Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes.

BACKGROUND & AIMS: Some colorectal and endometrial tumors with microsatellite instability not attributable to MLH1 hypermethylation or germline mutations contain 2 or more somatic mutations in genes encoding mismatch repair (MMR) proteins. We sought to define the molecular phenotype of this newly recognized tumor subtype. METHODS: From 2 prospective studies of the efficacy of screening for Lynch syndrome, we identified patients with colorectal and endometrial tumors who had 2 or more somatic (but not germline) mutations in genes encoding MMR proteins (double somatic). We determined the frequencies of tumor mutations in PIK3CA, BRAF, KRAS, NRAS, and PTEN by targeted next-generation sequencing and used logistic-regression models to compare them with those from patients with Lynch syndrome, MLH1-hypermethylated, or microsatellite-stable tumors. We validated our findings using independent data sets from The Cancer Genome Atlas. RESULTS: Among colorectal cancer cases, we found that 14 of 21 (67%) patients with double somatic tumors also had PIK3CA mutations, compared with 4 of 18 (22%) tumors from patients with Lynch syndrome, 2 of 10 (20%) tumors with MLH1 hypermethylation, and 12 of 78 (15%) tumors with microsatellite stability (P < .0001 for patients with double somatic tumors vs other subgroups). Mutations in PIK3CA were detected in all 13 patients with double somatic endometrial cancers (P = .04 compared with other subgroups). We did not detect BRAF mutations in patients with double somatic colorectal tumors or Lynch syndrome. We found highly similar results in a validation cohort from The Cancer Genome Atlas (113 patients with colorectal tumors, 178 endometrial tumors); 100% of double somatic cases had a somatic mutation in PIK3CA (P < .0001 compared with other subgroups). CONCLUSIONS: Most patients with colorectal or endometrial tumors with 2 or more somatic (but not germline) mutations in MMR proteins also have mutations in PIK3CA; mutations in PIK3CA are detected at substantially higher frequencies in these double somatic tumors than in other microsatellite-instability subgroups. PIK3CA mutation status might be used to identify a specific group of colorectal tumors, and to select treatment or determine prognosis.

Defining payments associated with the treatment of colorectal cancer.

BACKGROUND: While bundled payments aim to reduce variations in health care spending across the continuum of care, data reporting on variations in payments for privately insured patients undergoing treatment for colon cancer (CC) are lacking. The current study sought to characterize variations in payments received for the treatment of CC using a cohort of commercially insured patients. METHODS: Patients who underwent a colectomy for CC were identified using the MarketScan Database for 2010-2014. Multivariable regression analysis was used to calculate and compare risk-adjusted payments between patients. RESULTS: A total of 18,337 patients were identified who met inclusion criteria. The median risk-adjusted payment for surgery was $26,408 (IQR: $19,193-$38,037) ranging from $19,762 (IQR: $15,595-$25,636) among patients in the lowest quartile of payments to $33,809 (IQR: $24,783-$48,254) for patients in the highest (+△71.1%). The median risk-adjusted payment for chemotherapy was $70,090 (IQR: $57,813-$83,216); compared with patients in the lowest quartile of payments, payments associated with chemotherapy were 40.4% higher among patients in the highest quartile of payments (Q1 versus Q4: $56,827 [IQR: 49,173-65,353] versus $79,801 [IQR: 67,270-90,999]). When stratified by treatment type, patients in the highest two quartiles of risk-adjusted payments accounted for a total of 58.5% of all payments, whereas patients in the lower two quartiles of risk-adjusted payments accounted for only 41.5% of all payments. A younger patient age, increasing patient comorbidity and undergoing an open operation were associated with higher overall payments. CONCLUSIONS: Wide variations in payments exist for the treatment for colon cancer. Episode-based bundle payments for surgery and chemotherapy may differentially impact reimbursement for CC.

Beta-blockers may reduce intrusive thoughts in newly diagnosed cancer patients.

OBJECTIVE: A cancer diagnosis provokes significant levels of emotional distress, with intrusive thoughts being the most common manifestation among breast cancer survivors. Cancer-related intrusive thoughts can take the form of emotional memories, flashbacks, nightmares, and intrusive images. Emotional arousal after a severe life stressor prolongs adrenergic activation, which in turn may increase risk for post-traumatic symptomatology. However, antihypertensive beta-blockers block adrenergic activation and are known to reduce traumatic memories and related psychological distress. Thus, the current study examined the association between beta-blocker use and the severity of cancer-related intrusive thoughts and related symptoms following a cancer diagnosis. METHODS: The 174 breast and 36 female colorectal cancer patients who had recently undergone diagnostic screening or biopsy included 39 beta-blocker users and 171 non-users. Prior to any cancer treatment including surgery, participants completed questionnaires that included the Impact of Events Scale and the Center for Epidemiological Studies Depression Scale. Analyses controlled for age, education, cancer stage, cancer type, days since diagnosis, marital status, depression, and comorbidities. RESULTS: Although the high rates of cancer-related distress in this sample were similar to those of other studies with recently diagnosed patients, beta-blocker users endorsed 32% fewer cancer-related intrusive thoughts than non-users. CONCLUSIONS: Recently diagnosed cancer patients using beta-blockers reported less cancer-related psychological distress. These results suggest that beta-blocker use may benefit cancer patients' psychological adjustment following diagnosis, and provide a promising direction for future investigations on the pharmacological benefits of beta-blockers for cancer-related distress.

Antigen-directed cancer surgery for primary colorectal cancer: 15-year survival analysis.

BACKGROUND: Tumor-associated glycoprotein-72 (TAG-72) is a mucin-like high-molecular-weight glycosylated protein complex overexpressed by many adenocarcinomas. Antigen-directed cancer surgery using radiolabeled anti-TAG-72 murine monoclonal antibodies (muMAbs) has been previously investigated for colorectal cancer. Survival analysis of primary colorectal cancer patients with a minimum of 15-year follow-up after antigen-directed cancer surgery was performed to assess the impact of complete surgical resection of all detectable radiolabeled anti-TAG-72 muMAb. METHODS: Survival analysis was performed on 92 patients (study group) with primary colorectal cancer (July 1990 to August 1995) treated with antigen-directed cancer surgery using (125)I-labeled anti-TAG-72 muMAb. The study group was subdivided into those with no detectable TAG-72 antigen-bearing tissues (TAG-72 negative, N=33) and those with persistent detectable TAG-72 antigen-bearing tissues (TAG-72 positive, N=59) at completion of surgery. Comparisons were made with a control group (546 patients) from the same time period. RESULTS: Study group and control group were demographically similar, as were TAG-72-negative subgroup and TAG-72-positive subgroup. TAG-72-negative subgroup had significantly improved median survival (8.8 versus 2.5 years; P=0.005) and time-dependent survival (45.4% versus 22.0% at 10 years; P=0.002 and 39.4% versus 20.3% at 15 years; P=0.003) compared with TAG-72-positive subgroup. TAG-72 positivity was as an independent predictor of long-term mortality risk, when controlled for pathologic stage of disease. CONCLUSIONS: Absence of detectable TAG-72 antigen within the surgical field at completion of antigen-directed cancer surgery for primary colorectal cancer is of significant prognostic value, conferring a long-term survival advantage to those in whom complete surgical removal of all tissues with detectable radiolabeled anti-TAG-72 muMAb was accomplished.

General surgery versus specialty rotations: a new paradigm in surgery clerkships.

BACKGROUND: The most common 3rd-year surgery clerkship uses general surgery services while limiting the involvement of subspecialty services. A novel surgery clerkship in which students were assigned to either general surgery or subspecialty services for the entire clerkship was tried at a large Midwestern medical school. The purpose of this study was to investigate the outcomes of clerks from subspecialty services and compare them with clerks from general surgery services. METHODS: Outcome measures included scores on the National Board of Medical Examiners Surgery Content Examination, faculty evaluation scores, and residency match results. A multivariate analysis of covariance compared National Board of Medical Examiners test scores and faculty evaluation ratings across service groups. United States Medical Licensing Examination Step 1 scores served as a covariate. RESULTS: Results showed significant differences between groups on faculty evaluation scores (F = 28.03; P

Effect of surgeon "experience" with laparoscopy on postoperative outcomes after colorectal surgery.

BACKGROUND: Although the relationship between laparoscopic surgery and improved clinical outcomes has been well established across a variety of procedures, the effect of operative experience with laparoscopic surgery remains less defined. The present study sought to assess the comparative benefit of laparoscopic colorectal surgery relative to surgeon volume. METHODS: Commercially insured patients aged 18 to 64 years undergoing a colorectal resection were identified using the MarketScan Database from 2010-2014. Multivariable logistic regression analysis was used to calculate and compare postoperative mortality/morbidity by operative approach relative to surgeon volume. RESULTS: A total of 21,827 patients were identified who met inclusion criteria. The median age among patients was 53 years (interquartile range: 46-59) with a slight majority of patients being female (n = 11,248, 51.5%). Laparoscopic operations were performed in 49.2% of patients (n = 10,756), whereas 50.7% (n = 11,071) underwent an open colorectal resection. On multivariable analysis, laparoscopic surgery was associated with 64% decreased odds of developing a postoperative complication or mortality (odds ratio = 0.36, 95% confidence interval, 0.32-0.41, P < .001). Patients who underwent colectomy performed by a higher operative volume surgeon (high versus low: odds ratio = 0.68, 95% confidence interval, 0.61-0.77, P < .001) demonstrated decreased odds of developing a postoperative complication/mortality. Interestingly the potential decrease in risk-adjusted morbidity/mortality between laparoscopic and open surgery was somewhat greater among high-operative-volume surgeons (odds ratio = 0.29, 95% confidence interval, 0.25-0.34, P < .001) and intermediate-operative-volume surgeons (odds ratio = 0.30, 95% confidence interval, 0.25-0.36, P < .001) compared with low-operative-volume surgeons (odds ratio = 0.36, 95% confidence interval, 0.32-0.41, P < .001). CONCLUSION: Although laparoscopic surgery was associated with improved postoperative clinical outcomes, the effect of laparoscopic surgery varied somewhat according to surgeon volume.

Has implementation of the 80-hour work week made a career in surgery more appealing to medical students?

BACKGROUND: This study was conducted to determine if a surgical career became more appealing to medical students with the resident work week limited to 80 hours. METHODS: At the start and conclusion of each surgery clerkship rotation, students completed a survey addressing perception of surgeons, and surgery as a career. They were divided into the control groups (rotations before July 2003; n = 109) and the experimental group (rotations after July 2003; n = 108). RESULTS: Students in the experimental group had a significantly more favorable impression of a surgeon's lifestyle and work hours than those in the control group. This was especially true of female students post-rotation, who responded more positively to the statement that a surgical career would allow for a good balance between professional and personal life (1.87 vs 2.45, P <.01). CONCLUSION: The new Accreditation Council for Graduate Medical Education (ACGME) regulation has had a positive impact on students' perceptions of the surgeon's lifestyle, but does not necessarily increase their interest in a surgical career.

Pain, depression, and fatigue: loneliness as a longitudinal risk factor.

OBJECTIVE: Pain, depression, and fatigue function as a symptom cluster and thus may share common risk factors. Interpersonal relationships clearly influence health, suggesting that loneliness may promote the development of the pain, depression, and fatigue symptom cluster. We hypothesized that loneliness would be related to concurrent symptom cluster levels and increases in symptom cluster levels over time. METHOD: We utilized two observational studies with distinct longitudinal samples. Study 1 was a sample of cancer survivors and benign controls (N = 115) assessed annually for 2 years. Study 2 was a sample of older adults caring for a spouse with dementia (caregivers) and non-caregiver controls (N = 229) assessed annually for 4 years. Participants completed annual measures assessing loneliness, pain, depression, and fatigue. RESULTS: Across both samples, lonelier participants experienced more concurrent pain, depression, and fatigue and larger increases in symptom cluster levels from one year to the next than less lonely participants. Sleep quality did not mediate the results in either study. All analyses were adjusted for relevant demographic and health variables. CONCLUSIONS: Two longitudinal studies with different populations demonstrated that loneliness was a risk factor for the development of the pain, depression, and fatigue symptom cluster over time. The current research helps identify people most at risk for pain, depression, and fatigue, and lays the groundwork for research about their diagnosis and treatment. These data also highlight the health risks of loneliness; pain, depression, and fatigue often accompany serious illness and place people at risk for poor health and mortality.

Radioimmunoguided surgery (RIGS), PET/CT image-guided surgery, and fluorescence image-guided surgery: past, present, and future.

(125)I-labeled anti-TAG-72 antibodies were applied in radioimmunoguided surgery (RIGS) to remove gross and occult tumors. It is challenging to handle (125)I-labeled materials. PET/CT image-guided surgery utilizes (18)FDG to monitor the biochemical activity of the tumor and to integrate pre- and postoperative imaging for complete tumor removal. PET/CT image-guided surgery only detects later stage disease. Fluorescence image-guided surgery using anti-TAG-72 antibodies may provide opportunities for intraoperative cancer detection of both gross and occult tumors.

Positron emission tomography affects surgical management in recurrent colorectal cancer patients.

BACKGROUND: We determined the effect of positron emission tomography (PET) on surgical decision-making in patients with metastatic or recurrent colorectal cancer. METHODS: A total of 114 patients with advanced colorectal cancer were imaged with computed tomography (CT) and PET scans. The PET and CT scans were independently interpreted before surgery and recorded. RESULTS: Forty-two of the 114 patients had resectable disease on the basis of CT. PET altered therapy in 17 (40%) of these 42 patients on the basis of the following results: extrahepatic disease (n = 9), bilobar involvement (n = 3), thoracic involvement (n = 5), retroperitoneal lymphadenopathy (n = 2), bone involvement (n = 1), and supraclavicular disease (n = 1). In 25 patients with liver metastases only, PET found additional disease in 18 (72%), extrahepatic disease in 11, chest disease in 13, retroperitoneal lymphadenopathy in 4, and bone disease in 3. In five patients, both scans underestimated small-volume peritoneal metastases discovered at laparotomy. CONCLUSIONS: PET altered therapy in 40% of patients. In patients with isolated liver involvement, 72% had more extensive disease that precluded surgical resection. PET scans should be used in the management of patients with recurrent colorectal cancer who are being considered for potentially curative surgery.

Pilot study using a humanized CC49 monoclonal antibody (HuCC49DeltaCH2) to localize recurrent colorectal carcinoma.

BACKGROUND: CC49 is a monoclonal antibody directed against a pancarcinoma antigen (TAG-72) expressed by colorectal cancers. The use of murine CC49 in radioimmunoguided surgery (RIGS) was problematic because of the human anti-mouse antibodies (HAMA) generated. This study was designed to assess the clearance, safety, and effectiveness of localization of a complimentarity determining region (CDR)-grafted humanized domain-deleted antitumor CC49 antibody (HuCC49DeltaCH2). METHODS: After thyroid blockade, 1 mg of HuCC49DeltaCH2 radiolabeled with 2 mCi of iodine-125 was administered. All patients subsequently underwent traditional exploration followed by a survey with the gamma-detecting probe. In five patients, exploration was performed 10 to 24 days after injection, when precordial counts were sufficiently low (<30 counts per 2 seconds [cp2s]). Traditionally suggestive and probe-positive tissue was biopsied or excised and examined for the presence of carcinoma, when considered appropriate by the operating surgeon. Serum was assessed for HAMA. RESULTS: Seventeen sites were identified as suggestive of carcinoma on traditional exploration and 21 by RIGS. Of these, pathologic correlation was obtained in 15. The sensitivity of RIGS was 92%, and the positive predictive value was 100%. None of the patients expressed significant HAMA. CONCLUSIONS: This initial study indicates that the HuCC49DeltaCH2 monoclonal antibody, when used with RIGS, is safe and sensitive in detecting recurrent intra-abdominal colon cancer.