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.

Conditional Overall Survival After Diagnosis of Non-Metastatic Colon Cancer: Impact of Laterality, MSI, and KRAS Status.

BACKGROUND: The prognostic relevance of laterality, microsatellite instability (MSI), and KRAS status in colon cancer has been established. However, their effect on conditional overall survival (COS) remains unknown. METHODS: COS is the probability of surviving additional years after a time from diagnosis. The National Cancer Database (2010-2017) was queried for adults with non-metastatic colon cancer and known mutation status undergoing curative resection. COS was investigated at 2 years. RESULTS: Of 4838 patients, 3716 survived at least 2 years: 15% had stage I, 38% stage II, and 46% stage III disease. Fifty-nine percent had a right-sided tumor, 16% were MSI-high, and 37% were mutated KRAS (mKRAS). The proportion of patients alive at 2 years was higher for stage I compared with stage II and III (65 vs. 61 vs. 54%). The 5-year overall survival for stage I-III was 80, 76, and 67% for the initial cohort, and 90, 88, and 86% for those alive at 2 years. After adjustment, higher pathologic T and N stage, tumor deposits, and no chemotherapy were associated with worse COS (p < 0.01). While laterality and MSI status were not associated with COS, mKRAS was independently associated with decreased COS (HR 1.35, 95% CI 1.12-1.62). CONCLUSION: Patients with mKRAS had worse COS, suggesting that these mutations confer an aggressive biologic behavior, with patients remaining at higher risk of death 2 years after diagnosis. Routine evaluation of KRAS status should be considered in patients with non-metastatic disease for prognostication and to identify those who might benefit from modified surveillance protocols.

Untangling the adaptive strategies of thermophilic bacterium Anoxybacillus rupiensis TPH1 under low temperature.

The present study investigates the low temperature tolerance strategies of thermophilic bacterium Anoxybacillus rupiensis TPH1, which grows optimally at 55 °C , by subjecting it to a temperature down-shift of 10 °C (45 °C) for 4 and 6 h followed by studying its growth, morphophysiological, molecular and proteomic responses. Results suggested that although TPH1 experienced increased growth inhibition, ROS production, protein oxidation and membrane disruption after 4 h of incubation at 45 °C yet maintained its DNA integrity and cellular structure through the increased expression of DNA damage repair and cell envelop synthesizing proteins and also progressively alleviated growth inhibition by 20% within two hours i.e., 6 h, by inducing the expression of antioxidative enzymes, production of unsaturated fatty acids, capsular and released exopolysaccharides and forming biofilm along with chemotaxis proteins. Conclusively, the adaptation of Anoxybacillus rupiensis TPH1 to lower temperature is mainly mediated by the synthesis of large numbers of defense proteins and exopolysaccharide rich biofilm formation.

Evaluation of association between center colorectal neuroendocrine neoplasm volume and survival among patients with colorectal neuroendocrine carcinoma.

BACKGROUND: Although correlation between center volume and survival has been reported for several complex cancers, it remains unknown if this is true for colorectal neuroendocrine carcinomas (CRNECs). We hypothesized that higher center annual volume of colorectal neuroendocrine neoplasm resections would be associated with overall survival (OS) for patients with CRNECs. METHODS: Patients in the National Cancer Database diagnosed with stages I-III CRNEC between 2006 and 2018 and who underwent surgical resection were identified. The mean annual colorectal neuroendocrine neoplasm resection volume threshold associated with significantly worse mortality hazard was determined using restricted cubic splines. Kaplan-Meier (KM) method was used to compare OS, while Cox proportional hazards model was used for multivariable analysis. RESULTS: There were 694 patients with CRNEC who met inclusion criteria across 1229 centers. Based on the cubic spline, centers treating fewer than one colorectal neuroendocrine neoplasm patient every 3 years on average had worse outcomes. Centers below this threshold were classified as low-volume (LV) centers corresponding with 42% of centers and about 15% of the patient cohort. In unadjusted survival analysis, LV patients had a median OS of 14 months (95% confidence interval [CI]: 10-19) while those treated at HV centers had a median OS of 33 months (95% CI: 25-49). In multivariable analysis, resection at a LV center was associated with increased risk of mortality (1.42 [95% CI: 1.01-2.00], p = 0.04). CONCLUSION: CRNEC patients have a dire prognosis; however, treatment at an HV center may be associated with decreased risk of mortality.

Affordable lab-scale electrospinning setup with interchangeable collectors for targeted fiber formation.

The electrospinning method is increasingly in demand due to its capability to produce fibers in the nanometer to micrometer range, with applications in diverse fields including biomedical, filtration, energy storage, and sensing. Many of these applications demand control over fiber layout and diameter. However, a standard flat plate collector yields random fibers with limited control over diameter and density. Other viable solutions offering a higher level of control are either scarce or substantially expensive, impeding the accessibility of this vital technique. This study addresses the challenge by designing an affordable laboratory-scale electrospinning setup with interchangeable collectors, enabling the creation of targeted fibers from random, aligned, and coiled. The collectors include the standard flat plate and two additional designs, which are a rotating drum and a spinneret tip collector. The rotating drum collector has adjustable speed control to collect aligned fibers and exhibits stability even at high rotational speeds. The spinneret tip collector was designed to produce helically coiled fibers. The setup was validated by directed fiber formation using polycaprolactone (PCL), a biodegradable and FDA-approved polymer. Overall, the uniqueness of the design lies in its affordability, modifiability, and replicability using readily available materials, thus extending the reach of the electrospinning technique.

Comparison of Neuroinflammation Induced by Hyperphosphorylated Tau Protein Versus Ab42 in Alzheimer's Disease.

Both neurofibrillary tangles and senile plaques are associated with inflammation in Alzheimer's disease (AD). Their relative degree of induced neuroinflammation, however, is not well established. Mouse models of AD that expressed either human Aß42 (n = 7) or human hyperphosphorylated tau protein alone (n = 3), wild type (n = 10), and human AD samples (n = 29 with 18 controls) were studied. The benefit of using mouse models that possess only human tau or amyloid-b is that it allows for the individual evaluation of how each protein affects neuroinflammation, something not possible in human tissue. Three indicators of neuroinflammation were examined: TLRs/RIG1 expression, the density of astrocytes and microglial cells, and well-established mediators of neuroinflammation (IL6, TNFα, IL1ß, and CXCL10). There was a statistically significant increase in neuroinflammation with all three variables in the mouse models with human tau only as compared to human Aß42 only or wild-type mice (each at p < 0.0001). Only the Aß42 5xFAD mice (n = 4) showed statistically higher neuroinflammation versus wild type (p = 0.0030). The human AD tissues were segregated into Aß42 only or hyperphosphorylated tau protein with Aß42. The latter areas showed increased neuroinflammation with each of the three variables compared to the areas with only Aß42. Of the TLRs and RIG-1, TLR8 was significantly elevated in both the mouse model and human AD and only in areas with the abnormal tau protein. It is concluded that although Aß42 and hyperphosphorylated tau protein can each induce inflammation, the latter protein is associated with a much stronger neuroinflammatory response vis-a-vis a significantly greater activated microglial response.

Evaluating the antifungal effectiveness, leaching characteristics, flexural strength, and impact strength of polymethyl methacrylate added with small-scale silver nanoparticles - An in vitro study.

AIM: (1) To assess the release of stable silver nanoparticles (AgNPs) of small scale dimension added to heat polymerized polymethyl methacrylate (PMMA) in 6 months. (2) Assessing the influence of incorporating minimal concentrations of stable AgNPs with nanoscale dimensions into heat polymerized PMMA over a 6 month period on its antifungal efficacy (AF), flexural strength (FS), and impact strength (IS). SETTINGS AND DESIGN: Incorporating nanoparticles with a very small scale may have minimal impact on mechanical properties due to their diminutive size. However, the influence of these small scaled nanoparticles on antimicrobial efficacy and potential escalation in toxicity to host cells through leaching remains unexplored. AgNPs were prepared using an Ultrasonic Probe sonicator and the addition of ammonia to obtain stabilized AgNPs (< 0.01 nm) of small scale dimension. The characterization of these AgNPs involved ultraviolet visible spectroscopy, X ray diffraction, Zetasizer, and transmission electron microscopy with energy dispersive spectroscopy (TEM). MATERIALS AND METHODS: The prepared AgNPs were then added in various percentages by weight (0%-0.5%) to fabricate 252 modified PMMA samples of sizes 10 mm × 3 mm (AF, n = 108), 65 mm × 10 mm × 3 mm (FS, n = 72), and 65 mm × 10 mm × 2.5 mm (IS, n = 72) as per ADA specification no. 12. These samples underwent testing for leaching out of AgNPs and efficacy against Candida albicans for 6 months. The effect on FS and IS was evaluated using the three point bending test and Charpy's Impact Tester, respectively. STATISTICAL ANALYSIS USED: Intergroup comparison of CFU between various concentrations of AgNP was done using the Kruskal-Wallis ANOVA test succeeded by Mann-Whitney test for pair wise comparisons. Difference in CFU of various concentrations over 6 months was seen using one way ANOVA test. Intergroup comparison of FS and IS was performed using a one way ANOVA test, followed by a post hoc Tukey's test for pair wise comparisons. RESULTS: Repeated tests showed no leaching out of AgNPs from the denture base resin into the storage medium. All concentrations of AgNPs incorporated in resin showed inhibition of Candida growth. Intergroup comparison of FS and IS revealed highly statistically significant differences (F = 15.076, P < 0.01 and F = 28.266, P < 0.01) between the groups showing a reduction in strength. CONCLUSION: The AgNPs of small scale dimension incorporated into the denture base resin imparted a strong antifungal effectiveness against C. albicans, which did not decline during the study period and did not cause any release of nanoparticles. 0.5% showed the best antifungal efficacy. This may prove to be a viable and highly effective treatment for the prevention of Candida associated denture stomatitis. However, the inclusion of these particles resulted in a decrease in both FS and IS, and this reduction was directly proportional to the percentage of added AgNPs, with 0.5% demonstrating the least IS and FS.

Shiitake mushroom-induced flagellate dermatitis: The first case reported in Nepal.

Shiitake mushroom-induced flagellate dermatitis is a rare but important condition to consider in patients presenting with pruritic skin lesions following mushroom ingestion, especially in regions where such cases are uncommon. Early recognition and appropriate management with oral and topical steroids are crucial for effective symptom resolution and preventing complications. Clinicians should be aware of the characteristic rash and the temporal relationship between mushroom consumption and rash onset. Educating patients about the risks associated with consuming raw or undercooked shiitake mushrooms is essential to prevent recurrence.

NSQIP 5-factor modified frailty index and complications after ileal anal pouch anastomosis for ulcerative colitis.

Background: Frailty has been associated with worse postoperative outcomes. The 5-factor modified frailty index (mFI-5) is an objective measure although its validity in measuring frailty in patients undergoing ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (CUC) has not been reported. Methods: This study used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) targeted proctectomy database. The mFI-5 was calculated by five preoperative diagnoses: insulin-dependent or noninsulin-dependent diabetes, congestive heart failure, hypertension, chronic obstructive pulmonary disease, and dependent or partially dependent functional status. The impact of mFI-5 on minor and major postoperative morbidity in CUC patients undergoing IPAA was analyzed. Results: The cohort included 1454 patients (median age 38 years, median body mass index [BMI] 26 kg/m2) of which 87 % had a mFI-5 = 0, 11 % had a mFI-5 = 1, and 2.5 % a mFI-5 ≥ 2. In multivariable logistic regression, mFI-5 ≥ 2 was significantly associated with minor complications (OR = 2.29, 95 % CI [1.00-5.22], p = 0.049), but not with major complications (p = 0.860). Conclusion: IPAA for CUC is associated with high postoperative morbidity, however, the mFI-5 alone has limited utility in determining which patients are at a higher risk of complications due to frailty. These observations suggest there is a need for more relevant instruments to measure frailty in this patient cohort.

Radiomolecular Theranostics With Fibroblast-Activation-Protein Inhibitors and Peptides.

The advancement of theranostics, which combines therapeutic and diagnostic capabilities in oncology, has significantly impacted cancer management. This review explores fibroblast activation protein (FAP) expression in the tumor microenvironment (TME) and its association with various malignancies, highlighting its potential as a theranostic marker for PET/CT imaging using FAP-targeted tracers and for FAP-targeted radiopharmaceutical therapy. We examine the development and clinical applications of FAP inhibitors (FAPIs) and peptides, providing insights into their diagnostic accuracy, initial therapeutic efficacy, and clinical impact across diverse cancer types, as well as the synthesis of novel FAP-targeted ligands. This review aims to showcase the promising outcomes and challenges in integrating FAP-targeted approaches into cancer management.