Outcomes of rectal cancer patients who refuse surgery after incomplete clinical response to neoadjuvant therapy.

BACKGROUND AND OBJECTIVES: Total mesorectal excision (TME) remains the standard of care for patients with rectal cancer who have an incomplete response to total neoadjuvant therapy (TNT). A minority of patients will refuse curative intent resection. The aim of this study is to examine the outcomes for these patients. METHODS: A retrospective cohort study of stage 1-3 rectal adenocarcinoma patients who underwent neoadjuvant chemoradiation therapy or TNT at a single institution. Patients either underwent TME, watch-and-wait protocol, or if they refused TME, were counseled and watched (RCW). Clinical outcomes and resource utilization were examined in each group. RESULTS: One hundred seventy-one patients (Male 59%) were included with a median surveillance of 43 months. Twenty-nine patients (17%) refused TME and had shortened overall survival (OS). Twelve patients who refused TME converted to a complete clinical response (cCR) on subsequent staging with a prolonged OS. 92% of these patients had a near cCR at initial staging endoscopy. Increased physician visits and testing was utilized in RCW and WW groups. CONCLUSION: A significant portion of patients convert to cCR and have prolonged OS. Lengthening the time to declare cCR may be considered in select patients, such as those with a near cCR at initial endoscopic staging.

Rule of four: an anatomic and value-based approach to stent-graft inventory for blunt thoracic aortic injury.

PURPOSE: As blunt thoracic aortic injury (BTAI) treatment has shifted from open to thoracic endovascular aortic repair (TEVAR), logistical challenges exist in creating and maintaining inventories of appropriately sized stent-grafts, including storage demands, shelf-life management and cost. We hypothesized that most injured aortas can be successfully repaired with a narrow range of stent-graft sizes and present a value-based anatomic approach to optimizing inventory. METHODS: CT-scans of all patients with BTAI admitted to our Level I trauma center from Apr 2010-Dec 2018 were reviewed. Patients with anatomy incompatible with TEVAR were excluded. For each patient, after aortic sizing a set of two stent-grafts most likely to be utilized was selected from a list of twenty commercially available GORE conformable TAG endografts based on manufacturer instructions. Stent-graft sizes were then ranked based on the number of cases they would be suitable for. MATLAB was utilized to determine the combinations of stent-grafts which would cover the most patients. RESULTS: Twenty-eight patients with BTAI were identified and three were excluded based on iliac diameter. Most patients were male (68%), mean age 42.3 ± 20.2 years, mean ISS 37.0 ± 9.8. Overall mortality was 25%. Of the 20 available stent-graft options, a combination of four stent-grafts would successfully treat 100% of the patients in this series. CONCLUSIONS: Based on actual CT-scan aortic measurements, we demonstrated that an inventory of four sent-graft sizes was sufficient to treat 100% of patients with BTAI. These data can be utilized as a value-based anatomic approach to aortic stent-graft institutional inventory creation and maintenance.

The more you have, the more you lose: Muscle mass changes in trauma patients with prolonged hospitalizations.

INTRODUCTION: Sarcopenia is a clinically relevant loss of muscle mass with implications of increased morbidity and mortality in adult trauma populations.  Our study aimed to evaluate loss of muscle mass change in adult trauma patients with prolonged hospital stays. METHODS: Retrospective analysis using institutional trauma registry to identify all adult trauma patients with hospital length of stay >14 days admitted to our Level 1 center between 2010 and 2017. All CT images were reviewed, and cross-sectional area (cm2) of the left psoas muscle was measured at the level of the third lumbar vertebral body to determine total psoas area (TPA) and Total Psoas Index (TPI) normalized for patient stature.  Sarcopenia was defined as a TPI on admission below gender specific thresholds of 5.45(cm2/m2) in men and 3.85(cm2/m2) in women.  TPA, TPI, and rates of change in TPI were then evaluated and compared between sarcopenic and non-sarcopenic adult trauma patients. RESULTS: There were 81 adult trauma patients who met inclusion criteria. The average change in TPA was -3.8 cm2 and TPI was -1.3 cm2. On admission, 23% (n = 19) of patients were sarcopenic while 77% (n = 62) were not. Non-sarcopenic patients had a significantly greater change in TPA (-4.9 vs. -0.31, p<0.0001), TPI (-1.7 vs. -0.13, p<0.0001), and rate of decrease in muscle mass (p = 0.0002). 37% of patients who were admitted with normal muscle mass developed sarcopenia during admission.  Older age was the only risk factor independently associated with developing sarcopenia (OR: 1.04, 95%CI 1.00-1.08, p = 0.045). CONCLUSION: Over a third of patients with normal muscle mass at admission subsequently developed sarcopenia with older age as the primary risk factor. Patients with normal muscle mass at admission had greater decreases in TPA and TPI, and accelerated rates of muscle mass loss compared to sarcopenic patients.

The Enhanced Recovery After Surgery (ERAS) Elements that Most Greatly Impact Length of Stay and Readmission.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been shown to decrease length of stay (LOS) and improve patient outcomes in a wide variety of surgical fields; however, barriers exist preventing the implementation of all elements. We hypothesize that a subset of ERAS elements are most influential on LOS and readmission following colorectal surgery. STUDY DESIGN: A retrospective review of 840 patients was performed and their compliance with 24 ERAS components evaluated. Two independent machine-learning statistical algorithms were employed to determine which subset of ERAS elements was most impactful on LOS <3 days and hospital readmission. RESULTS: Increasing compliance with ERAS elements had an inverse linear relationship with LOS. Open (vs minimally invasive) surgery was associated with increased LOS. Early mobilization and multimodal pain management are the elements most protective against increased LOS. Readmissions increase with the number of morphine milligram equivalents (MME)/day. The subset of patients who underwent minimally invasive procedures, had multimodal pain control, and less than 16 MME per day were least likely (23%) to have >3-day LOS. Those patients who underwent an open procedure with less than 15 ERAS elements completed were most likely (84%) to have >3-day LOS. CONCLUSION: While increasing compliance with ERAS protocols and minimally invasive procedures decrease LOS and readmission overall, a subset of components-multimodal pain control, limited opioid use, and early mobilization-was most associated with decreased LOS and readmission. This study provides guidance on which ERAS elements should be emphasized.

The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure.

The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.

Fix it while you can Mortality after umbilical hernia repair in cirrhotic patients.

BACKGROUND: We hypothesize that patients with compensated cirrhosis undergoing elective UHR have an improved mortality compared to those undergoing emergent UHR. METHOD: The NIS was queried for patients undergoing UHR by CPT code, and ICD-10 codes were used to define separate patient categories of non-cirrhosis (NC), compensated cirrhosis (CC) and decompensated cirrhosis (DC). RESULTS: A total of 32,526 patients underwent UHR, 97% no cirrhosis, 1.1% compensated cirrhosis, 1.7% decompensated cirrhosis. On logistic regression, cirrhosis was found to be independently associated with mortality (OR 2.841, CI 2.14-3.77). On subset analysis of only cirrhosis patients, elective repair was found to be protective from mortality (OR 0.361, CI 0.15-0.87, p = 0.02). CONCLUSIONS: In this retrospective review, cirrhosis as well as emergent UHR in cirrhotic patients were independently associated with mortality. More specifically, electively (rather than emergently) repairing an umbilical hernia in cirrhotic patients was independently associated with a 64% reduction in mortality.

Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier.

Although metabolic adaptations have been demonstrated to be essential for tumor cell proliferation, the metabolic underpinnings of tumor initiation are poorly understood. We found that the earliest stages of colorectal cancer (CRC) initiation are marked by a glycolytic metabolic signature, including downregulation of the mitochondrial pyruvate carrier (MPC), which couples glycolysis and glucose oxidation through mitochondrial pyruvate import. Genetic studies in Drosophila suggest that this downregulation is required because hyperplasia caused by loss of the Apc or Notch tumor suppressors in intestinal stem cells can be completely blocked by MPC overexpression. Moreover, in two distinct CRC mouse models, loss of Mpc1 prior to a tumorigenic stimulus doubled the frequency of adenoma formation and produced higher grade tumors. MPC loss was associated with a glycolytic metabolic phenotype and increased expression of stem cell markers. These data suggest that changes in cellular pyruvate metabolism are necessary and sufficient to promote cancer initiation.

Secretory breast carcinoma in an 8-year-old girl: A case report and literature review.

Secretory breast carcinoma (SBC) is a rare form of breast cancer found in both children and adults, and is the most common breast cancer in the pediatric population. Although SBC usually carries a favorable prognosis, there have been reported cases of axillary and distant metastases. Surgery is the primary mode of treatment, however, there exists variability within the literature surrounding the management of SBC. We report a case of an 8-year-old girl who presented with a firm, mobile, palpable breast mass. Ultrasonography was performed, followed by local excision, with surgical pathology concerning for SBC. The patient was definitively treated with mastectomy and sentinel lymph node (SLN) biopsy. She received no adjuvant therapies and 2 years later, remains disease free. Herein, we review the literature, curate data from 89 reported cases of pediatric and adult SBC, and address some of the controversy surrounding its treatment. From this review we conclude that patients with SBC should be reviewed at multidisciplinary treatment planning conference, undergo surgery with mastectomy or lumpectomy with SLN biopsy, and have long-term postoperative follow-up.

Provider views on the management of Ewing sarcoma of the spine and pelvis.

BACKGROUND: Curative therapy for ES requires both chemotherapy and local control of primary tumor. There is no universally accepted standard approach to local control modalities. This survey was conducted to determine practice patterns and factors influencing the choice to offer various local control modalities to patients with ES of the spine and pelvis. METHODS: The survey consisted of four scenarios involving a 15-year-old girl who presented with Ewing sarcoma of thoracic vertebra, sacrum, iliac wing, and acetabulum with or without neurologic compromise. The questionnaire was sent to oncologists, orthopedic surgeons, and radiation oncologists, asking their recommendations for local control modality. RESULTS: Among 94 respondents, radiotherapy was most frequently chosen for sacral tumors (68.1%) and T10 vertebral tumors (46.2%) whereas surgery was preferred for iliac wing pelvic tumors (45.7%) and acetabular tumors (43.6%). Orthopedic surgeons were significantly more likely to offer surgery than radiation oncologists (OR 3.07, 95%CI 1.37-6.88, P = 0.007). Providers outside North America were more likely to offer combined surgery plus radiotherapy (OR 10.58, 95%CI 5.41-20.70, P < 0.001). CONCLUSION: Considerable heterogeneity exists in local control modalities for Ewing sarcoma of the spine and pelvis. Specialty and location of practice may influence treatment recommendations.

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.

A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC).

Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1), a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation. Exogenous human MPC1 RNA rescued failed intestinal differentiation in zebrafish models of apc deficiency. Our data demonstrate a novel role for apc in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of apc.

Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies.

Dysregulated metabolism is an emerging hallmark of cancer, and there is abundant interest in developing therapies to selectively target these aberrant metabolic phenotypes. Sitting at the decision-point between mitochondrial carbohydrate oxidation and aerobic glycolysis (i.e., the 'Warburg effect'), the synthesis and consumption of pyruvate is tightly controlled and is often differentially regulated in cancer cells. This review examines recent efforts toward understanding and targeting mitochondrial pyruvate metabolism, and addresses some of the successes, pitfalls, and significant challenges of metabolic therapy to date.

A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth.

Cancer cells are typically subject to profound metabolic alterations, including the Warburg effect wherein cancer cells oxidize a decreased fraction of the pyruvate generated from glycolysis. We show herein that the mitochondrial pyruvate carrier (MPC), composed of the products of the MPC1 and MPC2 genes, modulates fractional pyruvate oxidation. MPC1 is deleted or underexpressed in multiple cancers and correlates with poor prognosis. Cancer cells re-expressing MPC1 and MPC2 display increased mitochondrial pyruvate oxidation, with no changes in cell growth in adherent culture. MPC re-expression exerted profound effects in anchorage-independent growth conditions, however, including impaired colony formation in soft agar, spheroid formation, and xenograft growth. We also observed a decrease in markers of stemness and traced the growth effects of MPC expression to the stem cell compartment. We propose that reduced MPC activity is an important aspect of cancer metabolism, perhaps through altering the maintenance and fate of stem cells.