Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma receiving first-line combination immunotherapies: results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.

Potential of photoautotrophic microbial organisms in deciphering forensic issues.

In forensic pathology, solving the crime mystery of death due to drowning still remains a challenging issue. The amalgamation of autopsy findings and comparative study of diatoms recovered from the victim's body organs and suspected drowning site help to decipher the cause of death due to drowning or post-mortem immersion. Since the correct interpretation of the cause of death is an important criterion to provide justice to the victim, therefore, the main objective of our study is to throw light on the application of photoautotrophic micro-algal organisms, known as Diatoms, in solving seven cases of victims whose bodies were recovered from various water bodies of Himachal Pradesh, India. The diatom test was conducted by using reverse aqua regia solution (15 ml HNO3: 5 ml HCl) on the bone marrow extracted from the organs and water samples respectively. The informative outcomes of the experimental analysis demonstrated that the diatom test acts as a beneficial adjunct to solve drowning-related crimes where the exact cause of death remains hidden even after performing an autopsy of the victims. The protocol followed by the authors can be used conveniently to recover diatoms from bone marrow as well as from water samples. Our results showed that the maximum cases were of death due to accidental drowning but for one case of suicidal drowning in extremely cold water.

A Fokker-Planck Framework for Parameter Estimation and Sensitivity Analysis in Colon Cancer.

A new stochastic framework for parameter estimation and uncertainty quantification in colon cancer-induced immune response is presented. The dynamics of colon cancer is given by a stochastic process that captures the inherent randomness in the system. The stochastic framework is based on the Fokker-Planck equation that represents the evolution of the probability density function corresponding to the stochastic process. An optimization problem is formulated that takes input individual patient data with randomness present, and is solved to obtain the unknown parameters corresponding to the individual tumor characteristics. Furthermore, sensitivity analysis of the optimal parameter set is performed to determine the parameters that need to be controlled, thus, providing information of the type of drugs that can be used for treatment.

Standardization of Manual Method of Immunohistochemical Staining for Breast Cancer Biomarkers at Tertiary Cancer Care Center: An Audit.

Immunohistochemistry (IHC) is a necessary ancillary technique in surgical pathology laboratories, particularly for oncology tissue specimens. Automation in the IHC technique has an advantage over manual methods in terms of quality, except for the cost of the equipment. Thus, the manual method of IHC staining is the preferred method of choice in countries with limited resources. However, standardization of all steps in the preanalytic phase is critical to obtain reliable immunohistochemistry test results. The current audit was conducted to describe the preanalytic factors affecting manual IHC methods. The most important preanalytic factors were fixative, the composition of dehydrate, pH, drying of sections, and heat-mediated antigen retrieval method (HMAR). The domestic pressure cooker method was found to be the best for HMAR.

Expression of p53 and p16 in Carcinoma Breast Tissue: Depicts Prognostic Significance or Coincidence.

Breast cancer remains the most common malignancy among the Indian female population. The p16 and p53 genes are frequently mutated in breast cancer. Therefore, we aimed to evaluate the prognostic significance of p16 and p53 overexpression in breast cancer and their correlation with various traditional prognostic parameters. Total of 100 confirmed cases of breast cancers were selected. Patients who underwent chemotherapy treatment were excluded from the study. Estrogen receptor (ER), progesterone receptor (PR), and Her2neu immunohistochemistry were performed. The p16 and p53 immunohistochemistry was performed on all cases and association with various clinicopathologic parameters was determined. The mean age of carcinoma breast was 53.3+11.6 with age ranging from 28 to 82 years. On histopathological examination, 93% of cases were of invasive ductal cell carcinoma (IDC) with majority of grade I (43%). Only 14% of cases showed positive p53 expression and 19% of cases showed positive p16 expression. P16 was seen in a very significant correlation with p53 expression in all breast carcinoma cases (<0.002). p53 expression showed a positively significant (<0.05) correlation with age and grade III. The p16 expression was seen significantly correlated with low mitotic activity index (MAI) only. The p53 over-expression was seen in worse prognostic factors such as high tumor grade, Her2neu and triple-negative expression suggested its potential role in pathogenesis of carcinoma breast. In addition, high expression of p16 seen in low mitotic count and Her2neu expression also emphasized the role of this biomarker and recommends further molecular-based research.

ACR Appropriateness Criteria® Noncerebral Vasculitis.

Noncerebral vasculitis is a wide-range noninfectious inflammatory disorder affecting the vessels. Vasculitides have been categorized based on the vessel size, such as large-vessel vasculitis, medium-vessel vasculitis, and small-vessel vasculitis. In this document, we cover large-vessel vasculitis and medium-vessel vasculitis. Due to the challenges of vessel biopsy, imaging plays a crucial role in diagnosing this entity. While CTA and MRA can both provide anatomical details of the vessel wall, including wall thickness and enhancement in large-vessel vasculitis, FDG-PET/CT can show functional assessment based on the glycolytic activity of inflammatory cells in the inflamed vessels. Given the size of the vessel in medium-vessel vasculitis, invasive arteriography is still a choice for imaging. However, high-resolution CTA images can depict small-caliber aneurysms, and thus can be utilized in the diagnosis of medium-vessel vasculitis. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Current Trends of Carcinoma: Experience of a Tertiary Care Cancer Center in North India.

Objective Cancer incidence across the geographical area is mercurial and factors like dietary habits, environment, social structure, genetics govern relative incidence. Malwa region of Punjab is one such geographical area of India speculated to have a higher incidence of cancer. The current analysis was done to assess the occurrence of cancer in the region and to analyze the trends and types of carcinoma with age, gender, site, and histopathological type, and to compare with the trends mentioned in the literature. Methods A retrospective analysis was done to collect and collate 2088 cancer patients' pathological records for three years at a tertiary treatment center. The collated data was digitized and used to create tables and histograms. Result Of the 2088 cancer cases, the leading cancer site was breast (24.7%) in females, followed by cancer of female genetic tract (18.9%), whereas in males, the most common site involved was head and neck (17.5%) followed by esophagus (10.3%). The leading cancer type for males was squamous cell carcinoma and for females was infiltrating ductal cell carcinoma. Breast carcinoma was most commonly seen cancer (40.5%) followed by female genital tract carcinoma and esophageal carcinoma in female patients. Whereas in males, head and neck carcinoma was most commonly identified (37.5%) followed by the gastrointestinal tract and esophageal carcinoma. This higher incidence may be attributed to better medical facilities, cancer awareness, and novel government schemes. Conclusion Based on our comprehensive analysis, we conclude that there was a change in trends of all types of carcinomas in males and females except breast carcinoma, which was seen as the most common carcinoma in female patients. Our findings suggest and support the strong implementation of cancer awareness programs and epidemiological studies to know the changing trends of risk factors in the region.

ACR Appropriateness Criteria® Radiologic Management of Lower Gastrointestinal Tract Bleeding: 2021 Update.

Diverticulosis remains the commonest cause for acute lower gastrointestinal tract bleeding (GIB). Conservative management is initially sufficient for most patients, followed by elective diagnostic tests. However, if acute lower GIB persists, it can be investigated with colonoscopy, CT angiography (CTA), or red blood cell (RBC) scan. Colonoscopy can identify the site and cause of bleeding and provide effective treatment. CTA is a noninvasive diagnostic tool that is better tolerated by patients, can identify actively bleeding site or a potential bleeding lesion in vast majority of patients. RBC scan can identify intermittent bleeding, and with single-photon emission computed tomography, can more accurately localize it to a small segment of bowel. If patients are hemodynamically unstable, CTA and transcatheter arteriography/embolization can be performed. Colonoscopy can also be considered in these patients if rapid bowel preparation is feasible. Transcatheter arteriography has a low rate of major complications; however, targeted transcatheter embolization is only feasible if extravasation is seen, which is more likely in hemodynamically unstable patients. If bleeding site has been previously localized but the intervention by colonoscopy and transcatheter embolization have failed to achieve hemostasis, surgery may be required. Among patients with obscure (nonlocalized) recurrent bleeding, capsule endoscopy and CT enterography can be considered to identify culprit mucosal lesion(s). The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial.

BACKGROUND: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC. METHODS: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses. RESULTS: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification. CONCLUSIONS: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.

Bioinspired and eco-friendly high efficacy cinnamaldehyde antibacterial surfaces.

Antimicrobial essential oils are incorporated into mussel-inspired and natural plant polyphenol coatings as part of a single-step fabrication process. Polydopamine-cinnamaldehyde, polyethyleneimine-cinnamaldehyde, and tannic acid-cinnamaldehyde coatings exhibit strong antibacterial activities against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus (with the polydopamine- and tannic acid-based systems displaying log10 Reduction = 8). Cinnamaldehyde impregnation into porous non-woven polypropylene cloth, polytetrafluoroethylene membrane, and knitted cotton cloth also gives rise to high levels of antibacterial activity (log10 Reduction = 8). No loss in antibacterial efficacy is observed for non-woven polypropylene cloth impregnated with cinnamaldehyde over 17 recycle tests.

Morphology of enteric glia in colorectal carcinoma: A comparative study of tumor site and its proximal normal margin.

OBJECTIVE: Colorectal carcinoma (CRC) is the third most common cancer in the world and fifth most common cancer in India. To understand the extent of perineural invasion (PNI) in CRC it is essential to study the morphology of enteric glial cells (EGCs). The aim of the study was to analyze the numerical density of EGCs and area of myenteric ganglia (MG) in the colonic tissue samples collected from CRC patients. MATERIAL AND METHODS: Fifteen intraoperative tissue specimens were collected from the tumor site and 2cm proximal to the upper extent of tumor. The samples were divided into four groups: group 1 (n=15): proximal tumor free colonic tissue; group 2 (n=3): well-differentiated; group 3 (n=8): moderately differentiated; group 4 (n=4): poorly differentiated adenocarcinoma. After processing the tissues were subjected to hematoxylin and eosin staining. The anti-S100ß and anti-GFAP antibodies were used to observe the EGCs. RESULTS: In the H&E stained sections the number of myenteric ganglia appeared to be decreasing with increasing grade of adenocarcinoma. Immunostaining showed significant decreasing pattern in the numerical density of EGCs per myenteric ganglion and mean area of myenteric ganglia in relation to the thickness of circular muscle, corresponding to the increasing grades of adenocarcinoma. The morphology of the EGCs remained unaltered in the colonic tissue adjacent to the tumor site. CONCLUSION: Significant loss of EGCs and neurodegeneration corresponded with the grade of tumor emphasizing on its prognostic value. The PNI was not seen in the clear margin proximal to the tumor site.

Photoplethysmography in postoperative monitoring of deep inferior epigastric perforator (DIEP) free flaps.

OBJECTIVE: Deep inferior epigastric perforator (DIEP) free flaps are widely used as a reconstruction option following mastectomy in breast cancer. During such cases partial tissue necrosis can occur due to the insufficient blood supply to the transplanted tissue site. Therefore, monitoring of flap perfusion and early detection of flap failure is a prerequisite to flap survival. There is a need to develop a non-invasive, easy to use, reproducible and inexpensive monitoring device to assess flap perfusion postoperatively. APPROACH: A three-wavelength reflective optical sensor and processing system based on the principle of photoplethysmography (PPG) has been developed to investigate blood volumetric changes and estimate free flap blood oxygen saturation continuously and non-invasively in DIEP free flaps in the postoperative period. The system was evaluated in 15 patients undergoing breast reconstructive surgery using DIEP free flap. Main results and Significance: Good quality red, infrared and green PPG signals were obtained in the postoperative period. Initial estimation of blood oxygen saturation values estimated from the free flap PPGs seem to be in broad agreement with the commercial finger pulse oximeter used in this study. This pilot study has demonstrated that PPG has the potential to be used as a monitoring technique in assessing free flap viability.

Microarray based gene expression profiling of advanced gall bladder cancer.

BACKGROUND: Gall bladder cancer (GBC) is an aggressive cancer with specific predilection like female gender and specific geographical areas, however the molecular mechanisms and factors contributing to the clinical or biological behavior are not understood. AIM: The aim of this study was to perform a comprehensive analysis of differentially expressed genes in advanced GBC and chronic cholecystitis (CC) cases. MATERIALS AND METHODS: Microarray was planned on fresh specimens of advanced GBC and CC cases using single color cRNA based microarray technique (8X60K format; Agilent Technologies, USA). Twelve advanced GBC and four CC patients were included in the study. RESULTS: Of the total of 1307 differentially expressed genes, 535 genes were significantly upregulated, while 772 genes were significantly downregulated in advanced GBC vs CC samples. Differentially expressed genes were associated with biological processes (55.03%), cellular components (31.48%), and molecular functions (13.49%) respectively. The important pathways or key processes affected were cell cycle, DNA replication, oxidative stress, gastric cancer pathway. Using in silico analysis tools, three differentially expressed genes i.e. TPX2, Cdc45 and MCM4 were selected (for their significant role in DNA replication and microtubule function) and were further validated in 20 advanced GBC cohort by immunohistochemistry. Significant positive association of Cdc45 and MCM4 proteins was found in advanced GBC cases (p = 0.043), suggesting the probable oncogenic role of Cdc45 and MCM4 proteins in advanced GBC. CONCLUSION: Our data demonstrate the potential regulation of Cdc45-MCM4 axis in advanced GBC tumors. Additionally, our study also revealed a range of differentially expressed genes (e.g. TPX2, AKURA etc.) between GBC and CC, and further validation of these genes might provide a potential diagnostic or therapeutic target in future.

Capture and Release Recyclable Dimethylaminomethyl-Calixarene Functional Cloths for Point-of-Use Removal of Highly Toxic Chromium Water Pollutants.

Chromium(VI) contamination of drinking water arises from industrial activity wherever there is a lack of environmental legislation enforcement regarding the removal of such pollutants. Although it is possible to remove such harmful metal ions from drinking water through large-scale facilities, there currently exists no safe and simple way to filter chromium(VI) oxoanions at the point of use (which is potentially safer and necessary in remote locations or humanitarian scenarios). High-surface-area cloth substrates have been functionalized with calixarene molecules for the selective capture of aqueous chromium(VI) oxoanions in the presence of structurally similar anions. This is accomplished by pulsed plasmachemical deposition of a linker layer and subsequent functionalization with dimethylaminomethyl-calixarene (5,11,17,23-tetrakis[(dimethylamino)methyl]-25,26,27,28-tetrahydroxycalix[4]arene). Chromium(VI) oxoanions are captured by simply passing polluted water through the functionalized cloth, while other ions not harmful/beneficial to human health remain in the water. These cloth filters are simple to use, highly selective, and easily recyclable-thus making them attractive for point-of-use application in geographic regions lacking appropriate wastewater treatment plants or flawed environmental monitoring systems. Chromium(VI) pollutants have been successfully removed from real-world contaminated industrial wastewater streams using the dimethylaminomethyl-calixarene functionalized cloths.

Von Willebrand factor and cancer; metastasis and coagulopathies.

Von Willebrand factor (VWF) is a multimeric procoagulant plasma glycoprotein that mediates platelet adhesion along the endothelium. In addition to its role maintaining normal hemostasis, more recently novel biological functions for VWF have been described, including inflammation, angiogenesis, and metastasis. Significantly increased plasma VWF levels have been reported across a variety of cancer patient cohorts. Given that VWF is established as a risk factor for venous thrombosis, this is of direct clinical importance. Moreover, elevated VWF has also been observed localized within the tumor microenvironment, correlating with advanced disease stage and poorer clinical outcome. Critically, evidence suggests that elevated VWF levels in cancer patients may not only contribute to cancer associated coagulopathies but may also mediate cancer progression and metastasis. Studies have shown that VWF can promote pro-inflammatory signaling, regulate angiogenesis and vascular permeability, which may facilitate tumor cell growth and extravasation across the vessel wall. Endothelial secreted VWF multimers contribute to the adhesion and transendothelial migration of tumor cells key for tumor dissemination. In support of this, VWF inhibition attenuated metastasis in vivo. Perhaps most intriguingly, specific tumor cells have been reported to acquire de novo VWF expression which increases tumor-platelet heteroaggregates and confers enhanced metastatic activity. Current knowledge on the roles of VWF in cancer and in particular its contribution to metastasis and cancer associated coagulopathies is summarized in this review.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.

Idiopathic Spinal Cord Herniation Associated With a Thoracic Disc Herniation: Case Report, Surgical Video, and Literature Review.

PURPOSE: The aim of this publication is to present a case of idiopathic spinal cord herniation (ISCH) associated with a transdural disk herniation, demonstrate an operative technique used to treat this condition and provide an updated review the literature. BACKGROUND CONTEXT: ISCH is an infrequent condition that can cause progressive myelopathy leading to severe neurological dysfunction. This condition is characterized by ventral displacement of the spinal cord across a defect in the dura, either congenital or acquired, resulting in vascular compromise and adhesion that subsequently causes injury to the spinal cord. We present the management of such a patient, in addition to a review of the literature regarding management of ISCH. METHODS: This patient underwent surgery using the dural graft sling technique for repair of the dural defect and restoration of normal spinal cord position within the thecal sac. A review of the literature revealed a total of 171 patients supplemented by our 1 patient, which were then analyzed. RESULTS: The majority of patients, treated with a variety of surgical techniques, experienced improvements in symptomatology. Our patient experienced significant improvement in symptomatology. CONCLUSIONS: Although ISCH is a rare clinical condition that causes myelopathy, patients managed with surgery generally, though not universally, have a favorable neurological outcome. The associated surgical technique video demonstrates the dural sling technique for the treatment of this rare disorder.