Publications by authors named "Maheswari Senthil"

59 Publications

Cancer Screening Programs in Low- and Middle-Income Countries: Strategies for Success.

Ann Surg Oncol 2021 Jul 22. Epub 2021 Jul 22.

Division of Surgical Oncology, Department of Surgery, University of California Irvine Medical Center, Orange, CA, USA.

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http://dx.doi.org/10.1245/s10434-021-10509-wDOI Listing
July 2021

Promoting surgical research in the Global South.

Surgery 2021 Mar 9. Epub 2021 Mar 9.

Division of Trauma/Critical Care and Acute Surgery, Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC. Electronic address: https://twitter.com/AnthCharMD.

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http://dx.doi.org/10.1016/j.surg.2021.02.006DOI Listing
March 2021

Quality-of-Life Assessment in Patients Receiving Palliative Chemotherapy: Call for Action.

Ann Surg Oncol 2021 Jan 2;28(1):7-8. Epub 2020 Nov 2.

Division of Surgical Oncology, University of California Irvine, Orange, CA, USA.

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http://dx.doi.org/10.1245/s10434-020-09297-6DOI Listing
January 2021

Peritoneal carcinomatosis in gastric cancer: Are Hispanics at higher risk?

J Surg Oncol 2020 Dec 9;122(8):1624-1629. Epub 2020 Sep 9.

Division of Surgical Oncology, University of California, Irvine, California, USA.

Background: A recent study from our group identified Hispanic race/ethnicity as an independent predictor of peritoneal carcinomatosis (PC) in gastric cancer. We sought to identify the tumor factors that might contribute to this strong association in Hispanics.

Methods: California Cancer Registry data were used to identify patients diagnosed with gastric adenocarcinoma from 2004 to 2014. Logistic regression analyses were performed to determine odds ratios for cancer stage, tumor location, grade, histology, and PC.

Results: Of 16,275 patients with gastric adenocarcinoma who met inclusion criteria, 6463 (39.7%) were non-Hispanic White (NHW), 4953 (30.4%) were Hispanic, 1020 (6.3%) were non-Hispanic Black (NHB), and 3915 (23.6%) were Asian/other. Compared to NHW, Hispanics were more likely to have a poorly differentiated grade (65.9% vs. 57.6%; p < .001), signet ring adenocarcinoma (28.1% vs. 17.6%; p < .001) and stage IV (51.9% vs. 45.0%; p < .001) gastric cancer. The proportion of stage IV patients with PC was also significantly higher in Hispanics compared to NHW, NHB, and Asian/other (28.5% vs. 16.6%, 20.5%, and 25.2%, respectively; p < .001).

Conclusions: Hispanic ethnicity is an independent predictor of aggressive tumor phenotype and PC. Disproportionate incidence of signet ring adenocarcinoma and PC highlight the need to explore the genomic differences in Hispanic gastric cancer.
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http://dx.doi.org/10.1002/jso.26210DOI Listing
December 2020

ASO Author Reflections: Real-World Incidence of Peritoneal Carcinomatosis After Colon Cancer Resection and Why It Matters.

Ann Surg Oncol 2020 Dec 6;27(13):4949. Epub 2020 Jul 6.

Department of Surgery, University of California at Irvine, Orange, CA, USA.

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http://dx.doi.org/10.1245/s10434-020-08773-3DOI Listing
December 2020

Rate of Peritoneal Carcinomatosis in Resected Stage II and III Colon Cancer.

Ann Surg Oncol 2020 Dec 14;27(13):4943-4948. Epub 2020 Jun 14.

Department of Surgery, University of California at Irvine, Orange, CA, USA.

Introduction: Incidence of peritoneal carcinomatosis (PC) after curative resection of stage II and III colon cancer varies widely. Although certain features are considered high risk for PC, the impact of these features on PC incidence is unclear.

Methods: A retrospective analysis was performed on patients ≥ 18 years old with resected stage II and III colonic adenocarcinoma treated at two academic institutions from 2007 to 2018. Clinicopathologic features, treatment and outcomes data were recorded. Patients with reported high-risk features (pT3N0-2 with mucinous/signet ring components, pT4, pN1c, perforation) were identified. The remaining stage II and III patients were used for comparison.

Results: Of 219 eligible patients, 93/219 (42.5%) were stage II and 126/219 (57.5%) were stage III. Median follow-up time was 25 (1-146) months. Adjuvant systemic treatment was administered to 133/219 (60.7%) patients. Overall incidence of PC was 14/219 (6.4%) and the median time to PC was 18 (1-37) months. The high-risk and comparison groups contained 113 and 106 patients, respectively. Incidence of PC was significantly different between groups (high-risk 9.7% vs comparison 2.8%, p = 0.04). Median time to PC was not significantly different between the groups [high-risk 17 (1-37) months vs comparison 20 (7-36) months, p = 0.88].

Conclusion: Overall PC incidence in patients with resected stage II and III colon cancer was 6.4%. Although the high-risk group developed PC at a significantly higher rate, the rate of PC in this group was still below 10%. The results of this study represent real-world rates of PC and should be taken into account when designing future studies.
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http://dx.doi.org/10.1245/s10434-020-08689-yDOI Listing
December 2020

The Impact of Primary Tumor Surgery on Survival in HER2 Positive Stage IV Breast Cancer Patients in the Current Era of Targeted Therapy.

Ann Surg Oncol 2020 Aug 10;27(8):2711-2720. Epub 2020 Mar 10.

Department of Surgery, Division of Surgical Oncology, School of Medicine, Loma Linda University, Loma Linda, CA, USA.

Objective: We sought to examine the impact of primary tumor resection on survival in HER2+ stage IV breast cancer patients in the era of HER2 targeted therapy.

Methods: We conducted a retrospective cohort study of women with HER2+ stage IV breast cancer in the National Cancer Database from 2010 to 2012 comparing those who did and did not undergo definitive breast surgery.

Results: Of 3231 patients, treatment included primary site surgery in 35.0%; chemo/targeted therapy in 89.4%; endocrine therapy in 37.7%; and radiation in 31.8%. Surgery was associated with Medicare/other government (OR 1.36, 95% CI 1.03-1.81) or private insurance (OR 1.93, 95% CI 1.53-2.42) versus none/Medicaid, radiation (OR 2.10, 95% CI 1.76-2.51), chemo/targeted therapy (OR 1.99, 95% CI 1.47-2.70), and endocrine therapy (OR 1.73, 95% CI 1.40-2.14). Non-Hispanic Black versus White patients (OR 0.68, 95% CI 0.53-0.87) were less likely to have surgery. Overall mortality was associated with insurance (Medicare/other government versus none/Medicaid, HR 0.36, p < 0.0001), receipt of chemo/targeted therapy (HR 0.76, p = 0.008), endocrine therapy (HR 0.70, p = 0.0006), and radiation therapy (HR 1.33, p = 0.0009), NH Black versus White race/ethnicity (HR 1.39, p = 0.002), visceral versus bone-only metastases (HR 1.44, p = 0.0003), and lowest versus highest income quartile (HR 1.36, p = 0.01). Propensity score analysis showed surgery was associated with improved survival versus no surgery (HR 0.56, 95% CI 0.40-0.77).

Conclusions: Surgery of the primary site for metastatic HER2+ breast cancer is associated with improved overall survival in selected patients.
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http://dx.doi.org/10.1245/s10434-020-08310-2DOI Listing
August 2020

Costs and Complications: Delayed Gastric Emptying after Pancreaticoduodenectomy.

Am Surg 2019 Dec;85(12):1423-1428

Postoperative delayed gastric emptying (DGE) is a very common complication after a pancreaticoduodenectomy (PD). This along with other complications can lead to increased health-care costs. This study investigates the costs and length of stay (LOS) associated with these. A retrospective study of 131 patients undergoing PD between 2000 and 2016 at Loma Linda University Health was performed. Chi-squared test was used to determine statistically significant differences between patients with and without DGE (according to the definition of the International Study Group of Pancreatic Surgery). Multiple logistic and linear regression analyses were performed to obtain adjusted odds ratios for variables of interest in association with DGE and relationship to LOS. Of 150 patients undergoing PD, 131 patients with tumors were analyzed. The overall incidence of DGE was 56 per cent. No pre- or postoperative factors were associated with increased risk of DGE. The median LOS for patients with DGE was 15 days 9 days for patients without DGE. Patients with DGE added $21,198 to the overall cost of hospitalization. Fourteen patients (10.7%) were readmitted, of whom 11 were because of DGE. Further studies assessing the utility of intraoperative G-tube placement in decreasing hospital costs and readmissions are needed.
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December 2019

Response to Neoadjuvant Treatment Is Influenced by Grade in Gastric Cancer.

Am Surg 2019 Dec;85(12):1419-1422

From the *Loma Linda University Health, Loma Linda, California and.

Neoadjuvant therapy is commonly used in the management of gastric cancer. Primary tumor response to treatment correlates with prognosis. Published studies have compared efficacy of neoadjuvant therapy based on stage but not grade. The objective of this study was to determine the change in staging of gastric cancer after neoadjuvant therapy and resection based on grade. A retrospective analysis of gastric cancer patients treated at our institution between 2005 and 2017 was performed. Patient demographics, tumor characteristics, clinical and pathological stage, and microscopic treatment response were analyzed based on grade. Of the 269 patients identified during this period, 82 patients underwent definitive surgical resection, of which 38 patients received neoadjuvant therapy (low grade (grades 1 and 2), n = 17; high grade (grade 3), n = 18; and unknown grade, n = 3). Pathologic downstaging was observed in 52.9 per cent (9/17) of low-grade tumors compared with 22.2 per cent (4/18) of high-grade tumors. Majority of high-grade tumors (77.8%, 14/18) had either upstaging or unchanged stage. High-grade gastric cancers often lack response to neoadjuvant therapy. Novel targeted therapies based on biologic behavior should be evaluated and incorporated into neoadjuvant treatment. Neoadjuvant studies should stratify patients based on grade and report response by grade.
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December 2019

From Evidence to Practice: Are Low-Risk Breast Cancer Patients still Enduring Unnecessary Costs of Radiation?

Am Surg 2019 Dec;85(12):1414-1418

Radiation is routinely recommended after conservative surgery for breast cancer, despite long-standing Level I evidence showing no survival benefit for elderly patients with favorable disease using endocrine therapy. We sought to evaluate radiation use and costs in patients eligible for omission of radiation. A retrospective single-institution review from 2005 to 2017 was performed of women aged ≥70 years, with cT1N0M0, who were ER/PR positive and HER-2 negative, and receiving breast-conserving surgery. Patient, tumor, and treatment characteristics were compared by use of radiation. Cost estimates used Medicare's 2019 fee schedule. Of 84 patients meeting the study criteria, 72.6 per cent received radiation and 56 per cent received endocrine therapy, with four recurrences (4.9% radiated and 4.4% not radiated, = 0.9). Early and late grade I radiation toxicities occurred in 67.2 per cent and 26.2 per cent of radiated patients, respectively. Younger age ( = 0.01), receipt of endocrine therapy ( < 0.0001), and axillary surgery ( < 0.0001) were significantly associated with radiation use. There were no significant differences in radiation use based on race/ethnicity, language, comorbidities, BMI, or pathologic tumor size. Estimated total radiation cost was $646,426. Radiation remains overused and endocrine therapy, underused in breast cancer patients eligible to avoid radiation. As gatekeepers for radiation oncology referrals, surgeons can diminish both physical and financial costs of radiation in eligible patients.
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December 2019

Improved Survival with Immunotherapy but Lack of Synergistic Effect with Radiation for Stage IV Melanoma of the Head and Neck.

Am Surg 2019 Oct;85(10):1118-1124

Prospective randomized studies have demonstrated a survival benefit of immunotherapy in stage IV cutaneous melanoma. Some retrospective studies have hypothesized a synergistic effect of radiation and immunotherapy. Our objective was to identify whether there is a survival benefit for patients treated with radiation and immunotherapy in stage IV cutaneous melanoma of the head and neck (CMHN). The National Cancer Database was used to identify patients with stage IV CMHN between 2012 and 2014. These patients were stratified based on receipt of radiation and immunotherapy. Adjusted Cox regression was used to analyze overall survival. A total of 542 patients were identified with stage IV CMHN, of whom 153 (28%) patients received immunotherapy. Receipt of immunotherapy (hazard ratio [HR] 0.69, = 0.02) and negative LNs (HR 0.50, = 0.002) were independently associated with improved survival, whereas radiation conferred no survival benefit (HR 1.17, = 0.26). Patients who received immunotherapy without radiation were associated with significantly improved survival compared with those who received immunotherapy with radiation ( < 0.0001). However, of patients who received radiation, the addition of immunotherapy did not seem to improve survival ( = 0.979). In stage IV CMHN, immunotherapy confers a 32 per cent survival benefit. The use of immunotherapy in patients who require radiation, however, is not associated with improved survival.
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October 2019

Gastric Cancer Peritoneal Carcinomatosis Risk Score.

Ann Surg Oncol 2020 Jan 25;27(1):240-247. Epub 2019 Jul 25.

Division of Surgical Oncology, Loma Linda University Health, Loma Linda, CA, USA.

Background: Gastric cancer (GC) peritoneal carcinomatosis (PC) is associated with a poor prognosis. Although grade, histology, and stage are associated with PC, the cumulative risk of PC when multiple risk factors are present is unknown. This study aimed to develop a cumulative GCPC risk score based on individual demographic/tumor characteristics.

Methods: Patient-level data (2004-2014) from the California Cancer Registry were reviewed by creating a keyword search algorithm to identify patients with gastric PC. Multivariable logistic regression was used to assess demographic/tumor characteristics associated with PC in a randomly selected testing cohort. Scores were assigned to risk factors based on beta coefficients from the logistic regression result, and these scores were applied to the remainder of the subjects (validation cohort). The summed scores of each risk factor formed the total risk score. These were grouped, showing the percentages of patients with PC.

Results: The study identified 4285 patients with gastric adenocarcinoma (2757 males, 64.3%). The median age of the patients was 67 years (interquartile range [IQR], 20 years). Most of the patients were non-Hispanic white (n = 1748, 40.8%), with proximal (n = 1675, 39.1%) and poorly differentiated (n = 2908, 67.9%) tumors. The characteristics most highly associated with PC were T4 (odds ratio [OR], 3.12; 95% confidence interval [CI], 2.19-4.44), overlapping location (OR 2.27; 95% CI 1.52-3.39), age of 20-40 years (OR 3.42; 95% CI 2.24-5.21), and Hispanic ethnicity (OR 1.86; 95% CI 1.36-2.54). The demographic/tumor characteristics used in the risk score included age, race/ethnicity, T stage, histology, tumor grade, and location. Increasing GCPC score was associated with increasing percentage of patients with PC.

Conclusion: Based on demographic/tumor characteristics in GC, it is possible to distinguish groups with varying odds for PC. Understanding the risk for PC based on the cumulative effect of high-risk features can help clinicians to customize surveillance strategies and can aid in early identification of PC.
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http://dx.doi.org/10.1245/s10434-019-07624-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925067PMC
January 2020

Resection of Cavity Shave Margins in Stage 0-III Breast Cancer Patients Undergoing Breast Conserving Surgery: A Prospective Multicenter Randomized Controlled Trial.

Ann Surg 2021 05;273(5):876-881

Beaumont Hospital, Troy, MI.

Objective: Single-center studies have demonstrated that resection of cavity shave margins (CSM) halves the rate of positive margins and re-excision in breast cancer patients undergoing partial mastectomy (PM). We sought to determine if these findings were externally generalizable across practice settings.

Methods: In this multicenter randomized controlled trial occurring in 9 centers across the United States, stage 0-III breast cancer patients undergoing PM were randomly assigned to either have resection of CSM ("shave" group) or not ("no shave" group). Randomization occurred intraoperatively, after the surgeon had completed their standard PM. Primary outcome measures were positive margin and re-excision rates.

Results: Between July 28, 2016 and April 13, 2018, 400 patients were enrolled in this trial. Four patients (2 in each arm) did not meet inclusion criteria after randomization, leaving 396 patients for analysis: 196 in the "shave" group and 200 to the "no shave" group. Median patient age was 65 years (range; 29-94). Groups were well matched at baseline for demographic and clinicopathologic factors. Prior to randomization, positive margin rates were similar in the "shave" and "no shave" groups (76/196 (38.8%) vs. 72/200 (36.0%), respectively, P = 0.604). After randomization, those in the "shave" group were significantly less likely than those in the "no shave" group to have positive margins (19/196 (9.7%) vs. 72/200 (36.0%), P < 0.001), and to require re-excision or mastectomy for margin clearance (17/196 (8.7%) vs. 47/200 (23.5%), P < 0.001).

Conclusion: Resection of CSM significantly reduces positive margin and re-excision rates in patients undergoing PM.
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http://dx.doi.org/10.1097/SLA.0000000000003449DOI Listing
May 2021

Concomitant and mutations in colorectal cancer.

J Gastrointest Oncol 2019 Jun;10(3):577-581

Division of Medical Oncology and Hematology, Department of Internal Medicine, Loma Linda University, Loma Linda, California, USA.

and are two key oncogenes in the RAS/RAF/MEK/MAP-kinase signaling pathway. While previously considered mutually exclusive, concomitant mutations in both and genes have been identified in colorectal cancer (CRC). The clinical outcome of these patients remains undetermined. We present the clinical course of two patients with CRC harboring mutations at codon 12 of and non-V600E mutations. More research is needed to determine the clinical-pathological effect of these simultaneous mutations of and in CRC on disease course and treatment outcome.
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http://dx.doi.org/10.21037/jgo.2019.01.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534722PMC
June 2019

Attending Surgeon Variation in Operative Case Length: An Opportunity for Quality Improvement.

Am Surg 2018 Oct;84(10):1595-1599

Loma Linda University Health, Loma Linda, California, USA.

Balancing resident education with operating room (OR) efficiency, while accommodating different styles of surgical educators and learners, is a challenging task. We sought to evaluate variability in operative time for breast surgery cases. Accreditation Council for Graduate Medical Education case logs of breast operations from 2011 to 2017 for current surgical residents at Loma Linda University were correlated with patient records. The main outcome measure was operative time. Breast cases were assessed as these operations are performed during all postgraduate years (PGY). Breast procedures were grouped according to similarity. Variables analyzed included attending surgeon, PGY level, procedure type, month of operation, and American Society of Anesthesiologists class. Of 606 breast cases reviewed, median overall operative time was 150 minutes (interquartile range 187-927). One-way analysis of covariance demonstrated statistically significant variation in operative time by attending surgeon controlling for covariates (PGY level, procedure, American Society of Anesthesiologists class, and month) ( = 0.04). With institutional OR costs of $30 per minute, the average difference between slowest and fastest surgeon was $2400 per case [(218-138) minutes × $30/min]. Minimizing variability for common procedures performed by surgical educators may enhance OR efficiency. However, the impact of case length on surgical resident training requires careful consideration.
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October 2018

Factors Predictive of Outcomes after Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Colon and Appendiceal Carcinomatosis: A Single-Institution Experience.

Am Surg 2018 Oct;84(10):1575-1579

Loma Linda University Cancer Center, Loma Linda, California, USA.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), although considered an acceptable treatment option in the management of selected patients with colon and appendiceal peritoneal carcinomatosis (PC), concerns about morbidity have limited its acceptance. Our objective was to evaluate the short- and long-term outcomes of CRS/HIPEC for appendix and colon PC performed at our institution and to elucidate factors predictive of patient outcomes. All patients who underwent CRS/HIPEC for appendix or colon PC from 2011 to 2017 were identified from our institution's prospective database. Postoperative outcomes, overall survival, and recurrence-free survival were assessed. Of 125 patients who underwent CRS/HIPEC during the study period, 45 patients were eligible (appendix n = 26; colon n = 19). The median postoperative length of stay was nine days (5-28 days). Grade III/IV complications occurred in 4/45 (8.8%) patients. There were no postoperative mortalities. Median DFS and overall survival have not yet been reached, in both the colon and appendix groups. As of the study conclusion date, 37/45 (82.2%) patients were alive with or without disease. Lymph node status was predictive of recurrence in appendix PC. In our experience, CRS/HIPEC can be safely performed with acceptable short- and long-term outcomes. Lymph node status is an important predictor of recurrence.
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October 2018

Role of lymph node ratio in selection of adjuvant treatment (chemotherapy chemoradiation) in patients with resected gastric cancer.

J Gastrointest Oncol 2018 Aug;9(4):708-717

Division of Surgical Oncology, Loma Linda University, Loma Linda, CA, USA.

Background: Recent randomized controlled trials have failed to show a survival difference between adjuvant chemotherapy (CT) and adjuvant chemoradiotherapy (CRT) in patients with resected gastric cancer (GC). However, a subset of patients with lymph node (LN) positive disease may still benefit from CRT. Additional evidence is needed to help guide physicians in identifying patients in whom CRT should be considered. Our objective was then to compare survival outcomes based on lymph node ratio (LNR) (ratio of metastatic to harvested LNs) for patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma treated with surgery and either CT or CRT.

Methods: This retrospective population-based study used California Cancer Registry (CCR) data from 2004 to 2013. It included 1,493 patients diagnosed with stage IB-III gastric/GEJ adenocarcinoma and treated with CT or CRT following total or partial gastrectomy. Overall survival (OS) was the primary outcome and GC-specific survival was secondary. Mortality hazards ratios (HR) for these outcomes were computed using propensity score weighted Cox regression models, stratified by LNR strata categories as 0%, 1-9%, 10-25% and >25%.

Results: Out of 1,493 patients that met inclusion criteria, 462 were treated with CT while 1,031 received CRT. Median follow-up for all subjects was 76 months and median survival was 54 months for CRT and 35 for the CT cohort, P<0.001. Compared to CT, CRT was associated with improved survival among patients with LNR of 10-25% [HR =0.62 (95% CI, 0.46-0.83)] and >25% [HR =0.67 (95% CI, 0.56-0.80)]. Similar findings were observed for GC-specific survival and for analyses limited to patients that had at least 15 LNs evaluated.

Conclusions: LNR appears to be a simple and readily available measure that could be used in treatment planning for resected GC. CRT offers significant survival advantage over CT among patients with high LN disease burden (LNR of ≥10%).
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http://dx.doi.org/10.21037/jgo.2018.05.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087859PMC
August 2018

Sexual and urinary outcomes in robotic rectal surgery: review of the literature and technical considerations.

Updates Surg 2018 Sep 17;70(3):415-421. Epub 2018 Aug 17.

Division of Surgical Oncology, Department of Surgery, Loma Linda University, 11175 Campus Street, 21111, Loma Linda, CA, 92350, USA.

Several studies have reported high rates of urogenital dysfunction after open and laparoscopic surgery for rectal cancer. Robotic surgery has several features that could facilitate identification and preservation of autonomic nerves. This manuscript aims to summarize the literature regarding urogenital function after robotic rectal cancer surgery and focus on technical aspects of nerve-sparing total mesorectal excision. Comprehensive searches were conducted through online databases. Selection criteria included: original articles assessing urinary and sexual function after robotic surgery of males and/or females with standardized questionnaires. A total of 16 articles were included in the review. Seven of the nine cohort studies evaluating male sexual function showed earlier recovery or better outcomes in patients operated with robotic techniques. Two studies did not find any statistically significant difference. Three out of four case series found no difference in sexual function scores measured preoperatively and after 1 year. Female sexual function was assessed in seven studies: two case series show no deterioration of at 1 year. Three comparative studies showed no difference between robotic and laparoscopic groups. Two randomized control trials showed different results in terms of male and female sexual functions with better preservation at 1 year in the robotic group in one and no difference in another. Urinary functions assessed in males and/or females in the 16 studies showed no statistically significant differences at long-term follow-up. At present, there is no evidence of superiority of robotic surgery for performing nerve-sparing rectal cancer surgery.
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http://dx.doi.org/10.1007/s13304-018-0581-xDOI Listing
September 2018

High-Risk Stage II Colon Cancer: Not All Risks Are Created Equal.

Ann Surg Oncol 2018 Jul 19;25(7):1980-1985. Epub 2018 Apr 19.

Loma Linda University Cancer Center, Loma Linda, CA, USA.

Introduction: Adjuvant chemotherapy is recommended in patients with stage II colon cancer with high-risk features (HRF). However, there is no quantification of the amount of risk conferred by each HRF or the overall survival (OS) benefit gained by chemotherapy based on the risk factor.

Objective: To assess survival benefits associated with adjuvant chemotherapy among stage II colon cancer patients having one or more HRF [T4 tumors, less than 12 lymph nodes examined (< 12LN), positive margins, high-grade tumor, perineural invasion (PNI), and lymphovascular invasion (LVI)].

Methods: Patients diagnosed with stage II colon cancer between 2010 and 2013 were identified from California Cancer Registry. Propensity score weighted all-cause mortality hazard ratios (HR) were calculated for combinations of HRF.

Results: A total of 5160 stage II colon cancer patients were identified, of which 2398 had at least one HRF and 510 of 2398 (21%) received adjuvant chemotherapy. Compared with patients with a single HRF, presence of any 2 or ≥ 3 HRF showed increasingly poorer survival [HR 1.42, 95% confidence interval (CI) 1.16-1.73 and HR 2.50, 95% CI 1.96-3.20, respectively]. Chemotherapy was associated with improved overall survival only among patients with T4 as the single HRF (HR 0.51, 95% CI 0.34-0.78) or combinations involving T4 as T4/< 12 LN (HR 0.31, 95% CI 0.11-0.90), T4/high grade (HR 0.26, 95% CI 0.11-0.61), and T4/LVI (HR 0.16, 95% CI 0.04-0.61).

Conclusions: Not all high-risk features have similar adverse effects on OS. T4 tumors and their combination with other HRF achieve the most survival benefit with adjuvant therapy. Type and number of high-risk features should be taken into consideration when recommending adjuvant chemotherapy in stage II colon cancer.
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http://dx.doi.org/10.1245/s10434-018-6484-8DOI Listing
July 2018

Comparison of perioperative chemotherapy with adjuvant chemoradiotherapy for resectable gastric cancer: findings from a population-based study.

J Gastrointest Oncol 2018 Feb;9(1):35-45

Division of Surgical Oncology, Loma Linda University, Loma Linda, CA, USA.

Background: Both perioperative chemotherapy (PC) and adjuvant chemoradiotherapy (CRT) improve survival in resectable gastric cancer; however, these treatments have never been formally compared. Our objective was to evaluate treatment trends and compare survival outcomes for gastric cancer patients treated with surgery and either PC or CRT.

Methods: We performed a retrospective population-based cohort study between 2007 through 2013 using California Cancer Registry data. Patients diagnosed with stage IB-III gastric adenocarcinoma and treated with total or partial gastrectomy were eligible for this study. Based on the type of treatment received, patients were grouped into surgery-only, PC, or CRT. Primary and secondary outcomes were overall survival (OS) and gastric cancer-specific survival (GCCS) respectively. Mortality hazards ratios (HRs) for each of these outcomes were computed using propensity score weighted and covariate-adjusted Cox regression models, stratified by clinical node status.

Results: Of 2,146 patients who underwent surgical resection, 1,067 had surgery-only, while 771 and 308 received PC or CRT, respectively. Median OS was 25, 33, and 52 months for surgery-only, PC, and CRT, respectively; P<0.001. Overall, patients treated with PC had significantly poorer survival compared to CRT (HR =1.45; 95% CI: 1.22-1.73). PC was also associated with higher mortality in patients with signet ring histology (HR =1.66; 95% CI: 1.21-2.28) and clinical node negative cancer (HR =1.85; 95% CI: 1.32-2.60). Survival was not different between PC CRT in clinical node positive patients (HR =1.29; 95% CI: 0.84-2.08). Of note, the percentage of patients receiving PC increased from 17.5% in 2007-2008, to 41.5% in 2013-2014; P<0.001.

Conclusions: Despite the rapid adoption of PC, overall, CRT is associated with better survival than PC. Specifically, clinical node negative and signet ring histology patients had better survival when treated with CRT compared to PC. Based on these findings, we recommend against indiscriminate adoption of PC and consideration for CRT over PC in clinical node negative patients.
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http://dx.doi.org/10.21037/jgo.2017.10.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848040PMC
February 2018

Benefit of Surgical Resection of the Primary Tumor in Patients Undergoing Chemotherapy for Stage IV Colorectal Cancer with Unresected Metastasis.

J Gastrointest Surg 2018 03 9;22(3):460-466. Epub 2017 Nov 9.

Department of Surgery, Loma Linda University Health, 11234 Anderson St, Loma Linda, CA, 92354, USA.

Purpose: Resection of the primary tumor in patients with unresected metastatic colorectal cancer is controversial, and often performed only for palliation of symptoms. Our goal was to determine if resection of the primary tumor in this patient population is associated with improved survival.

Methods: This is a retrospective cohort study of the National Cancer Data Base from 2004 to 2012. The study population included all patients with synchronous metastatic colorectal adenocarcinoma who were treated with systemic chemotherapy. The study groups were patients who underwent definitive surgery for the primary tumor and those who did not. Patients were excluded if they had surgical intervention on the sites of metastasis or pathology other than adenocarcinoma. Primary outcome was overall survival.

Results: Of the 65,543 patients with unresected stage IV colorectal adenocarcinoma undergoing chemotherapy, 55% underwent surgical resection of the primary site. Patients who underwent surgical resection of the primary tumor had improved median survival compared to patients treated with chemotherapy alone (22 vs 13 months, p < .0001). The surgical survival benefit was present for patients who were treated with either multi-agent or single-agent chemotherapy (23 vs 14 months, p < 0.001; 19 vs 9 months, p < 0.001). Surgical resection of the primary tumor was also associated with improved survival when using multivariate analysis with propensity score matching (OR = 0.863; 95% CI [0.805-.924]; HR = 0.914; 95% CI [0.888-0.942]).

Conclusions: Our results show that in patients with synchronous unresected stage IV colorectal adenocarcinoma undergoing single- or multi-agent chemotherapy, after adjusting for confounding variables, definitive resection of the primary site was associated with improved overall survival. Large randomized controlled trials are needed to determine if there is a causal relationship between surgery and increased overall survival in this patient population.
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http://dx.doi.org/10.1007/s11605-017-3617-5DOI Listing
March 2018

Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer.

JAMA Surg 2018 01;153(1):60-67

Division of Surgical Oncology, Department of Surgery, Loma Linda University School of Medicine, Loma Linda, California.

Importance: Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT.

Objective: To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC.

Design, Setting, And Participants: This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1, 2004, through December 31, 2014. Patients were stratified by tumor origin in the left vs right sides.

Interventions: Treatment with SC or SC plus bevacizumab or cetuximab.

Main Outcomes And Measures: Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed.

Results: A total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P = .002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P < .001).

Conclusions And Relevance: Primary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.
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http://dx.doi.org/10.1001/jamasurg.2017.3466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833618PMC
January 2018

Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ: Precautions for Active Surveillance.

JAMA Surg 2017 Nov;152(11):1007-1014

Division of Surgical Oncology, Department of Surgery, Loma Linda University School of Medicine, Loma Linda, California.

Importance: Recent recognition of the overdiagnosis and overtreatment of ductal carcinoma in situ (DCIS) detected by mammography has led to the development of clinical trials randomizing women with non-high-grade DCIS to active surveillance, defined as imaging surveillance with or without endocrine therapy, vs standard surgical care.

Objective: To determine the factors associated with underestimation of invasive cancer in patients with a clinical diagnosis of non-high-grade DCIS that would preclude active surveillance.

Design, Setting, And Participants: A retrospective cohort study was conducted using records from the National Cancer Database from January 1, 1998, to December 31, 2012, of female patients 40 to 99 years of age with a clinical diagnosis of non-high-grade DCIS who underwent definitive surgical treatment. Data analysis was conducted from November 1, 2015, to February 4, 2017.

Exposures: Patients with an upgraded diagnosis of invasive carcinoma vs those with a diagnosis of DCIS based on final surgical pathologic findings.

Main Outcomes And Measures: The proportions of cases with an upgraded diagnosis of invasive carcinoma from final surgical pathologic findings were compared by tumor, host, and system characteristics.

Results: Of 37 544 women (mean [SD] age, 59.3 [12.4] years) presenting with a clinical diagnosis of non-high-grade DCIS, 8320 (22.2%) had invasive carcinoma based on final pathologic findings. Invasive carcinomas were more likely to be smaller (>0.5 to ≤1.0 cm vs ≤0.5 cm: odds ratio [OR], 0.73; 95% CI, 0.67-0.79; >1.0 to ≤2.0 cm vs ≤0.5 cm: OR, 0.42; 95% CI, 0.39-0.46; >2.0 to ≤5.0 cm vs ≤0.5 cm: OR, 0.19; 95% CI, 0.17-0.22; and >5.0 cm vs ≤0.5 cm: OR, 0.11; 95% CI, 0.08-0.15) and lower grade (intermediate vs low: OR, 0.75; 95% CI, 0.69-0.80). Multivariate logistic regression analysis demonstrated that younger age (60-79 vs 40-49 years: OR, 0.84; 95% CI, 0.77-0.92; and ≥80 vs 40 to 49 years: OR, 0.76; 95% CI, 0.64-0.91), negative estrogen receptor status (positive vs negative: OR, 0.39; 95% CI, 0.34-0.43), treatment at an academic facility (academic vs community: OR, 2.08; 95% CI, 1.82-2.38), and higher annual income (>$63 000 vs <$38 000: OR, 1.14; 95% CI, 1.02-1.28) were significantly associated with an upgraded diagnosis of invasive carcinoma based on final pathologic findings.

Conclusions And Relevance: When selecting patients for active surveillance of DCIS, factors other than tumor biology associated with invasive carcinoma based on final pathologic findings may need to be considered. At the time of randomization to active surveillance, a significant proportion of patients with non-high-grade DCIS will harbor invasive carcinoma.
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http://dx.doi.org/10.1001/jamasurg.2017.2181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710412PMC
November 2017

Making Meaningful Clinical Use of Biomarkers.

Biomark Insights 2017 19;12:1177271917715236. Epub 2017 Jun 19.

Division of Biochemistry, Department of Basic Sciences and Center for Health Disparities & Molecular Medicine, Loma Linda University Medical Center, Loma Linda, CA, USA.

This review discusses the current state of biomarker discovery for the purposes of diagnostics and therapeutic monitoring. We underscore relevant challenges that have defined the gap between biomarker discovery and meaningful clinical use. We highlight recent advancements in and propose a way to think about future biomarker development.
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http://dx.doi.org/10.1177/1177271917715236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479428PMC
June 2017

Peritoneal carcinomatosis: limits of diagnosis and the case for liquid biopsy.

Oncotarget 2017 Jun;8(26):43481-43490

Department of Surgery, Division of Surgical Oncology, Loma Linda University Medical Center, Loma Linda, CA, USA.

Peritoneal Carcinomatosis (PC) is a late stage manifestation of several gastrointestinal malignancies including appendiceal, colorectal, and gastric cancer. In PC, tumors metastasize to and deposit on the peritoneal surface and often leave patients with only palliative treatment options. For colorectal PC, median survival is approximately five months, and palliative systemic therapy is able to extend this to approximately 12 months. However, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) with a curative intent is possible in some patients with limited tumor burden. In well-selected patients undergoing complete cytoreduction, median survival has been reported as high as 63 month. Identifying patients earlier who are either at risk for, or who have recently developed PC may provide them with additional treatment options such as CRS/HIPEC. PC is diagnosed late by imaging findings or often times during an invasive procedures such as laparoscopy or laparotomy. In order to improve the outcomes of PC patients, a minimally invasive, accurate, and specific PC screening method needs to be developed. By utilizing circulating PC biomarkers in the serum of patients, a "liquid biopsy," may be able to be generated to allow a tailored treatment plan and early intervention. Exosomes, stable patient-derived nanovesicles present in blood, urine, and many other bodily fluids, show promise as a tool for the evaluation of labile biomarkers. If liquid biopsies can be perfected in PC, manifestations of this cancer may be more effectively treated, thus offering improved survival.
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http://dx.doi.org/10.18632/oncotarget.16480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522163PMC
June 2017

Is Fecal Diversion Needed in Pelvic Anastomoses During Hyperthermic Intraperitoneal Chemotherapy (HIPEC)?

Ann Surg Oncol 2017 Aug 14;24(8):2122-2128. Epub 2017 Apr 14.

Department of Surgery, University of California Irvine, Orange, CA, USA.

Background: The role of fecal diversion with pelvic anastomosis during cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is not well defined.

Methods: A retrospective review of patients who underwent CRS and HIPEC between 2009 and 2016 was performed to identify those with a pelvic anastomosis (colorectal, ileorectal, or coloanal anastomosis).

Results: The study identified 73 patients who underwent CRS and HIPEC at three different institutions between July 2009 and June of 2016. Of these patients, 32 (44%) underwent a primary anastomosis with a diverting ileostomy, whereas 41 (56%) underwent a primary anastomosis without fecal diversion. The anastomotic leak rate for the no-diversion group was 22% compared with 0% for the group with a diverting ileostomy (p < 0.01). The 90-day mortality rate for the no-diversion group was 7.1%. The hospital stay was 14.1 ± 8.0 days in the diversion group compared with 17.9 ± 12.5 days in the no-diversion group (p = 0.12). Of those patients with a diverting ileostomy, 68% (n = 22) had their bowel continuity restored, 18% of which required a laparotomy for reversal. Postoperative complications occurred for 50% of those who required a laparotomy and for 44% of those who did not require a laparotomy (p = 0.84).

Conclusion: Diverting ileostomies in patients with a pelvic anastomosis undergoing CRS and HIPEC are associated with a significantly reduced anastomotic leak rate. Reversal of the diverting ileostomy in this patient population required a laparotomy in 18% of the cases and had an associated morbidity rate of 50%.
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http://dx.doi.org/10.1245/s10434-017-5853-zDOI Listing
August 2017

Is Sentinel Lymph Node Dissection Necessary in All Patients with Ductal Carcinoma In Situ Undergoing Total Mastectomy?

Am Surg 2016 Oct;82(10):982-984

Loma Linda University Medical Center, Loma Linda, California, USA.

When ductal carcinoma in situ (DCIS) is found on core needle biopsy, rates of upgrade to invasive cancer of 25 per cent and nodal positivity of 10 per cent have been reported. Sentinel lymph node dissection (SLND) is recommended when mastectomy is performed for DCIS. We investigated the role of SLND in DCIS patients undergoing partial and total mastectomy (TM). During the study period 2004 to 2013, 170 patients with DCIS were identified with a median age of 60 years (range 26-84 years). Of these, 58.2 per cent had partial mastectomy (PM) alone, 10.6 per cent had PM with SLND, and 31.1 per cent had TM with or without contralateral prophylactic mastectomy with SLND. Overall, SLND identified positive nodes in 4.2 per cent of patients. Upgrade to invasive carcinoma on final breast pathology was found in 8.2 per cent of patients overall, including 4.0 per cent of patients undergoing PM alone, 22.2 per cent undergoing PM with SLND, and 11.3 per cent for TM with SLND (P = 0.8). In this study, patients diagnosed with DCIS on core needle biopsy had lower than expected rates of positive sentinel nodes and upgrade to invasive carcinoma. Surgeons and patients should revisit the necessity of SLND in DCIS patients undergoing mastectomy, which could lead to decreased health expenditure, resources, time, morbidity, and emotional impact on patients.
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October 2016

Outcomes of Nipple-Sparing Mastectomy: Role of Anatomic Measurements.

Am Surg 2016 Oct;82(10):944-948

Division of Surgical Oncology, Department of Surgery, Loma Linda University School of Medicine, Loma Linda, California, USA.

Nipple-sparing mastectomy (NSM) offers improved cosmesis for women undergoing mastectomy; however, there is increased risk for complications with this technique. We sought to determine if standard anatomic measurements could be used to predict complications of NSM. We performed a retrospective review of NSM for which anthropometric measurements of sternal notch to nipple distance, base width, and inframammary fold to nipple distance were available, and compared outcomes by anatomic measurements. We identified 102 cases of NSM with measurements available for study performed in 55 patients. Areola necrosis was associated with base width of greater than 15 cm (42.9% vs 10.9%, P = 0.02), infections were more likely with inframammary fold to nipple distance of more than 10 cm (29.2% vs 10.3%, P = 0.02), hematomas were more likely with sternal notch to nipple distance more than 30 cm (22.2% vs 4.3%, P = 0.03), and delayed wound healing was more likely with sternal notch to nipple distance of more than 25 cm (10.3% vs 1.6%, P = 0.03). There were no significant differences in nipple necrosis, skin flap necrosis, wound care requirements, or operative intervention based on anatomic measurement. Standard anatomic measurements are inconsistent predictors of outcome from NSM and should not be used alone to exclude attempts at NSM.
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October 2016

Percutaneous Sentinel Node Biopsy in Breast Cancer: Results of a Phase 1 Study.

Ann Surg Oncol 2016 10 22;23(10):3330-6. Epub 2016 Jun 22.

Division of Surgical Oncology, Department of Surgery, Loma Linda University School of Medicine, Loma Linda, CA, USA.

Background: While sentinel lymph node dissection (SLND) provides axillary staging, recent trials question the necessity of removing positive nonsentinel axillary lymph nodes (LN) in breast cancer. We sought to determine the technical feasibility of percutaneous core needle biopsy (PNB) of axillary sentinel lymph nodes (SLNs).

Methods: After dual tracer injection, 25 patients underwent intraoperative axillary ultrasound and ultrasound guided per PNB of the axillary LN at the site of radiotracer uptake, followed by standard SLND. The primary outcome measure was successful correlation of PNB with SLN, defined as: (1) similar final pathology in core and SLN and (2) presence of blue staining and/or radiotracer in the core or gross evidence of PNB at the SLN (e.g., transected SLN).

Results: Preincision axillary ultrasound identified a LN (mean size 1.15 ± 0.67 cm) at the site of radioactive tracer in 92 % (23 of 25) of cases. Gross evidence of PNB at the SLN was found in 76 % (19 of 25) of cases. Blue staining, radioisotope, and pathology matched in core and SLN specimens in 36 % (9 of 25), 64 % (16 of 25), and 72 % (18 of 25) of cases, respectively. Overall, successful correlation of core biopsy with SLN occurred in 72 % (18 of 25) of cases.

Conclusions: Results of this phase I study demonstrate that PNB of the SLN is technically feasible, but further refinement of technique is warranted to improve correlation of core biopsy to SLND.
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http://dx.doi.org/10.1245/s10434-016-5320-2DOI Listing
October 2016
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