Pre/Asymptomatic COVID-19.

OBJECTIVE: To describe the epidemiologic features and clinical courses of gastrointestinal cancer patients with pre/asymptomatic COVID-19 and to explore evidence of SARS-CoV-2 in the surgically resected specimens. SUMMARY BACKGROUND DATA: The advisory of postponing or canceling elective surgeries escalated a worldwide debate regarding the safety and feasibility of performing elective surgical procedures during this pandemic. Limited data are available on gastrointestinal cancer patients with pre/asymptomatic COVID-19 undergoing surgery. METHODS: Clinical data were retrospectively collected and analyzed. Surgically resected specimens of the cases with confirmed COVID-19 were obtained to detect the expression of ACE2 and the presence of SARS-CoV-2. RESULTS: A total of 52 patients (male, 34) with a median age 62.5 years were enrolled. All the patients presented no respiratory symptoms or abnormalities on chest computed tomography before surgery. Six patients (11.5%) experienced symptom onset and were confirmed to be COVID-19. All were identified to be preoperatively pre/asymptomatic, as 5 were with SARS-CoV-2 presenting in cytoplasm of enterocytes or macrophages from the colorectal tissues and 1 had symptom onset immediately after surgery. The case fatality rate in patients with COVID-19 was 16.7%, much higher than those without COVID-19 (2.2%). CONCLUSIONS: Gastrointestinal cancer patients with pre/asymptomatic COVID-19 were at high risk of postoperative onset and death. At current pandemic, elective surgery should be postponed or canceled. It highlights the need for investigating the full clinical spectrum and natural history of this infection. The early colorectal tropism of SARS-CoV-2 may have major implications on prevention, diagnosis, and treatment of COVID-19.

Understanding the Barriers to Reporting Sexual Harassment in Surgical Training.

OBJECTIVE: To investigate the occurrence, nature, and reporting of sexual harassment in surgical training and to understand why surgical trainees who experience harassment might not report it. This information will inform ways to overcome barriers to reporting sexual harassment. SUMMARY/ BACKGROUND DATA: Sexual harassment in the workplace is a known phenomenon with reports of high frequency in the medical field. Aspects of surgical training leave trainees especially vulnerable to harassing behavior. The characteristics of sexual harassment and reasons for its underreporting have yet to be studied on the national level in this population. METHODS: An electronic anonymous survey was distributed to general surgery trainees in participating program; all general surgery training programs nationally were invited to participate. RESULTS: Sixteen general surgery training programs participated, yielding 270 completed surveys (response rate of 30%). Overall, 48.9% of all respondents and 70.8% of female respondents experienced at least 1 form of sexual harassment during their training. Of the respondents who experienced sexual harassment, 7.6% reported the incident. The most common cited reasons for nonreporting were believing that the action was harmless (62.1%) and believing reporting would be a waste of time (47.7%). CONCLUSION: Sexual harassment occurs in surgical training and is rarely reported. Many residents who are harassed question if the behavior they experienced was harassment or feel that reporting would be ineffectual-leading to frequent nonreporting. Surgical training programs should provide all-level education on sexual harassment and delineate the best mechanism for resident reporting of sexual harassment.

Results of COVID-minimal Surgical Pathway During Surge-phase of COVID-19 Pandemic.

OBJECTIVE: The outcomes of patients treated on the COVID-minimal pathway were evaluated during a period of surging COVID-19 hospital admissions, to determine the safety of continuing to perform urgent operations during the pandemic. SUMMARY OF BACKGROUND DATA: Crucial treatments were delayed for many patients during the COVID-19 pandemic, over concerns for hospital-acquired COVID-19 infections. To protect cancer patients whose survival depended on timely surgery, a "COVID-minimal pathway" was created. METHODS: Patients who underwent a surgical procedure on the pathway between April and May 2020 were evaluated. The "COVID-minimal surgical pathway" consisted of: (A) evolving best-practices in COVID-19 transmission-reduction, (B) screening patients and staff, (C) preoperative COVID-19 patient testing, (D) isolating pathway patients from COVID-19 patients. Patient status through 2 weeks from discharge was determined as a reflection of hospital-acquired COVID-19 infections. RESULTS: After implementation, pathway screening processes excluded 7 COVID-19-positive people from interacting with pathway (4 staff and 3 patients). Overall, 122 patients underwent 125 procedures on pathway, yielding 83 admissions (42 outpatient procedures). The median age was 64 (56-79) and 57% of patients were female. The most common surgical indications were cancer affecting the uterus, genitourinary tract, colon, lung or head and neck. The median length of admission was 3 days (1-6). Repeat COVID-19 testing performed on 27 patients (all negative), including 9 patients evaluated in an emergency room and 8 readmitted patients. In the postoperative period, no patient developed a COVID-19 infection. CONCLUSIONS: A COVID-minimal pathway comprised of physical space modifications and operational changes may allow urgent cancer treatment to safely continue during the COVID-19 pandemic, even during the surge-phase.

Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

A phase 1 trial of the oral DNA methyltransferase inhibitor CC-486 and the histone deacetylase inhibitor romidepsin in advanced solid tumors.

BACKGROUND: Epigenetic abnormalities are manifold in all solid tumors and include changes in chromatin configuration and DNA methylation. The authors designed a phase 1 study to evaluate the oral DNA methyltransferase inhibitor CC-486 combined with the histone deacetylase inhibitor romidepsin in advanced solid tumors with dose expansion to further evaluate pharmacodynamics and possible clinical benefit of the recommended phase 2 dose (RP2D). METHODS: This was a phase 1 study with a 3 + 3 dose-escalation design and an expansion phase for patients with virally mediated cancers. The disease control rate (DCR) was the primary outcome for the expansion cohort. Correlative studies included long interspersed nucleotide element 1 (LINE-1) methylation and drug exposure in blood samples (clinicaltrials.gov identifier NCT01537744). RESULTS: Fourteen patients were enrolled in the dose-escalation portion at 3 dose levels. Three patients experienced dose-limiting toxicities; the RP2D was oral CC-486 300 mg daily on days 1 through 14 and romidepsin 8 mg/m2 on days 8 and 15. Because of slow accrual into the expansion phase, the trial was closed after 4 patients enrolled. Common toxicities of the combination included nausea (83.3%), anorexia (72.2%), fatigue (61.1%), and constipation (55.6%). There were 12 patients evaluable for response, 5 with stable disease, of whom 2 received >4 cycles; there were no responses. Exposure to CC-486 and romidepsin was consistent with prior data. LINE-1 methylation on C1D8 was significantly reduced (mean, -6.23; 95% CI, -12.23, -0.24; P = .04). CONCLUSIONS: Although, at the RP2D, the combination of CC-486 and romidepsin was tolerable, no significant anticancer activity was observed. Significant demethylation in post-treatment circulating tumor DNA and biopsies provided proof of target acquisition.

A Roadmap for Aspiring Surgeon-Scientists in Today's Healthcare Environment.

OBJECTIVE: Surgeon-scientists are an essential component of the field of academic surgery, contributing to the fundamental understanding of disease and the discovery of innovative therapies. Despite this recognized value, the current landscape of academic medicine presents significant barriers to establishing and maintaining a successful career as a surgeon performing basic/translational research. Our objective is to define these barriers to academic success for surgeons, and to provide a consensus strategy for optimizing the chances of success. SUMMARY BACKGROUND DATA: There is a significant decline in the proportion of academic surgeons who are pursuing basic science/translational research, which represents a potential threat to the very identify of the translational surgeon-scientist. METHODS: Based on published literature and expert opinion, the Basic Science Committee of the Society of University of Surgeons prepared this roadmap to encourage and guide the next generation of surgeon-scientists as they embark on their academic careers. RESULTS: This roadmap highlights key elements to consider in choosing an initial job and the importance of identifying a team of committed mentors. Expectations and guidelines for the first several years in practice are offered. CONCLUSIONS: With guidance and mentorship, aspiring surgeonscientists can overcome the challenges inherent in choosing this career path and sustain the important legacy of those before them.

Low Frequency of Lymph Node Metastases in Patients in the United States With Early-stage Gastric Cancers That Fulfill Japanese Endoscopic Resection Criteria.

BACKGROUND & AIMS: In the West, early gastric cancer is increasingly managed with endoscopic resection (ER). This is, however, based on the assumption that the low prevalence and risk of lymph node metastases observed in Asian patients is applicable to patients in the United States. We sought to evaluate the frequency of and factors associated with metastasis of early gastric cancers to lymph nodes, and whether the Japanese ER criteria are applicable to patients in the US. METHODS: We performed a retrospective study of 176 patients (mean age 68.5 years; 59.1% male; 58.5% white) who underwent surgical resection with lymph node dissection of T1 and Tis gastric adenocarcinomas, staged by pathologists, at 7 tertiary care centers in the US from January 1, 1999, through December 31, 2016. The frequency of lymph node metastases and associated risk factors were determined. RESULTS: The mean size of gastric adenocarcinomas was 23.0 ± 16.6 mm-most were located in the lower-third of the stomach (67.0%), invading the submucosa (55.1%), and moderately differentiated (31.3%). Lymphovascular invasion was observed in 18.2% of lesions. Overall, 20.5% of patients had lymph node metastases. Submucosal invasion (odds ratio, 3.9; 95% CI, 1.4-10.7) and lymphovascular invasion (odds ratio, 4.6; 95% CI, 1.8-12.0) were independently associated with increased risk of metastasis to lymph nodes. The frequency of lymph node metastases among patients fulfilling standard and expanded Japanese criteria for ER were 0 and 7.5%, respectively. CONCLUSIONS: The frequency of lymph node metastases among patients with early gastric cancer in a US population is higher than that of published Asian series. However, early gastric cancer lesions that meet the Japanese standard criteria for ER are associated with negligible risk of metastasis to lymph nodes, so ER can be recommended for definitive therapy. Expanded criteria cancers appear to have a higher risk of metastasis to lymph nodes, so ER may be considered for select cases.

Trends in Outcomes After Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) have been shown to improve clinical outcomes among select patients presenting with peritoneal carcinomatosis. The aim of the present study was to describe temporal trends in clinical outcomes among patients undergoing CRS/HIPEC. MATERIALS AND METHODS: Patients who underwent CRS/HIPEC were identified using the American College of Surgeons National Surgical Quality Improvement Program databases from 2005 to 2013. A multivariable logistic regression analysis was performed to identify risk factors associated with postoperative morbidity and mortality. RESULTS: A total of 889 patients were identified who met the inclusion criteria. The most common primary tumor sites were the peritoneum (59.8%), followed by the appendix (13.7%) and colon (6.4%). The median operative time for all patients was 438 min (interquartile range: 328-550); postoperative morbidity was 41.3%, and 2.0% of patients died within 30 d of surgery. Over the time evaluated, a statistically significant decrease was observed in the median operative time (2005 versus 2013, 600 versus 403 min), postoperative morbidity (50.0% versus 36.1%), and length of stay (13.5 versus 8 d; all P < 0.05). On multivariable analysis, age > 65 y (odds ratio [OR] = 1.51; 95% confidence interval [CI]: 1.02-2.24; P = 0.037), a low preoperative hematocrit (OR = 1.66; 95% CI: 1.19-2.33; P = 0.003), and preoperative serum albumin < 3 g/dL (OR = 2.10; 95% CI: 1.13-3.90; P = 0.019) were independently associated with greater odds for developing a postoperative complication and/or postoperative death. CONCLUSIONS: Operative time, postoperative morbidity, and length of stay after CRS/HIPEC were observed to improve over the study period. Careful patient selection may result in favorable outcomes for select patients undergoing CRS/HIPEC.