Pathologic Complete Response, Total Neoadjuvant Therapy and the Survival Paradox in Locally Advanced Rectal Cancer.

BACKGROUND: Pathologic complete response (pCR) after preoperative chemoradiation (nCRT) correlates with improved overall survival for patients with locally advanced rectal cancers (LARCs). Escalation protocols including total neoadjuvant therapy (TNT), which delivers multi-agent chemotherapy and chemoradiation before surgery, are associated with increased complete response rates. However, TNT is not associated with improved overall survival. The authors hypothesized that the route to pCR may be an important predictor of oncologic outcome. METHODS: Adults with LARC between 2006 and 2017 were identified in the National Cancer Database. The cohort was limited to those who received neoadjuvant radiation (45-70 Gy) and underwent proctectomy. RESULTS: Of 25,880 patients, 16 % received TNT and 84 % had nCRT followed by either multi-agent (27 %), single-agent (14 %), or no adjuvant chemotherapy (44 %). Overall, 18 % achieved pCR, with higher rates in the TNT cohort than in the nCRT (18 %) or multi-agent (14 %) chemotherapy cohorts. With control for covariates, the OS in the pCR cohort was similar for the patients that received single-agent therapy and those that received multi-agent adjuvant therapy, and superior to the TNT and no adjuvant therapy cohorts. Conversely, among the patients who did not achieve pCR, those who received single-agent chemotherapy had OS comparable with those who had multi-agent adjuvant therapy and TNT, which was better than no adjuvant therapy. CONCLUSION: Patients achieving pCR after TNT had worse OS than those who had CRT alone, suggesting that the neoadjuvant route by which pCR is achieved is prognostically relevant. Therefore, in the era of neoadjuvant therapy escalation, pCR does not necessarily portend a uniformly favorable prognosis.

Management and staging of anal adenocarcinoma in the United States: a population-based analysis.

BACKGROUND: Anal adenocarcinoma is rare with no standardized treatment regimen or staging system. Therefore, different combinations of chemotherapy, radiation, and surgery are used in management. Within the staging system, tumor stage can be based on the depth of invasion, as for rectal adenocarcinoma, or size, as in anal squamous cell carcinoma. This study aimed to analyze patterns of care and clinically available staging systems for anal adenocarcinoma using a national database. METHODS: Adults diagnosed with anal adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results database (2004-2019). In addition, 6 different treatment regimens were identified. Stages were categorized according to the American Joint Committee on Cancer classifications of rectal adenocarcinoma and anal squamous cell carcinoma. RESULTS: Of 1040 patients, 48% were female, the median age was 67 years, and 18% had distant metastases. Chemoradiotherapy + abdominoperineal resection was the most common treatment regimen (22%). Moreover, 5-year overall survival (OS) and disease-specific survival (DSS) were the highest for local excision only (67% and 85%) and the lowest in the alternative group (34% and 48%). After adjustment, the treatment groups that did not include surgery were associated with worse 5-year OS. In multivariable analysis, the T stage based on depth of invasion showed incrementally lower OS for T2 and T3 anal adenocarcinomas. CONCLUSION: Omission of surgical resection in combination with chemoradiotherapy was associated with worse OS and DSS, suggesting the relevance of surgery in anal adenocarcinoma management. Prognostically, rectal staging based on depth of invasion better discriminated between T stages, indicating that providers should consider using this system in practice.

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model.

Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E2 synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E2 (PGE2)-a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE-/- angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.

FOXS1 is increased in liver fibrosis and regulates TGFß responsiveness and proliferation pathways in human hepatic stellate cells.

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFß) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFß induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFß to activate fibrotic pathways, and FOXS1 mRNA was significantly increased. To study TGFß-FOXS1 signaling, we developed human LX2 FOXS1 CRISPR KO and scrambled control HSCs. To determine differentially expressed gene transcripts controlled by TGFß-FOXS1, we performed RNA-seq in the FOXS1 KO and control cells and over 400 gene responses were attenuated in the FOXS1 KO HSCs with TGFß-activation. To validate the RNA-seq findings, we used our state-of-the-art PamGene PamStation kinase activity technology that measures hundreds of signaling pathways nonselectively in real time. Using our RNA-seq data, kinase activity data, and descriptive measurements, we found that FOXS1 controls pathways mediating TGFß responsiveness, protein translation, and proliferation. Our study is the first to identify that FOXS1 may serve as a biomarker for liver fibrosis and HSC activation, which may help with early detection of hepatic fibrosis or treatment options for end-stage liver disease.

Are COVID-Era General Surgery Interns Starting Residency Behind on Basic Surgical Skills?

OBJECTIVE: To compare incoming general surgery interns' performance on a basic skills assessment before and after the COVID pandemic. DESIGN: A retrospective cohort study compared surgical skill performances of incoming general surgery interns. Each underwent an evidence-based standardized assessment (pretest) with 12-basic surgical knot tying and suturing tasks. A post-test was administered after a 3-month self-directed skills curriculum. Student's t-tests compared proficiency scores from pre-COVID vs. COVID-era general surgery interns before and after curriculum completion. p < 0.05 was significant. SETTING: Data was collected from surgical residents in an academic general surgery program in the United States. PARTICIPANTS: General surgery interns from 2017 to 2019 (pre-COVID) and 2021 to 2022 (COVID-era) were included. Interns with missing data or extreme outliers were excluded. A total of 100 interns in general surgery were included in the pretest cohort (59 pre-COVID, 41 COVID-era) and 101 interns were in the post-test cohort (66 pre-COVID, 35 COVID-era). RESULTS: COVID-era interns scored significantly lower on the pretest compared to pre-COVID interns (COVID-era 721.9+/-268.8 vs. pre-COVID 935.9+/- 228.0, p < 0.001). After the skills curriculum both cohorts improved their proficiency scores. However COVID-era interns still scored significantly lower (COVID-era 1255.0+/-166.3 vs. pre-COVID 1369.8+/-165.6, p = 0.001). CONCLUSIONS: This analysis objectively described deficits in fundamental surgical skills for incoming interns whose medical school education was disrupted by the COVID-19 pandemic. A targeted surgical skills curriculum partially remediated these deficiencies. However, many surgical interns may need additional intervention and potentially more time in order to fully develop their surgical skills and meet the competency requirements required for advancement.

Analgesic effects of a highly selective mPGES-1 inhibitor.

The growing opioid use and overdose crisis in the US is closely related to the abuse of pain medications. Particularly for postoperative pain (POP), ~ 310 million major surgeries are performed globally per year. Most patients undergoing surgical procedures experience acute POP, and ~ 75% of those with POP report the severity as moderate, severe, or extreme. Opioid analgesics are the mainstay for POP management. It is highly desirable to develop a truly effective and safe non-opioid analgesic to treat POP and other forms of pain. Notably, microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1) was once proposed as a potentially promising target for a next generation of anti-inflammatory drugs based on studies in mPGES-1 knockouts. However, to the best of our knowledge, no studies have ever been reported to explore whether mPGES-1 is also a potential target for POP treatment. In this study, we demonstrate for the first time that a highly selective mPGES-1 inhibitor can effectively relieve POP as well as other forms of pain through blocking the PGE2 overproduction. All the data have consistently demonstrated that mPGES-1 is a truly promising target for treatment of POP as well as other forms of pain.

Development of pharmacotherapies for abdominal aortic aneurysms.

The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease often goes undiagnosed until a late stage and associated rupture has a high mortality rate. No pharmacological treatment options are available. Three hallmark factors of AAA pathology include inflammation, extracellular matrix remodeling, and vascular smooth muscle dysfunction. Here we discuss drugs for AAA treatment that have been studied in clinical trials by examining the drug targets and data present for each drug's ability to regulate the aforementioned three hallmark pathways in AAA progression. Historically, drugs that were examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments (biologics, small-molecule compounds etc.) have not been able to reach the clinic, stalling out in pre-clinical studies. Here we discuss the backgrounds of previous investigational drugs in hopes of better informing future development of potential therapeutics. Overall, the highlighted themes discussed here stress the importance of both centralized anti-inflammatory drug targets and rigor of translatability. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting. Additionally, data suggest that a potentially successful drug target may be a central inflammatory biomarker. Specifically, one that can effectively modulate all three hallmark factors of AAA formation, not just inflammation. It is suggested that inhibiting PGE2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment to this end.

Multiple-Organ Deceased Donation Is Associated With Superior Outcomes for Grafts and Transplant Recipients Compared With Kidney-Only Donation.

OBJECTIVES: Since the development of Kidney Donor Profile Index, outcome differences based on number of donated organs per donor have not been evaluated. MATERIALS AND METHODS: We retrospectively analyzed data from the United Network for Organ Sharing national database, which identified 176 311 adult renal transplant recipients from 2000 to 2019 with a deceased donor kidney from a kidney-only donor, from a donor of kidney and liver but no other organs, or from a multiorgan donor. Graft failure and transplant recipient survival were primary outcomes. A multivariate Cox proportional hazards model controlled for Kidney Donor Profile Index differences. RESULTS: Overall, multiorgan donors had a lower Kidney Donor Profile Index versus other donor types (odds ratio, 0.042; P < .001). Kidneys from donors with a higher Kidney Donor Profile Index were 95% less likely to be procured with other organs (P < .001). The recipient and graft survival rates for kidney transplants from kidney-only donors and from donors of kidney and liver but no other organs were 76% and 70%, respectively, whereas recipient and graft survival rates for kidney transplants from multiorgan donors were approximately 82% and 77%, respectively, at 5 years. CONCLUSIONS: After adjustment for the Kidney Donor Profile Index, the recipients of multiorgan donor grafts demonstrated superior outcomes for graft survival and mortality compared with kidney-only donors or kidney and liver only donors. The multiorgan donor status may be an additional consideration in future renal allocation calculators.

Colorectal Resection in Transplant Centers Benefits Kidney But Not Pancreas Transplant Recipients.

As graft and patient survival rates improve, transplant recipients are likely to undergo colorectal surgery in their lifetime. Current literature on the surgical outcomes of colorectal resection in kidney and pancreas transplant recipients is sparse. This investigation identifies areas of surgical risk for kidney, pancreas, and pancreas-kidney transplant recipients undergoing colorectal resection at transplant and teaching centers. Multivariate logistic regression and linear regression tests computed odds ratios (OR) and coefficients of the linear regression using National Inpatient Sample data from 2005 to 2014 to identify differences in mortality, morbidity, length of stay (LOS), and total hospital charges among people with pancreas transplant alone (PTx), kidney transplant alone (KTx), pancreas and kidney transplant (PKTx), and nontransplant (non-Tx) undergoing colorectal resection in transplant and teaching centers. Of the 2,737,454 individuals who underwent colorectal resection, 138 PTx, 3,874 KTx, 130 PKTx, and 2,733,312 non-Tx met the inclusion criteria. Overall KTx, PTx, and PKTx were not more likely to suffer a mortality. However, PTx were more likely to suffer a mortality in transplant and teaching centers. Overall, PTx and PKTx had significantly higher morbidity odds ratios (PTx OR: 2.268, p = 0.002; PKTx OR: 2.578, p < 0.001) along with longer LOS and higher total hospital charges. KTx incurred no increased morbidity risk in transplant centers. Surgeons and transplant recipients should be aware of the increased morbidity and mortality risks when considering colorectal resection at different center types.

Does health insurance protect against risk of financial catastrophe for pancreatic tumor care? A cost-based review of patients undergoing pancreatic resection at an academic institution.

BACKGROUND: Pancreatic cancer is a leading cause of financial insolvency and cancer related deaths in the United States. The risk of catastrophic health expenditure (CHE) was calculated for patients undergoing pancreatic resection at an academic institution. METHODS: Patients who underwent pancreatic resection between 2013 and 2017 were identified through an institutional cancer registry. A CHE was an out-of-pocket payment (OOP) > 10% of the estimated median household income. RESULTS: 319 patients met inclusion criteria. Hospital median charge was $76,700. 99% of patients had insurance and hospital bill adjustments. As a result, 61% (n = 193) made no OOP. Only 3 patients risked CHE. For all tumors combined there were no differences in survival outcomes by OOP. CONCLUSION: This is the first study to use institutional financial data to calculate CHE risk for pancreatic resection patients. Insurance adjustments to hospital charges that accompany health insurance and voluntary hospital adjustments for the uninsured protect patients against CHE.

Kidney and pancreas transplant recipients undergoing cholecystectomy experience superior outcomes in transplant centers.

BACKGROUND: This retrospective analysis aims to identify differences in surgical outcomes between pancreas and/or kidney transplant recipients and the general population undergoing cholecystectomy. METHODS: Multivariate logistic regression and linear regression tests computed odds ratios (OR) and coefficients of the linear regression by analyzing weighted data from the NIS database between 2005 and 2014 to identify differences in mortality, morbidity, length of stay (LOS) and costs amongst KTx, PTx, PKTx, and non-Tx undergoing cholecystectomy in all centers and transplant centers. RESULTS: Overall 6007 KTx, 164 PTx, 535 PKTx, and 4,207,241 non-Tx met the inclusion criteria. Mortality from cholecystectomy was 1.0%. Transplant recipients did not experience a significant increase in mortality. However KTx and PTx suffered increased morbidity risks (KTx OR1.244 p < 0.01; PTx OR2.165 p < 0.01) compared to non-Tx. However transplant recipients did not incur an increased morbidity risk in transplant centers. CONCLUSION: Transplant recipients undergoing cholecystectomy should be counseled about their increased complication risks. Surgeons should consider transferring KTx and PTx to transplant centers for their cholecystectomy procedure to mitigate these risks.

Using a Prerequisite Skills Assessment to Identify Optimal Modalities for Mand Training.

This study examined the utility of a brief prerequisite assessment in predicting the subsequent effectiveness and rate of acquisition of mand training in each of three response modalities (sign, picture exchange, and vocalizations). Overall, the picture exchange was the most effective and efficient modality for acquiring the targeted mand. The vocal modality was the least effective except when the prerequisite assessment indicated that two-syllable vocal imitation was intact. The implications for selection of response modality for early mand training are discussed.

Biliverdin reductase and bilirubin in hepatic disease.

The buildup of fat in the liver (hepatic steatosis) is the first step in a series of incidents that may drive hepatic disease. Obesity is the leading cause of nonalcoholic fatty liver disease (NAFLD), in which hepatic steatosis progresses to liver disease. Chronic alcohol exposure also induces fat accumulation in the liver and shares numerous similarities to obesity-induced NAFLD. Regardless of whether hepatic steatosis is due to obesity or long-term alcohol use, it still may lead to hepatic fibrosis, cirrhosis, or possibly hepatocellular carcinoma. The antioxidant bilirubin and the enzyme that generates it, biliverdin reductase A (BVRA), are components of the heme catabolic pathway that have been shown to reduce hepatic steatosis. This review discusses the roles for bilirubin and BVRA in the prevention of steatosis, their functions in the later stages of liver disease, and their potential therapeutic application.

Bilirubin in the Liver-Gut Signaling Axis.

Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.

Neurological Complications of Childhood Cancer.

Though the treatment of pediatric cancers has come a long way, acute and chronic effects of cancer are still affecting the life of many children. These effects may be caused not only by the malignancy itself but also by the interventions used for the purpose of treatment. This article focuses primarily on the indirect effects of pediatric cancers and their treatment on the central and peripheral nervous system. Chemotherapy, radiation, and stem cell transplantation cause an immune-compromised state and place the patient at risk of infection, the leading cause of mortality in pediatric cancer. The underlying cancer and the treatments also cause neurovascular changes that may lead to neurological sequelae immediately or many years in the future. Chemotherapy and radiation have both immediate and long-term neurotoxic effects on the central and peripheral nervous system. Cancers may also trigger an immune response that damages nervous system components, leading to altered mental status, seizures, abnormal movements, and even psychosis. Knowledge of these effects can help the practitioner be more vigilant for the signs and symptoms of potential neurological complications during the management of pediatric cancers.