Characteristics of pathologic complete response for locally advanced rectal cancer.

BACKGROUND: Neoadjuvant chemoradiation (NACRT) is the standard of care for locally advanced rectal cancers. The purpose of this study was to determine patient and tumor factors associated with a pathologic complete response (pCR). METHODS: The National Surgical Quality Improvement Program proctectomy-targeted database was utilized to identify all patients from 2016 to 2020 who underwent NACRT followed by proctectomy with curative intent for T3-4N0-2 rectal cancers. RESULTS: A total of 1891 patients were included, of which 253 (13.4%) demonstrated a pCR. Pretreatment N0 staging was associated with a higher rate of pCR (18.9%) when compared to N1 (6.7%) and N2 (6.7%) (p < 0.0001). Patients clinically staged at T3N0 had the highest rate of pCR (19.5%). Gender, age, race, weight, smoking status, and tumor height were not associated with pCR. CONCLUSIONS: Patients with cN0 disease were more likely to experience a pCR compared to cN1-2 patients. Tumor height relative to anal verge or patient demographics were not associated with pCR.

Colorectal cancer: Review of signaling pathways and associated therapeutic strategies.

Tumor profiling and targeted therapy revolutionized the treatment strategies of metastatic colorectal cancer (mCRC) in the last decade. The heterogeneity of CRC tumors plays a critical role in the development of treatment resistance, which underscores the need to understand the molecular mechanism involved in CRC to develop novel targeted therapeutic strategies. This review provides an overview of the signaling pathways driving CRC, the existing targeted agents, their limitations, and future trends.

Perianal Paget's-an aggressive disease.

AIM: Perianal Paget's disease (PAPD) is a rare disorder with a predisposition to anal and colorectal malignancies and an unclear prognosis. Our previous 25-year series demonstrated a non-aggressive nature. This study aims to describe our updated institutional experience. METHODS: This is a retrospective review of all patients diagnosed with primary PAPD from 1991 to 2021. A prospectively maintained institutional database was searched which included demographics, clinical and pathological manifestations, treatment methods, recurrence, oncological outcome and mortality. RESULTS: Thirty patients were diagnosed with PAPD. Fifteen were women (50%); the average age at diagnosis was 71 ± 10.7 years, and the average lesion size was 3.7 ± 2.6 cm. At diagnosis, 12 (40%) were harbouring invasive anal adenocarcinoma. Eight (27%) developed adenocarcinomas concurrent with PAPD recurrence at a mean interval of 9 ± 4.4 years (range 1.9-14.8). The Kaplan-Meier curve estimated overall survival of 93%, 86%, 82%, 65% and 56% at 1, 3, 5, 10 and 15 years, respectively. Median survival was 16 years. Six (20%) had disease-related mortality. Initially, nine (30%) were treated with abdominoperineal resection (APR), 15 (50%) underwent local resection, three (10%) were treated with radiotherapy, two (7%) received only topical therapy and one (3%) chose observation. Fifteen (50%) experienced recurrence of PAPD, two after undergoing APR. Five (17%) had persistent disease until death. Only 10 (33%) did not experience PAPD recurrence, seven of whom underwent APR. The mean follow-up time was 9.2 ± 6.2 years. CONCLUSIONS: Perianal Paget's disease is an aggressive entity with high rates of synchronous anal adenocarcinoma at diagnosis and development of metachronous adenocarcinoma later in life.

Management of Diverticulitis in Renal Transplant Patients.

BACKGROUND: Renal transplant patients presenting with diverticulitis remain a clinical challenge for health care professionals. Secondary to immunosuppression, renal transplant recipients are often considered for early operative intervention due to concerns for an unreliable physical exam and feared morbidity and mortality associated with non-operative management. METHODS: This study aimed to evaluate trends in management of renal transplant patients with diverticulitis at a quaternary referral center. RESULTS: One hundred ninety-one renal transplant patients admitted to the hospital with diverticulitis were identified. Of this cohort, 71 (37%) underwent surgical resection, of which 20 (28%) were performed emergently. The overall 30-day operative mortality was 8% (6/71), of which there was a significant difference between emergent (25%, 5/20) and elective (2%, 1/51) groups (P = .006). Patients who underwent elective surgery were more likely to receive a minimally invasive approach (51%) and were significantly more likely to undergo stoma reversal (P = .006). DISCUSSION: Our study shows that not all renal transplants with diverticulitis will require operative intervention and many can be safely treated non-operatively. Elective resection and surgical management should be considered on an individual basis. Patients treated with elective resection were more likely to undergo a minimally invasive approach and restoration of intestinal continuity.

Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome.

BACKGROUND: The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis and function. However, the role of Notch signaling in aortic pathology and aortic smooth muscle cell (SMC) differentiation in Marfan syndrome (MFS) is not completely understood. METHODS: RNA-sequencing on ascending aortic tissue from a mouse model of MFS, Fbn1mgR/mgR , and wild-type controls was performed. Notch 3 expression and activation in aortic tissue were confirmed with real-time RT-PCR, immunohistochemistry, and Western blot. Fbn1mgR/mgR and wild-type mice were treated with a γ-secretase inhibitor, DAPT, to block Notch activation. Aortic aneurysms and rupture were evaluated with connective tissue staining, ultrasound, and life table analysis. RESULTS: The murine RNA-sequencing data were validated with mouse and human MFS aortic tissue, demonstrating elevated Notch3 activation in MFS. Data further revealed that upregulation and activation of Notch3 were concomitant with increased expression of SMC contractile markers. Inhibiting Notch3 activation with DAPT attenuated aortic enlargement and improved survival of Fbn1mgR/mgR mice. DAPT treatment reduced elastin fiber fragmentation in the aorta and reversed the differentiation of SMCs. CONCLUSIONS: Our data demonstrated that matrix abnormalities in the aorta of MFS are associated with increased Notch3 activation. Enhanced Notch3 activation in MFS contributed to aortic aneurysm formation in MFS. This might be mediated by inducing a contractile phenotypic change of SMC. Our results suggest that inhibiting Notch3 activation may provide a strategy to prevent and treat aortic aneurysms in MFS.

Enhanced Notch3 signaling contributes to pulmonary emphysema in a Murine Model of Marfan syndrome.

Marfan syndrome (MFS) is a heritable disorder of connective tissue, caused by mutations in the fibrillin-1 gene. Pulmonary functional abnormalities, such as emphysema and restrictive lung diseases, are frequently observed in patients with MFS. However, the pathogenesis and molecular mechanism of pulmonary involvement in MFS patients are underexplored. Notch signaling is essential for lung development and the airway epithelium regeneration and repair. Therefore, we investigated whether Notch3 signaling plays a role in pulmonary emphysema in MFS. By using a murine model of MFS, fibrillin-1 hypomorphic mgR mice, we found pulmonary emphysematous-appearing alveolar patterns in the lungs of mgR mice. The septation in terminal alveoli of lungs in mgR mice was reduced compared to wild type controls in the early lung development. These changes were associated with increased Notch3 activation. To confirm that the increased Notch3 signaling in mgR mice was responsible for structure alterations in the lungs, mice were treated with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglucine t-butyl ester (DAPT), a γ-secretase inhibitor, which inhibits Notch signaling. DAPT treatment reduced lung cell apoptosis and attenuated pulmonary alteration in mice with MFS. This study indicates that Notch3 signaling contributes to pulmonary emphysema in mgR mice. Our results may have the potential to lead to novel strategies to prevent and treat pulmonary manifestations in patients with MFS.

Ex vivo expansion of regulatory T cells from abdominal aortic aneurysm patients inhibits aneurysm in humanized murine model.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease. Studies of human aneurysm tissue demonstrate dense inflammatory cell infiltrates with CD4+ T cells predominating. Regulatory T cells (Tregs) play an important role in inhibiting pro-inflammatory T cell proliferation, therefore, limiting collateral tissue destruction. The aim of this study was to investigate whether ex vivo augmentation of human Tregs attenuates aneurysm formation in humanized murine model of AAA. METHODS: Circulating Treg population in AAA patients and age- and gender-matched controls were determined by real-time polymerase chain reaction and flow cytometry. To create humanized murine model of AAA, irradiated Rag1-deficient (Rag1-/-) mice, without mature T lymphocytes, at 7 weeks of age were given 5 × 106 of human CD4+ T cells intraperitoneally. Then the mice underwent CaCl2 aneurysm induction. Aortic diameters were measured before and at 6 weeks after aneurysm induction. Aortic tissue was collected for histology and protein extraction. Verhoeff-Van Gieson stain was used for staining elastic fiber. CD4+ T cells in the aortic tissue were detected by immunohistochemical staining. RESULTS: In human peripheral blood mononuclear cells, the proportion of Tregs are decreased in AAA patients compared with matched control patients with significant vascular disease. We first validated the role of Tregs in the CaCl2 model of AAA. To determine the role of human T cells in AAA formation, Rag1-/- mice, resistant to CaCl2-aneurysm induction, were transplanted with human CD4+ T cells. Human CD4+ T cells were able to drive aneurysm formation in Rag1-/- mice. We show that ex vivo augmentation of human Tregs by interleukin-2 resulted in decreased aneurysm progression. CONCLUSIONS: These data suggest that the ex vivo expansion of human Tregs may be a potential therapeutic strategy for inhibiting progression of AAA.

Managing Squamous Cell Esophageal Cancer.

This article reviews the pathophysiology, risk factors, clinical presentation/diagnosis, and management of SCC.

CD95-ligand contributes to abdominal aortic aneurysm progression by modulating inflammation.

AIMS: Abdominal aortic aneurysm (AAA) is one of the number of diseases associated with a prominent inflammatory cell infiltration, matrix protein degradation, and smooth muscle cell apoptosis. CD95 is an inflammatory mediator and an apoptosis inducer. Previous studies have shown elevated expression of CD95 or CD95L in the aortic tissue of AAA patients. However, how the CD95L/CD95 contributes to aneurysm degeneration and whether blocking its signalling would be beneficial to disease progression remains largely unknown. In the present study, we sought to determine the role of CD95L and its downstream target, caspase 8, in AAA progression. METHODS AND RESULTS: By using the CaCl2 murine model of AAA, abdominal aortic aneurysms were induced in C57BL/6 mice. We found that both mRNA and protein levels of CD95L were increased in aneurysm tissue compared with NaCl-treated normal aortic tissue. To determine whether CD95L contributes directly to aneurysm formation, we used CD95L null (CD95L-/-) mice to examine their response to CaCl2 aneurysm induction. Six weeks after periaortic application of CaCl2, aortic diameters of CD95L-/- mice were significantly smaller compared to CaCl2-treated wild-type controls. Connective tissue staining of aortic sections from CaCl2-treated CD95L-/- mice showed minimal damage of medial elastic lamellae which was indistinguishable from the NaCl-treated sham control. Furthermore, CD95L deficiency attenuates macrophage and T cell infiltration into the aortic tissue. To study the role of CD95L in the myelogeous cells in AAA formation, we created chimaeric mice by infusing CD95L-/- bone marrow into sub-leathally irradiated wild-type mice (WT/CD95L-/-BM). As controls, wild-type bone marrow were infused into sub-leathally irradiated CD95L-/- mice (CD95L-/-/WTBM). WT/CD95L-/-BM mice were resistant to aneurysm formation compared to their controls. Inflammatory cell infiltration was blocked by the deletion of CD95L on myeloid cells. Western blot analysis showed the levels of caspase 8 in the aortas of CaCl2-treated wild-type mice were increased compared to NaCl-treated controls. CD95L deletion inhibited caspase 8 expression. Furthermore, a caspase 8-specific inhibitor was able to partially block aneurysm development in CaCl2-treated aneurysm models. CONCLUSION: These studies demonstrated that inflammatory cell infiltration during AAA formation is dependent on CD95L from myelogeous cells. Aneurysm inhibition by deletion of CD95L is mediated in part by down-regulation of caspase 8.

Correction: Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome.

[This corrects the article DOI: 10.1371/journal.pone.0186603.].

IL-1ß (Interleukin-1ß) and TNF-α (Tumor Necrosis Factor-α) Impact Abdominal Aortic Aneurysm Formation by Differential Effects on Macrophage Polarization.

OBJECTIVE: Abdominal aortic aneurysms are inflammatory in nature and are associated with some risk factors that also lead to atherosclerotic occlusive disease, most notably smoking. The purpose of our study was to identify differential cytokine expression in patients with abdominal aortic aneurysm and those with atherosclerotic occlusive disease. Based on this analysis, we further explored and compared the mechanism of action of IL (interleukin)-1ß versus TNF-α (tumor necrosis factor-α) in abdominal aortic aneurysm formation. APPROACH AND RESULTS: IL-1ß was differentially expressed in human plasma with lower levels detected in patients with abdominal aortic aneurysm compared with matched atherosclerotic controls. We further explored its mechanism of action using a murine model and cell culture. Genetic deletion of IL-1ß and IL-1R did not inhibit aneurysm formation or decrease MMP (matrix metalloproteinase) expression. The effects of IL-1ß deletion on M1 macrophage polarization were compared with another proinflammatory cytokine, TNF-α. Bone marrow-derived macrophages from IL-1ß-/- and TNF-α-/- mice were polarized to an M1 phenotype. TNF-α deletion, but not IL-1ß deletion, inhibited M1 macrophage polarization. Infusion of M1 polarized TNF-α-/- macrophages inhibited aortic diameter growth; no inhibitory effect was seen in mice infused with M1 polarized IL-1ß-/- macrophages. CONCLUSIONS: Although IL-1ß is a proinflammatory cytokine, its effects on aneurysm formation and macrophage polarization differ from TNF-α. The differential effects of IL-1ß and TNF-α inhibition are related to M1/M2 macrophage polarization and this may account for the differences in clinical efficacy of IL-1ß and TNF-α antibody therapies in management of inflammatory diseases.

Transesophageal Echocardiogram-Guided Stent Placement in Superior Vena Cava Syndrome Secondary to Granulomatous Lung Disease: A Case Series and Literature Review.

Obstruction of the superior vena cava (SVC) is an uncommon, but potentially life-threatening condition due to likely development of edema in the head and neck and potential respiratory compromise. Less than half of those affected by SVC syndrome survive more than a year. Obstruction can be from neoplasms or secondary to benign disease. Treatment for most cases of symptomatic SVC syndrome involves placement of a stent to relieve the stenosis. Serious complications such as stent migration, pulmonary embolism, and cardiac tamponade can occur in 5% to 10% of cases, and inadequate imaging of the SVC-atrial junction by fluoroscopy contributes to these problems. The overlapping contrast in the atrium makes it difficult to precisely place the distal end of the stent, potentially allowing for embolization of the stent to occur. We present a case series of 3 patients wherein transesophageal echocardiography was used for guidance of stent placement in the SVC and significantly aided in placement.

Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome.

Thoracic aortic aneurysm and dissection are life-threatening complications of Marfan syndrome (MFS). Studies of human and mouse aortic samples from late stage MFS demonstrate increased TGF-ß activation/signaling and diffuse matrix changes. However, the role of the aortic smooth muscle cell (SMC) phenotype in early aneurysm formation in MFS has yet to be fully elucidated. As our objective, we investigated whether an altered aortic SMC phenotype plays a role in aneurysm formation in MFS. We describe previously unrecognized concordant findings in the aortas of a murine model of MFS, mgR, during a critical and dynamic phase of early development. Using Western blot, gelatin zymography, and histological analysis, we demonstrated that at postnatal day (PD) 7, before aortic TGF-ß levels are increased, there is elastic fiber fragmentation/disorganization and increased levels of MMP-2 and MMP-9. Compared to wild type (WT) littermates, aortic SMCs in mgR mice express higher levels of contractile proteins suggesting a switch to a more mature contractile phenotype. In addition, tropoelastin levels are decreased in mgR mice, a finding consistent with a premature switch to a contractile phenotype. Proliferation assays indicate a decrease in the proliferation rate of mgR cultured SMCs compared to WT SMCs. KLF4, a regulator of smooth muscle cell phenotype, was decreased in aortic tissue of mgR mice. Finally, overexpression of KLF4 partially reversed this phenotypic change in the Marfan SMCs. This study indicates that an early phenotypic switch appears to be associated with initiation of important metabolic changes in SMCs that contribute to subsequent pathology in MFS.

How Can Social Media Get Us in Trouble?

When utilized properly, social media offers several personal and professional benefits for the practicing surgeon, including peer networking, education, e-mentorship, marketing, recruitment, and patient outreach. However, unprofessional online behavior is common among surgeons, and this improper use of social media can be quite dangerous. This article reviews the dangers of social media and illustrates this with examples of unprofessional behavior and the associated consequences. It also provides recommendations for maintaining a professional and productive online persona. Surgeons must understand the various social media platforms and their target audience while upholding online professionalism at all times.

Effect of Surgical Intervention on Survival of Patients With Clinical N2 Non-Small Cell Lung Cancer: A Veterans' Affairs Central Cancer Registry (VACCR) Database Analysis.

BACKGROUND: Optimal management of locally advanced non-small cell lung cancer (NSCLC) lacks consensus. A retrospective analysis of patient data entered in the Veterans Affairs Central Cancer Registry was conducted to evaluate these issues. PATIENTS AND METHODS: Data of patients with cT1-4, cN2, and cM0 NSCLC diagnosed in the VA Health System between 1995 and 2003 were evaluated. Age, sex, race, smoking history, TNM stage, treatment, and overall survival were abstracted. Survival was compared using multivariate Cox proportional hazards regression analysis. RESULTS: Of the 7328 patients analyzed, 7218 (98.5%) were male, 6061 (82.7%) were white, and 321 (4.4%) were never smokers. The treatment received included: none, 23.8%; chemotherapy alone, 14.3%; radiation alone, 23%; and chemoradiation (sequential or concurrent), 31.4%. Only 7.5% of patients had a surgical resection, with or without multimodality therapy. The median survival (months) of these patient groups were: surgery, 19.3; chemoradiation, 13; chemotherapy alone, 9.2; radiation alone, 7.3; and no treatment, 4 (P<0.0001). African Americans had a significantly decreased risk of mortality compared with whites (hazard ratio 0.92; 95% confidence interval, 0.87-0.98). CONCLUSIONS: Inclusion of surgical resection as a treatment modality was associated with a better overall survival. Also, African Americans appeared to do better than whites. These hypothesis-generating findings should be useful in the ongoing pursuit of better treatment strategies for locally advanced NSCLC.

Impact of an electronic medical record on the incidence of antiretroviral prescription errors and HIV pharmacist reconciliation on error correction among hospitalized HIV-infected patients.

BACKGROUND: Previous review of admissions from 2009-2011 in our institution found a 35.1% error rate in antiretroviral (ART) prescribing, with 55% of errors never corrected. Subsequently, our institution implemented a unified electronic medical record (EMR) and we developed a medication reconciliation process with an HIV pharmacist. We report the impact of the EMR on incidence of errors and of the pharmacist intervention on time to error correction. METHODS: Prospective medical record review of HIV-infected patients hospitalized for >24 h between 9 March 2013 and 10 March 2014. An HIV pharmacist reconciled outpatient ART prescriptions with inpatient orders within 24 h of admission. Prescribing errors were classified and time to error correction recorded. Error rates and time to correction were compared to historical data using relative risks (RR) and logistic regression models. RESULTS: 43 medication errors were identified in 31/186 admissions (16.7%). The incidence of errors decreased significantly after EMR (RR 0.47, 95% CI 0.34, 0.67). Logistic regression adjusting for gender and race/ethnicity found that errors were 61% less likely to occur using the EMR (95% CI 40%, 75%; P<0.001). All identified errors were corrected, 65% within 24 h and 81.4% within 48 h. Compared to historical data where only 31% of errors were corrected in <24 h and 55% were never corrected, errors were 9.4× more likely to be corrected within 24 h with HIV pharmacist intervention (P<0.001). CONCLUSIONS: Use of an EMR decreased the error rate by more than 50% but despite this, ART errors remained common. HIV pharmacist intervention was key to timely error correction.

Effect of smoking on survival from non-small cell lung cancer: a retrospective Veterans' Affairs Central Cancer Registry (VACCR) cohort analysis.

Although a well-established risk factor for lung cancer, the impact of smoking on the survival of non-small cell lung cancer (NSCLC) is not well known. We performed a retrospective analysis of the Veteran's Affairs Comprehensive Cancer Registry of NSCLC patients. Smoking status was categorized as never smoker, past smoker and current smoker based on self-reported history. Multivariate analysis was performed to evaluate the impact of smoking on overall survival (OS) from NSCLC. The study population (n = 61,440) comprised predominantly of males (98 %) and Caucasians (81 %). The median age at diagnosis was 68 years (range 22-108 years). Current smokers were diagnosed with NSCLC at a younger age (65 years) compared to never smokers (71 years) and past smokers (72 years) (p < 0.001). On multivariate analysis, current smokers (n = 34,613) [Hazard ratio (HR) 1.059; 95 % confidence interval (CI) 1.012-1.108], but not past smokers (n = 23,864) (HR 1.008; 95 % CI 0.962-1.056), had worse OS for Stage III and IV NSCLC, compared to never smokers (n = 2,963). Smoking status was not prognostic in stages I and II NSCLC. Current smokers were diagnosed with NSCLC at a younger age than never smokers. Although current smoking was associated with worse prognosis, especially in stages III and IV, the impact of smoking status on OS was modest.

A personalized treatment for lung cancer: molecular pathways, targeted therapies, and genomic characterization.

Lung cancer is a heterogeneous, complex, and challenging disease to treat. With the arrival of genotyping and genomic profiling, our simple binary division of lung cancer into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) is no longer acceptable. In the past decade and with the advent of personalized medicine, multiple advances have been made in understanding the underlying biology and molecular mechanisms of lung cancer. Lung cancer is no longer considered a single disease entity and is now being subdivided into molecular subtypes with dedicated targeted and chemotherapeutic strategies. The concept of using information from a patient's tumor to make therapeutic and treatment decisions has revolutionized the landscape for cancer care and research in general.Management of non-small-cell lung cancer, in particular, has seen several of these advances, with the understanding of activating mutations in EGFR, fusion genes involving ALK, rearrangements in ROS-1, and ongoing research in targeted therapies for K-RAS and MET. The next era of personalized treatment for lung cancer will involve a comprehensive genomic characterization of adenocarcinoma, squamous-cell carcinoma, and small-cell carcinoma into various subtypes. Future directions will involve incorporation of molecular characteristics and next generation sequencing into screening strategies to improve early detection, while also having applications for joint treatment decision making in the clinics with patients and practitioners. Personalization of therapy will involve close collaboration between the laboratory and the clinic. Given the heterogeneity and complexity of lung cancer treatment with respect to histology, tumor stage, and genomic characterization, mind mapping has been developed as one of many tools which can assist physicians in this era of personalized medicine. We attempt to utilize the above tool throughout this chapter, while reviewing lung cancer epidemiology, lung cancer treatment, and the genomic characterization of lung cancer.