John T. Mullen

The obesity paradox: body mass index and outcomes in patients undergoing nonbariatric general surgery.

Objective:We sought to examine the effect of body mass index (BMI) on 30-day morbidity and mortality in a large cohort of patients undergoing nonbariatric general surgery. Summary Background Data:Obesity has long been considered a risk factor for poor outcomes from a variety of surgical procedures, yet recent studies of critically and chronically ill patients suggest that overweight and obese patients may paradoxically have better outcomes than “normal” weight patients. Methods:A prospective, multi-institutional, risk-adjusted cohort study of 118,707 patients undergoing nonbariatric general surgery who were included in the National Surgical Quality Improvement Program Participant Use database in 2005 and 2006 was performed. Outcomes and risk variables were compared across NIH-defined BMI class using analysis of variance, Bonferroni multiple comparisons of means tests, and multivariable logistic regression. Results:After adjusting for all significant perioperative risk factors, the risk of death according to BMI exhibited a reverse J-shaped relationship, with the highest rates in the underweight and morbidly obese extremes and the lowest rates in the overweight and moderately obese. Overweight (odds ratio, 0.85; 95% CI, 0.75–0.99) and moderately obese (odds ratio, 0.73; 95% CI, 0.57–0.94) patients had a significantly lower risk of death than normal weight patients. There was a progressive increase in the likelihood of a complication with increasing BMI class, almost entirely due to increasing rates of wound infection. Conclusions:Overweight and moderately obese patients undergoing nonbariatric general surgery have paradoxically “lower” crude and adjusted risks of mortality compared with patients at a “normal” weight. This finding is in contrast to observations from the general population, confirming the existence of an “obesity paradox” in this patient population.

Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases

Some investigators have suggested that wedge resection (WR) confers a higher incidence of positive margins and an inferior survival compared with anatomic resection (AR) of colorectal liver metastases (CLM). We sought to investigate the margin status, pattern of recurrence, and overall survival of patients with CLM treated with WR or AR. We identified 253 consecutive patients, in a multi-institutional database from 1991 to 2004, who underwent either WR or AR. WR was defined as a nonanatomic resection of the CLM, and AR was defined as single or multiple resections of one or two contiguous Couinaud segments. Clinicopathologic factors were analyzed with regard to pattern of recurrence and survival. One hundred six WRs were performed in 72 patients and 194 ARs in 181 patients. There was no difference in the rate of positive surgical margin (8.3%), overall recurrence rates, or patterns of recurrence between patients treated with WR vs. AR. Patients who had a positive surgical resection margin were more likely to recur at the surgical margin regardless of whether they underwent WR or AR. The median survival was 76.6 months for WR and 80.8 months for AR, with 5-year actuarial survival rates of 61% and 60%, respectively. AR is not superior to WR in terms of tumor clearance, pattern of recurrence, or survival. WR should remain an integral component of the surgical treatment of CLM.

Invasive Squamous Cell Carcinoma of the Skin: Defining a High-Risk Group

BackgroundUnlike its more common non-invasive form, invasive squamous cell carcinoma (SCC) of the skin can be biologically aggressive and is prone to recur. The objectives of this study were to identify relevant clinicopathologic prognostic factors associated with the outcomes of patients with invasive SCC in order to define a high-risk group.MethodsWe retrospectively reviewed the records of patients with invasive cutaneous SCC of the trunk or extremities who received surgical treatment at a tertiary care cancer center over the past 10 years. We examined the patterns of presentation, all known clinical and histological risk factors for recurrence, and their association with survival.Results136 patients were identified, of whom 102 (74%) were male. Patterns of presentation included primary (n = 91), locally recurrent (n = 16), regional nodal (n = 24), and distant (n = 5) disease. Univariate analysis identified poorly differentiated carcinomas (hazard ratio [HR] = 2.92, P = .016), scar carcinomas (HR = 3.12, P = .008), tumor size > 2 cm (HR = 3.79, P = .006), and regional nodal disease (HR = 5.77, P < .0001) as significant risk factors for recurrence or death. On multivariate analysis, however, only regional nodal disease at presentation (HR = 7.64, P < .0001) was found to be significant.ConclusionsPatients with invasive SCCs metastatic to regional nodes constitute a group at high risk for recurrence and death. Such patients should be considered for adjuvant therapy trials.

Pancreaticoduodenectomy After Placement of Endobiliary Metal Stents

Contemporary treatment programs for patients with potentially resectable pancreatic cancer often involve preoperative therapy. When the duration of preoperative therapy exceeds 2 months, the risk of plastic endobiliary stent occlusion increases. Metal stents have much better patency but may complicate subsequent pancreaticoduodenectomy (PD). We evaluated rates of perioperative morbidity, mortality, and stent complications in 272 consecutive patients who underwent PD at our institution from May 2001 to November 2004. Of these 272 patients, 29 (11%) underwent PD after placement of a metal stent, 141 underwent PD after placement of a plastic stent, 10 had PD after biliary bypass without stenting, and 92 had PD without any form of biliary decompression. No differences were found between the Metal Stent group and all other patients in median operative time, intraoperative blood loss, or length of hospital stay. No perioperative deaths occurred in the Metal Stent group versus 3 (1.2%) deaths in the other 243 patients. The incidence of major perioperative complications was similar between the two groups, including the rates of pancreatic fistula, intra-abdominal abscess, and wound infection. Furthermore, there were no differences in the perioperative morbidity or mortality rates between patients who underwent preoperative biliary decompression with a stent of any kind (metal or plastic) and those patients who underwent no biliary decompression at all. Metal stent-related complications occurred in 2 (7%) of 29 patients during a median preoperative interval of 4.1 months; in contrast, 75 (45%) of the 166 patients who had had plastic stents experienced complications, including 98 stent occlusions, during a median preoperative interval of 3.9 months (P < 0.001). We conclude that the use of expandable metal stents does not increase PD-associated perioperative morbidity or mortality, and as such an expandable metal stent is our preferred method of biliary decompression in patients with symptomatic malignant distal bile duct obstruction in whom surgery is not anticipated, or in whom there is a significant delay in the time to surgery.

Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

PURPOSE To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. RESULTS Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. CONCLUSION High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC.

Blunt transection of the pancrease treated by distal pancreatectomy, splenic salvage and hyperalimentation. Four cases and review of the literature.

The increasing awareness among surgeons of overwhelming postsplenectomy sepsis has led to new and innovative procedures to save the spleen. In pancreatic transection injuries (Type II)26 the classical treatment has been distal pancreatectomy and splenectomy. The opportunity to treat several patients with pancreatic transections sustained during blunt abdominal trauma lead to the review of the literature on the subject. Particular attention was paid to treatment of these injuries using distal pancreatectomy with splenic salvage, appropriate drainage, and hyperalimentation. Associated complications were likewise investigated and reviewed.

Carcinoid tumors of the appendix: A population-based study

Carcinoid tumors of the appendix are rare, and as such there are few data guiding their optimal treatment.

Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach

Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner’s office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment.

β-Catenin Mutation Status and Outcomes in Sporadic Desmoid Tumors

BACKGROUND Mutations in the gene-encoding β-catenin, CTNNB1, are highly prevalent in sporadic desmoid tumors and may predict the risk for recurrence. We sought to determine the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoid tumors and to determine whether CTNNB1 mutation status correlates with disease outcome. METHODS Single-base extension genotyping of the CTNNB1 gene was performed on 145 sporadic, paraffin-embedded desmoid tumor specimens. Correlation of mutation status with outcome was performed on a subset of 115 patients who underwent macroscopically complete surgical resection. RESULTS CTNNB1 mutations were detected in 106 of 145 (73%) tumor specimens and in 86 of 115 (75%) specimens from patients who underwent curative-intent surgical resection, including discrete mutations in the following codons of CTNNB1 exon 3: T41A (46%), S45F (25%), S45P (1.7%), and S45C (0.9%). Desmoid tumors of the superficial trunk were significantly less likely to harbor CTNNB1 mutations than tumors located elsewhere, but none of the other examined clinicopathologic factors were found to be associated with CTNNB1 mutation status. At a median follow-up of 31 months, 5-year recurrence-free survival was slightly, although not statistically significantly, worse for patients with β-catenin-mutated tumors than for those with wild-type tumors (58% vs. 74%, respectively). The specific CTNNB1 codon mutation did not correlate with the risk for recurrence. CONCLUSION CTNNB1 mutations are indeed common in sporadic desmoid tumors. However, our study did not detect a statistically significant difference in recurrence risk according to either the CTNNB1 mutation status or the specific CTNNB1 mutation.

Long-term follow-up of patients treated with neoadjuvant chemotherapy and radiotherapy for large, extremity soft tissue sarcomas

Patients with large, high‐grade, extremity soft tissue sarcomas (STS) are at significant risk for distant recurrence and death. A regimen of preoperative chemotherapy consisting of mesna, Adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID), interdigitated with radiotherapy (RT) and followed by resection and postoperative chemotherapy with or without RT, has demonstrated high rates of local and distant control. We report the long‐term follow‐up data on 48 patients treated with this regimen compared to an historical matched‐control patient population.