Revisiting the Trans-Sacral Approach for Large Rectal Adenomas, Surgical Technique, and Oncological Outcome: a Case Series.

The standard oncologic surgeries for rectal carcinoma are radical trans abdominal procedures, However, these radical procedures are not suitable for large rectal adenomas. The transsacral approach for rectal adenoma was first described by Kraske and since then it has been utilized for various benign conditions of low and mid-rectum as well as for certain cancers. We are presenting a series of 5 consecutive cases of trans-sacral resection done in the past 7 years between January, 2016, until June, 2023, at the Department of Surgical Oncology, Cancer Research Institute, HIMS Dehradun, for large mid- and lower rectal adenoma. There were 5 patients who underwent transsacral excision of rectal adenoma. Three patients were male and 2 were female. All the patients underwent surgery after confirming the diagnosis of adenoma and metastatic work up. The postoperative histopathological examination showed adenocarcinoma infiltrating submucosa (T1) in one patient; however, other 4 patients had adenoma reconfirmed. The transsacral approach may not be the method of choice for the rectal carcinoma but it is a very useful surgical alternative to the large rectal adenoma where there is no invasive component and which cannot be managed by any other methods.

Rare Case of Squamous Cell Carcinoma of Midline Dorsum of Tongue: Diagnostic and Management Dilemma.

Squamous cell carcinoma is the most common carcinoma of the tongue. However, the majority of carcinoma originates in the lateral border of the tongue and midline dorsum only represents about 2-5% of tongue cancer patients. We present a rare case of squamous cell carcinoma in a 59 years old male patient originating in the midline dorsum of tongue and the management dilemma.

Microbiome interactions with different risk factors in development of myocardial infarction.

Among all non-communicable diseases, Cardiovascular Diseases (CVDs) stand as the leading global cause of mortality. Within this spectrum, Myocardial Infarction (MI) strikingly accounts for over 15 % of all deaths. The intricate web of risk factors for MI, comprising family history, tobacco use, oral health, hypertension, nutritional pattern, and microbial infections, is firmly influenced by the human gut and oral microbiota, their diversity, richness, and dysbiosis, along with their respective metabolites. Host genetic factors, especially allelic variations in signaling and inflammatory markers, greatly affect the progression or severity of the disease. Despite the established significance of the human microbiome-nutrient-metabolite interplay in associations with CVDs, the unexplored terrain of the gut-heart-oral axis has risen as a critical knowledge gap. Moreover, the pivotal role of the microbiome and the complex interplay with host genetics, compounded by age-related changes, emerges as an area of vital importance in the development of MI. In addition, a distinctive disease susceptibility and severity influenced by gender-based or ancestral differences, adds a crucial insights to the association with increased mortality. Here, we aimed to provide an overview on interactions of microbiome (oral and gut) with major risk factors (tobacco use, alcohol consumption, diet, hypertension host genetics, gender, and aging) in the development of MI and therapeutic regulation.

To study the survival analysis and recurrence pattern in women treated for breast cancer: Retrospective study, a tertiary cancer center experience from Sub-Himalayan Region of India.

BACKGROUND: Breast cancer is a leading health concern in India, comprising 25% of female cancers with significant mortality. This study was conducted at the Cancer Research Institute in the Northern Sub-Himalayan region of India from 2016 to 2021, evaluated 674 breast cancer cases to analyze factors that influence recurrence. METHODOLOGY: Retrospective clinical audit assessing patients' survival outcomes using Kaplan-Meier curves and Cox proportional hazard regression. Factors including age, molecular subtype, TNM staging, and treatment modalities were evaluated. RESULTS: Notable findings include a high occurrence of breast cancer in young patients (24.48% ≤ 40 years) and varying recurrence rates among molecular subtypes with human epidermal growth factor receptor 2 neu-enriched (25.24%) and triple­negative breast cancer (22.58%) being the most common. Advanced T and N stages, neoadjuvant chemotherapy, and the number of nodes dissected showed significant associations with higher recurrence rates. CONCLUSION: This study sheds light on survival and recurrence patterns in Northern Sub-Himalayan breast cancer patients, emphasizing the need for tailored treatment strategies, comprehensive follow-up care, with improved understanding of regional outcomes. These findings contribute valuable insights for optimizing patient care and improving survival rates in this region.

Diagnostic delays in breast cancer among young women: An emphasis on healthcare providers.

Despite advances in breast cancer care, breast cancer in young women (BCYW) faces unique challenges, diagnostic delays, and limited awareness in many countries. Here, we discuss the challenges and consequences associated with the delayed diagnosis of BCYW. The consequences of delayed diagnosis in young women - which generally varies among developed, developing, or underdeveloped countries - are severe due to a faster breast tumor growth rate than tumors in older women, also contributing to advanced cancer stages and poorer outcomes. Though there are many underlying reasons for diagnostic delays due to age, the article delves explicitly deep into the diagnostic delay of BCYW, focusing on healthcare providers, potential contributing factors, its consequences, and the urgent need to start minimizing such incidences. The article suggests several strategies to address these issues, including increasing awareness, developing educational programs for healthcare providers to identify signs and symptoms in young women, developing clear diagnostic guidelines, and improving screening strategies.

Herpes Virus Infections in Kidney Transplant Patients (HINT) - a prospective observational cohort study.

BACKGROUND: Kidney transplant recipients receive maintenance immunosuppressive therapy to avoid allograft rejection resulting in increased risk of infections and infection-related morbidity and mortality. Approximately 98% of adults are infected with varicella zoster virus, which upon reactivation causes herpes zoster. The incidence of herpes zoster is higher in kidney transplant recipients than in immunocompetent individuals, and kidney transplant recipients are at increased risk of severe herpes zoster-associated disease. Vaccination with adjuvanted recombinant glycoprotein E subunit herpes zoster vaccine (RZV) prevents herpes zoster in older adults with excellent efficacy (90%), and vaccination of kidney transplant candidates is recommended in Danish and international guidelines. However, the robustness and duration of immune responses after RZV vaccination, as well as the optimal timing of vaccination in relation to transplantation remain unanswered questions. Thus, the aim of this study is to characterize the immune response to RZV vaccination in kidney transplant candidates and recipients at different timepoints before and after transplantation. METHODS: The Herpes Virus Infections in Kidney Transplant Patients (HINT) study is a prospective observational cohort study. The study will include kidney transplant candidates on the waiting list for transplantation (n = 375) and kidney transplant recipients transplanted since January 1, 2019 (n = 500) from all Danish kidney transplant centers who are offered a RZV vaccine as routine care. Participants are followed with repeated blood sampling until 12 months after inclusion. In the case of transplantation or herpes zoster disease, additional blood samples will be collected until 12 months after transplantation. The immune response will be characterized by immunophenotyping and functional characterization of varicella zoster virus-specific T cells, by detection of anti-glycoprotein E antibodies, and by measuring cytokine profiles. DISCUSSION: The study will provide new knowledge on the immune response to RZV vaccination in kidney transplant candidates and recipients and the robustness and duration of the response, potentially enhancing preventive strategies against herpes zoster in a population at increased risk. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05604911).

A controversial ER negative PR positive molecular subtype of breast carcinoma-Report of two cases.

ER-/PR+ is a controversial subtype and is not formally recognised as molecular subtype of breast carcinoma. Few studies concluded that this subtype does not exist and is due to technical errors, however, in contrast others consider it to be distinct entity with different response to therapy and clinical outcome. It is also essential to know whether this subtype shows any distinct histomorphological features or prognosis.Therefore, the present two cases of controversial subtype ER-/PR+ breast cancer is being reported with both the cases showing neuroendocrinal differentiation.

Impact of Enhanced Recovery Protocols on Short-Term Outcomes in Esophagectomy: A Retrospective Cohort Study from Cancer Research Institute, Uttarakhand, India.

OBJECTIVE: Surgery for esophageal cancer is associated with high mortality and morbidity, especially in low and middle-income countries. The recent enhanced recovery after surgery guidelines for esophagectomy (2018) which attempt to reduce complications and length of stay (LOS) have rarely been validated in these settings. This study aimed to analyse the effect of this protocol on short-term outcomes in our subset of patients. METHODS: A retrospective review was conducted to investigate the outcomes of enhanced recovery protocol (ERP) compared to standard pre-protocol care (PP) in patients who underwent esophagectomy for cancer (31 in ERP vs 61 in PP group) at Cancer Research Institute, Uttarakhand, India. The main outcomes measured were 30-day mortality, morbidity and LOS. Risk assessment was stratified as per Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) systems while complications were classified as per the Clavien-Dindo scale. RESULTS: Preoperative clinical characteristics were similar between groups. Though the predicted POSSUM mortality and morbidity were significantly higher in the ERP group (p = 0.007), 30-day morbidity (19.35% vs 42.62%, p = 0.027) as well as median LOS (12 vs 15 days, p < 0.001) was significantly lower in ERP group. The PP group reported 4 deaths within 30 days as compared to none in the ERP group (p = 0.296). Furthermore, the ERP group reported lower occurrence of pulmonary complications (6.4%vs24.6%,p = 0.046), hemodynamic instability (0%vs14.75%,p = 0.026) as well as need for prolonged postoperative ventilation (> 24 h; 0% vs 11.48%, p = 0.004). Both minor and major complications as assessed by the Clavien-Dindo scale were lower in the group ERP though these differences were not statistically significant (0.059). CONCLUSIONS: Implementation of ERP improved short-term outcomes; hence can be strongly recommended in patients undergoing esophagectomy.

Radiation Safety and External Radiation Exposure Rate of Patients Receiving I-131 Therapy for Hyperthyroidism and Remnant Ablation as Outpatient: An Institutional Experience.

Objective Our objective was to study the radiation exposure rate as function of time in the administration of radioiodine iodine-131 (I-131) for the treatment of thyrotoxicosis or Graves' disease and remnant ablation on an outpatient basis at the Department of Nuclear Medicine, and also, to study the impact of revised discharge criteria for radioiodine therapy enforced by the Atomic Energy Regulatory Board (AERB) of India. Materials and Methods This study included patients who underwent low-dose radioiodine therapy using I-131. Patients were classified into two different groups, that is, group A and group B. Group A included patients receiving low dose I-131 for the treatment of thyrotoxicosis, whereas group B included patients receiving I-131 therapy for the ablation of residual thyroid tissue after total thyroidectomy. The radiation exposure rate was measured using a radiation detector in milli roentgen per hour (mR/h) at 5 cm distance of stomach and neck levels and with the patient standing at the distance of 1 m after oral administration of I-131 at 0, 1, and 2 hours. Results A total of 134 (17 males and 117 females) patients were included in the study. Group A comprised 102 (14 male and 88 females) patients and group B of 32 (3 males and 29 females) patients. At the neck level, the average exposure rate in group A versus group B after 0, 1, and 2 hours was observed to be 6.9 versus 22.27 mR/h, 33.67 versus 43.39 mR/h, and 41.75 versus 48.90 mR/h, respectively. At the stomach level, the exposure rate was 23.65 versus 71.32 mR/h, 13.27 versus 48.45 mR/h, and 9.91 versus 39.43 mR/h after 0, 1, and 2 hours, respectively. At a distance of 1 m, the exposure rate was 1.31 versus 2.99 mR/h, 1.05 versus 2.58 mR/h, and 0.92 versus 2.21 mR/h, respectively. Conclusion Exposure rate measured for patients treated with up to 1,110 MBq (30 mCi) of I-131 was under permissible limits as per revised discharged limits, that is, 50 µSv/h (5 mR/h) prescribed by AERB, India. The patients undergoing radioiodine therapy I-131 (up to 1,110 MBq/30 mCi) can be discharged safely 2 hours postadministration following good work practice along with providing proper radiation safety instructions to patients.

Additive effects of booster mRNA vaccination and SARS-CoV-2 Omicron infection on T cell immunity across immunocompromised states.

Suboptimal immunity to SARS-CoV-2 mRNA vaccination has frequently been observed in individuals with various immunodeficiencies. Given the increased antibody evasion properties of emerging SARS-CoV-2 subvariants, it is necessary to assess whether other components of adaptive immunity generate resilient and protective responses against infection. We assessed T cell responses in 279 individuals, covering five different immunodeficiencies and healthy controls, before and after booster mRNA vaccination, as well as after Omicron infection in a subset of patients. We observed robust and persistent Omicron-reactive T cell responses that increased markedly upon booster vaccination and correlated directly with antibody titers across all patient groups. Poor vaccination responsiveness in immunocompromised or elderly individuals was effectively counteracted by the administration of additional vaccine doses. Functionally, Omicron-reactive T cell responses exhibited a pronounced cytotoxic profile and signs of longevity, characterized by CD45RA+ effector memory subpopulations with stem cell-like properties and increased proliferative capacity. Regardless of underlying immunodeficiency, booster-vaccinated and Omicron-infected individuals appeared protected against severe disease and exhibited enhanced and diversified T cell responses against conserved and Omicron-specific epitopes. Our findings indicate that T cells retain the ability to generate highly functional responses against newly emerging variants, even after repeated antigen exposure and a robust immunological imprint from ancestral SARS-CoV-2 mRNA vaccination.

Simvastatin prevents BMP-2 driven cell migration and invasion by suppressing oncogenic DNMT1 expression in breast cancer cells.

Both epigenetic and genetic changes in the cancer genome act simultaneously to promote tumor development and metastasis. Aberrant DNA methylation, a prime epigenetic event, is often observed in various cancer types. The elevated DNA methyltransferase 1 (DNMT1) enzyme creates DNA hypermethylation at CpG islands to drive oncogenic potential. This study emphasized to decipher the molecular mechanism of endogenous regulation of DNMT1 expression for finding upstream signaling molecules. Cancer database analyses found an upregulated DNMT1 expression in most cancer types including breast cancer. Overexpression of DNMT1 showed an increased cell migration, invasion, and stemness potential whereas 5-azacytidine (DNMT1 inhibitor) and siRNA mediated knockdown of DNMT1 exhibited inhibition of such cancer activities in breast cancer MDA-MB-231 and MCF-7 cells. Infact, cancer database analyses further found a positive correlation of DNMT1 transcript with both cholesterol pathway regulatory genes and BMP signaling molecules. Experimental observations documented that the cholesterol-lowering drug, simvastatin decreased DNMT1 transcript as well as protein, whereas BMP-2 treatment increased DNMT1 expression in breast cancer cells. In addition, expression of various key cholesterol regulatory genes was found to be upregulated in response to BMP-2 treatment. Moreover, simvastatin inhibited BMP-2 induced DNMT1 expression in breast cancer cells. Thus, this study for the first time reveals that both BMP-2 signaling and cholesterol pathways could regulate endogenous DNMT1 expression in cancer cells.

Integra® Dermal Regeneration Template: From Design to Clinical Use.

Integra® Dermal Regeneration Template (IDRT, Integra LifeSciences, Princeton, NJ, USA) is a bilayer membrane developed, by Yannas and Burke in the 1980s, to fulfill the unmet need of surgeons having a readily available off-the-shelf dermal regeneration method. IDRT is composed of a sheet of porous cross-linked type I collagen and glycosaminoglycans, with a semi-permeable silicone sheet cover. IDRT is bio-engineered, from adult bovine Achilles tendons and chondroitin-6-sulfate derived from shark cartilage, in a multi-step process involving cross-linking using glutaraldehyde. By design, the composition, porosity, and biodegradation rate of IDRT guides the mechanism of wound repair towards a regenerative pathway. Its mechanism of action involves four distinct phases: imbibition, fibroblast migration, neovascularization, and remodeling/maturation. Originally developed for the post-excisional treatment of deep-partial to full-thickness burns where autograft is limited, over the years its use has expanded to reconstructive surgery.

A review article on the dosimetry in intraluminal HDR brachytherapy of lung carcinoma.

Lung cancer is one of the most common cancers in the world. Intraluminal brachytherapy (BT) is one of the most adopted treatment modalities for lung malignancies with Ir-192 source in radiotherapy. In intraluminal BT, treatment delivery is required to be very accurate and precise with respect to the plan created in the treatment planning system (TPS). The BT dosimetry is necessary for better treatment outcomes. Therefore in this review article, some relevant studies were identified and analyzed for dosimetric outcomes in intraluminal BT in lung malignancies. The dosimetry in BT for plan verification is not presently in practice, which needs to be performed to check the variation between the planned and measured doses. The necessary dosimetric work done by the various researchers in intraluminal BT such as the Monte Carlo CYLTRAN code was used to calculate and measure the dose rate in any medium. Anthropomorphic phantom was used to measure doses at some distance from the source with Thermo luminescence dosimeters (TLDs). The dosimetric influence of air passage in the bronchus was evaluated with the GEANT4 Monte Carlo method. A pinpoint chamber was used to measure and quantify the impact of inhomogeneity in wax phantom for the Ir-192 source. The Gafchromic films and Monte Carlo methods were used to find the phantom and heterogeneities, which were found to underestimate the dose for the lungs and overestimated for the bones in TPS. The exact tool to quantify the variation in planned and delivered doses should be cost-effective and easy to use possibly with tissue equivalent phantoms and Gafchromic films in lung malignancies treatment.

Herpesvirus immunology in solid organ transplant recipients - liver transplant study (HISTORY): a retrospective and prospective observational cohort study.

BACKGROUND: Life-long immunosuppressive treatment after liver transplantation (LT) prevents graft rejection but predisposes the LT recipient to infections. Herpesvirus infections are associated with morbidity and mortality among LT recipients. Among those, especially cytomegalovirus (CMV) and varicella-zoster virus (VZV) pose challenges after LT. The aim of this study is to provide an in-depth characterization of the cellular immune response against CMV and VZV infections in LT recipients and identify potential risk factors for infection. METHODS: The Herpesvirus Infections in Solid Organ Transplant Recipients - Liver Transplant Study (HISTORY) consists of an epidemiological and immunological substudy. The epidemiological substudy is a retrospective observational cohort study that includes all patients who underwent LT in Denmark between 2010 and 2023 (N ≈ 500). Using data from nationwide hospital records and national health registries, the incidence of and clinical risk factors for CMV and VZV infections will be determined. The immunological substudy is an explorative prospective observational cohort study including patients enlisted for LT in Denmark during a 1.5-year period (N > 80). Participants will be followed with scheduled blood samples until 12 months after LT. CMV- and VZV-derived peptides will be predicted for their likelihood to be presented in participants based on their HLA type. Peptide-MHC complexes (pMHC) will be produced to isolate CMV- and VZV-specific T cells from peripheral blood mononuclear cells before and after CMV and VZV infection. Their frequency, T cell receptor sequences, and phenotypic characteristics will be examined, and in a subset of participants, CMV- and VZV-specific T cells will be expanded ex vivo. DISCUSSION: This study will provide novel insight into T cell immunity required for viral control of CMV and VZV and has the potential to develop a prediction model to identify LT recipients at high risk for infection based on a combination of clinical and immunological data. Furthermore, this study has the potential to provide proof-of-concept for adoptive T cell therapy against CMV and VZV. Combined, this study has the potential to reduce the burden and consequence of CMV and VZV infections and improve health and survival in LT recipients. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05532540), registered 8 September 2022.

Mitochondrial Complex Abundance, Mitophagy Proteins, and Physical Performance in People With and Without Peripheral Artery Disease.

Background Mitochondrial abnormalities exist in gastrocnemius muscle of people with peripheral artery disease (PAD). Whether abnormalities in mitochondrial biogenesis and autophagy are associated with greater ischemia or walking impairment in PAD is unknown. Methods and Results Protein markers of mitochondrial biogenesis and autophagy and the abundance of mitochondrial electron transport chain complexes were quantified in gastrocnemius muscle biopsies from people with and without PAD. Their 6-minute walk distance and 4-m gait speed were measured. Sixty-seven participants (mean age 65.0 years [±6.8], 16 [23.9%] women, 48 [71.6%] Black) were enrolled, including 15 with moderate to severe PAD (ankle brachial index [ABI] <0.60), 29 with mild PAD (ABI 0.60-0.90), and 23 without PAD (ABI 1.00-1.40). Abundance of all electron transport chain complexes was significantly higher in participants with lower ABI (eg, complex I: 0.66, 0.45, 0.48 arbitrary units [AU], respectively, P trend=0.043). Lower ABI values were associated with a higher LC3A/B II-to-LC3A/B I (microtubule-associated protein 1A/1B-light chain 3) ratio (2.54, 2.31, 2.15 AU, respectively, P trend=0.017) and reduced abundance of the autophagy receptor p62 (0.71, 0.69, 0.80 AU, respectively, P trend=0.033). The abundance of each electron transport chain complex was positively and significantly associated with 6-minute walk distance and 4-m gait speed at usual and fast pace only among participants without PAD (eg, complex I: r=0.541, P=0.008; r=0.477, P=0.021; r=0.628, P=0.001, respectively). Conclusions These results suggest that accumulation of electron transport chain complexes in gastrocnemius muscle of people with PAD may be because of impaired mitophagy in the setting of ischemia. Findings are descriptive, and further study in larger sample sizes is needed.

Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity.

Over the last three decades, p21-activated kinases (PAKs) have emerged as prominent intracellular nodular signaling molecules in cancer cells with a spectrum of cancer-promoting functions ranging from cell survival to anchorage-independent growth to cellular invasiveness. As PAK family members are widely overexpressed and/or hyperactivated in a variety of human tumors, over the years PAKs have also emerged as therapeutic targets, resulting in the development of clinically relevant PAK inhibitors. Over the last two decades, this has been a promising area of active investigation for several academic and pharmaceutical groups. Similar to other kinases, blocking the activity of one PAK family member leads to compensatory activity on the part of other family members. Because PAKs are also activated by stress-causing anticancer drugs, PAKs are components in the rewiring of survival pathways in the action of several therapeutic agents; in turn, they contribute to the development of therapeutic resistance. This, in turn, creates an opportunity to co-target the PAKs to achieve a superior anticancer cellular effect. Here we discuss the role of PAKs and their effector pathways in the modulation of cellular susceptibility to cancer therapeutic agents and therapeutic resistance.

Let the Kid Speak: Dynamics of Triadic Medical Interactions Involving Pediatric Patients.

Communication in healthcare represents the complex interplay between multiple individual and contextual factors unfolding over the course of the medical encounter. Despite significant improvements in patient-centered care delivery, studies of health communication typically focus exclusively on clinical interactions between adult patients and their clinicians. Much less is known about non-dyadic interactions, such as pediatric triads involving a child patient and accompanying parent. Understanding the dynamics of triadic pediatric healthcare communication is the first step toward evaluating and ultimately optimizing these healthcare interactions. Thus, we undertook a mixed-method analysis of 28 audio-recorded triadic medical interactions between healthcare providers, pediatric asthma and allergy patients, and their parents to explore the prevalence of various features of these interactions. Our findings point to mechanisms through which healthcare providers and parents may facilitate or hinder children's involvement in their own asthma and allergy care, including interruptions, unclarified technical medical language, the flow of information exchange, and the formation of dyadic conversational partnerships (coalitions) between providers and parents. Our analyses further reveal that children's participation during their medical visits was minimal (13% of the interaction). Providers in our sample elicited input directly from pediatric patients more often than from parents, though the difference was small. Taken together, these findings provide a foundation on which to develop training and communication interventions to ensure that children have a voice in their medical care.

Definitive chemoradiation in nonmetastatic squamous cell carcinoma anal canal: A single-institution experience.

Purpose: The purpose of the study was to analyze the survival outcomes and toxicities in squamous cell carcinoma anal canal treated with definitive chemoradiotherapy. Materials and Methods: Retrospective analysis of 51 patients with squamous cell carcinoma anal canal treated with chemoradiotherapy was done. Data were collected and analyzed for disease-free survival (DFS), colostomy-free survival (CFS), overall survival (OS), and acute/late toxicities. Results: Out of total 51 patients, only 44 patients had a follow-up of more than 36 months and were analyzed. After a median follow-up of 46 months (range 10-68 months), the 3-year DFS was 73.9%. Three patients developed locoregional recurrence, while one patient developed distant metastasis. At 3-year OS rate was 77%. Out of 44 patients, six patients lost to follow-up, while two patients died due to progressive disease and two due to noncancer causes. 3-year CFS rate was 59%. Most common grade >3 acute toxicities were skin reactions in nine (18%), followed by hematological in eight (16%) patients. Conclusion: Definitive chemoradiotherapy in anal canal results in good oncological outcomes with sphincter preservation. No severe treatment-related toxicities were observed.