Insights into Allosteric Inhibition of the AcrB Efflux Pump: Role of Distinct Binding Pockets, Protomer Preferences, and Crosstalk Disruption.

AcrB, a key component in bacterial efflux processes, exhibits distinct binding pockets that influence inhibitor interactions. In addition to the well-known distal binding pocket within the periplasmic domain, a noteworthy pocket amidst the transmembrane (TM) helices serves as an alternate binding site for inhibitors. The bacterial efflux mechanism involves a pivotal functional rotation of the TM protein, inducing conformational changes in each protomer and propelling drugs toward the outer membrane domain. Surprisingly, inhibitors binding to the TM domain display a preference for L protomers over T protomers. Metadynamics simulations elucidate that Lys940 in the TM domain of AcrB can adopt two conformations in L protomers, whereas the energy barrier for such transitions is higher in T protomers. This phenomenon results in stable inhibitor binding in l protomers. Upon a detailed analysis of unbinding pathways using random accelerated molecular dynamics and umbrella sampling, we have identified three distinct routes for ligand exit from the allosteric site, specifically involving regions within the TM domains─TM4, TM5, and TM10. To explore allosteric crosstalk, we focused on the following key residues: Val452 from the TM domain and Ala831 from the porter domain. Surprisingly, our findings reveal that inhibitor binding disrupts this communication. The shortest path connecting Val452 and Ala831 increases upon inhibitor binding, suggesting sabotage of the natural interdomain communication dynamics. This result highlights the intricate interplay between inhibitor binding and allosteric signaling within our studied system.

Decoding Inhibitor Egression from Wild-Type and G2019S Mutant LRRK2 Kinase: Insights into Unbinding Mechanisms for Precision Drug Design in Parkinson's Disease.

Leucine-rich repeat kinase 2 (LRRK2) remains a viable target for drug development since the discovery of the association of its mutations with Parkinson's disease (PD). G2019S (in the kinase domain) is the most common mutation for LRRK2-based PD. Though various types of inhibitors have been developed for the kinase domain to reduce the effect of the mutation, understanding the working of these inhibitors at the molecular level is still ongoing. This study focused on the exploration of the dissociation mechanism (pathways) of inhibitors from (WT and G2019S) LRRK2 kinase (using homology model CHK1 kinase), which is one of the crucial aspects in drug discovery. Here, two ATP-competitive type I inhibitors, PF-06447475 and MLi-2 (Comp1 and Comp2 ), and one non-ATP-competitive type II inhibitor, rebastinib (Comp3), were considered for this investigation. To study the unbinding process, random accelerated molecular dynamics simulations were performed. The binding free energies of the three inhibitors for different egression paths were determined using umbrella sampling. This work found four major egression pathways that were adopted by the inhibitors Comp1 (path1, path2, and path3), Comp2 (path1, path2 and path3), and Comp3 (path3 and path4). Also, the mechanism of unbinding for each path and key residues involved in unbinding were explored. Mutation was not observed to impact the preference of the particular egression pathways for both LRRK2-Comp1 and -Comp2 systems. However, the findings suggested that the size of the inhibitor molecules might have an effect on the preference of the egression pathways. The binding energy and residence time of the inhibitors followed a similar trend to experimental observations. The findings of this work might provide insight into designing more potent inhibitors for the G2019S LRRK2 kinase.

Machine Learning-Guided Discovery of AcrB and MexB Efflux Pump Inhibitors.

Multidrug efflux pump is one of the reasons behind the antimicrobial inactivity related to infection caused by Gram-negative pathogens. The inner membrane resistance-nodulation-cell division transporter proteins, AcrB and MexB, in association with outer membrane proteins, TolC and OprM, are responsible for the extrusion of a broad range of substrates, followed by recognizing them. Although various inhibitors were proposed to stop the efflux activity of the transporter protein, none of them had been approved clinically. Our study aims to identify potent inhibitor-like molecules employing supervised classification models trained upon the molecular descriptors of previously known inhibitors. Based on the intrinsic minimum inhibitory concentration (MIC) values of the reported inhibitors, they were classified into highly potent and less potent categories. A total of 10 different classification models were built using various molecular descriptors; among them, support vector machine, Random Forest, AdaBoost, and LightGBM models appeared to deliver promising results with >80% accuracy. These top four models were implemented on a library of 5043 to obtain 8 hit molecules after the multistep filtering process. To assess their activity toward AcrB and MexB, several molecular dynamics simulations of their ligand-bound structures were performed. We also calculated the binding free-energy values and analyzed other structural properties. Mol.3488 of the unknown molecules showed higher binding affinities for both AcrB and MexB. Also, the presence of "pyridopyrimidone" and "benzothiazole" moieties in the molecules and "V"-shaped orientation of ligands inside the deep binding pocket increase the binding affinity, thereby higher inhibitory properties.

Probing the pH Sensitivity of OprM: Insights into Metastable States and Semi-Open Conformation.

Efflux pumps are specialized transport proteins that play a key role in the bacterial defense against a wide spectrum of antibiotics. Hence, understanding the biophysical mechanism associated with this complex system of drug expulsion becomes crucial. This work deals with some vital aspects of the outer membrane factor (OMF) of MexAB-OprM. After being passed through MexB and MexA, efflux substrates have to go through OprM for their final judgment. Thus, it is very important to understand the periplasmic pore opening mechanism and the associated biophysical changes during this process. Our study captures a detailed analysis of the pore opening mechanism involving OprM. With powerful molecular dynamics (MD) techniques such as well-tempered metadynamics, the presence of metastable states in between open and closed states was confirmed. Also, upon mutating R376, the energy barrier for the conversion of the close to open conformation decreases, indicating an important role played by the residue. Further, constant pH MD was performed to capture the effect of pH in both conformations. OprM exhibits distinct conformational states at pH values greater than 5.5 and lower than 5.5, suggesting its pH-responsive characteristics. Overall, our study elucidates a crucial undertaking toward discovering potential inhibitors for MexAB-OprM efflux pumps.

Structural insight into G2019S mutated LRRK2 kinase and brain-penetrant type I inhibitor complex: a molecular dynamics approach.

More than 40 mutations in the multidomain leucine-rich repeat kinase 2 (LRRK2) are found and mutation G2019S in the kinase domain is the most concerned with Parkinson's disease (PD). The discovery of the various types of inhibitors has largely emerged recently. However, the comparative study on molecular insight in WT and G2019S LRRK2 kinase domain upon binding of the inhibitors has not yet been explored in detail. This work considered five ATP-competitive Type I inhibitors complexed with WT and mutated LRRK2 kinase. Three reported potent and brain-penetrant inhibitors, GNE-7915, PF-06447475 and MLi-2 (comp1, comp2 and comp3 respectively) and also, another two inhibitors, Pyrrolo[2,3-b] pyridine derivative (comp4) and Pyrrolo[2,3-d] pyrimidine derivative (comp5), were used. In this work, classical and accelerated molecular dynamics (cMD and aMD) simulations were performed for a total of 12 systems (apo and holo). This study found structural and thermodynamic stability for all the inhibitors. Comparatively larger molecules (size 15.3 - 15.4 Å), comp1, comp3 and comp5, showed more selectivity towards mutated LRRK2 kinase in terms of flexibility of residues, compactness and dynamics of kinase, the stability inside the binding-pocket. Also, inhibitors comp3 and comp5 showed higher binding affinity towards G2019S LRRK2 among the five. Residues, E1948 and A1950 (in hinge region) were observed mainly to form hydrogen bonds with inhibitors. Finally, MLi-2 showed a conformational rearrangement by dihedral flipping in both WT and mutated systems but got stability in G2019S LRRK2. This work could potentially help design more improved and effective Type I inhibitors for G2019S LRRK2 kinase.

Ligustrazine improves the compensative effect of Akt survival signaling to protect liver Kupffer cells in trauma-hemorrhagic shock rats.

Trauma-hemorrhagic shock (THS) is a medical emergency that is encountered by physicians in the emergency department. Chuan Xiong is a traditional Chinese medicine and ligustrazine is a natural compound from it. Ligustrazine improves coronary blood flow and reduces cardiac ischemia in animals through Ca2+ and ATP-dependent vascular relaxation. It also decreases the platelets' bioactivity and reduces reactive oxygen species formation. We hypothesized that ligustrazine could protect liver by decreasing the inflammation response, protein production, and apoptosis in THS rats. Ligustrazine at doses of 100 and 1000 µg/mL was administrated in Kupffer cells isolated from THS rats. The protein expressions were detected via western blot. The THS showed increased inflammation response proteins, mitochondria-dependent apoptosis proteins, and had a compensation effect on the Akt pathway. After ligustrazine treatment, the hemorrhagic shock Kupffer cells decreased inflammatory response and mitochondria-dependent apoptosis and promoted a more compensative effect of the Akt pathway. It suggests ligustrazine reduces inflammation response and mitochondria-dependent apoptosis induced by THS in liver Kupffer cells and promotes more survival effects by elevating the Akt pathway. These findings demonstrate the beneficial effects of ligustrazine against THS-induced hepatic injury, and ligustrazine could be a potential medication to treat the liver injury caused by THS.

Role of the Residue Q1919 in Increasing Kinase Activity of G2019S LRRK2 Kinase: A Computational Study.

Mutations in multi-domain leucine-rich repeat kinase 2 (LRRK2) have been an interest to researchers as these mutations are associated with Parkinson's disease. G2019S mutation in LRRK2 kinase domain leads to the formation of additional hydrogen bonds by S2019 which results in stabilization of the active state of the kinase, thereby increasing kinase activity. Two additional hydrogen bonds of S2019 are reported separately. Here, a mechanistic picture of the formation of additional hydrogen bonds of S2019 with Q1919 (also with E1920) is presented using 'active' Roco4 kinase as a homology model and its relationship with the stabilization of the 'active' G2019S LRRK2 kinase. A conformational flipping of residue Q1919 was found which helped to form stable hydrogen bond with S2019 and made 'active' state more stable in G2019S LRRK2. Two different states were found within the 'active' kinase with respect to the conformational change (flipping) in Q1919. Two doubly-mutated systems, G2019S/Q1919A and G2019S/E1920 K, were studied separately to check the effect of Q1919 and E1920. For both cases, the stable S2 state was not formed, leading to a decrease in kinase activity. These results indicate that both the additional hydrogen bonds of S2019 (with Q1919 and E1920) are necessary to stabilize the active G2019S LRRK2.

Feasibility of a Palliative Care Intervention Utilizing Community Health Workers to Facilitate Delivery of Home-based Palliative Care in India.

Objectives: The purpose of this study was to evaluate the feasibility of a home-based palliative care program delivered by community health workers (CHW) in rural areas outside of Kolkata, India. The specific aims were to assess CHWs' ability to implement the intervention protocol and maintain records of care, to characterize patient problems and CHW activities to assist patients, and to assess change in patient pain scores over the course of the intervention. Materials and Methods: Four CHWs were hired to facilitate delivery of home-based palliative care services. CHWs were trained using the Worldwide Hospice and Palliative Care Alliance's Palliative Care Toolkit. CHWs provided care for patients for 3-months, making regular home visits to monitor health, making and implementing care plans, and referring patients back to the cancer center team for serious problems. Results: Eleven patients enrolled in the intervention, with ten of these patients participating in the intervention and one patient passing away before starting the intervention. All ten participants reported physical pain, for which CHWs commonly recommended additional or higher dose medication and/or instructed patients how to take medication properly. For two patients, pain levels decreased between baseline and end of study, while pain scores did not decrease for the remaining patients. Other symptoms for which CHWs provided care included gastro-intestinal, bleeding, and respiratory problems. Conclusion: The study findings suggest that utilization of CHWs to provide palliative care in low-resource settings may be a feasible approach for expanding access to palliative care. CHWs were able to carry out the study visit protocol and assess and document patient problems and their activities to assist. They were also able to alleviate many common problems patients experienced with simple suggestions or referrals. However, most patients did not see a decrease in pain levels and more emphasis was needed on the emotional aspects of palliative care, and so CHWs may require additional training on provision of pain management and emotional support services.

Prediction of COMT Inhibitors Using Machine Learning and Molecular Dynamics Methods.

Catechol O-methyltransferase (COMT) plays a vital role in deactivating neurotransmitters like dopamine, norepinephrine, etc., by methylating those compounds. However, the deactivation of an excess amount of neurotransmitters leads to serious mental ailments such as Parkinson's disease. Molecules that bind inside the enzyme's active site inhibit this methylation mechanism by methylating themselves, termed COMT inhibitors. Our study is focused on designing these inhibitors by various machine learning methods. First, we have developed a classification model with experimentally available COMT inhibitors, which helped us generate a new data set of small inhibitor-like molecules. Then, to predict the activity of the new molecules, we have applied regression techniques such as Random Forest, AdaBoost, gradient boosting, and support vector machines. Each of the regression models yielded an R2 value > 70% for both training and test data sets. Finally, to validate our models, 200 ns long molecular dynamics (MD) simulations of the two known inhibitors with known IC50 values and the resultant inhibitors were performed inside the binding pockets to check their stability within. The free energy barrier of the methyl transfer from S-adenosyl-l-methionine (SAM) to each inhibitor was determined by combining steered molecular dynamics (SMD) and umbrella sampling using the quantum mechanics/molecular mechanics (QM/MM) method.

CONCORDANCE: A real-world evidence study to evaluate the concordance of detecting epidermal growth factor receptor (EGFR) mutation by circulating tumor DNA* versus tissue biopsy in patients with metastatic non-small cell lung cancer.

Background: Molecular tissue testing in non-small cell lung cancer (NSCLC) is done for the assessment of epidermal growth factor receptor (EGFR) mutation. EGFR mutation status is the basis for deciding the targeted treatment option for patients with metastatic NSCLC. The nonavailability of tissue samples and contraindications for biopsy pose a significant challenge. Hence, circulating tumor DNA (ctDNA) by liquid biopsy can be a viable alternative for NSCLC patients. Methods: This study was conducted at 15 sites across India. EGFR mutation testing from plasma was done as part of the study at the central laboratory by the next-generation sequencing (NGS) method, and EGFR mutation test results from tissue samples (done as part of routine practice) were recorded for all the patients. Results: Out of the total patients enrolled (N = 245), the majority (64.5%, n = 158) were men. The median age of patients was 58.0 (range: 26-84) years. The concordance between plasma and tissue testing was found to be 82.9% (95% confidence interval [CI]: 77.55, 87.45). The sensitivity and specificity of NGS were 68.4% (95% CI: 56.92, 78.37) and 90.1% [95% CI: 84.36, 94.21), respectively. Plasma testing detected 1.2% (n = 3) and tissue sample testing detected 2.4% (n = 6) positive status of exon 20 T790M EGFR mutation. Out of the total number of patients enrolled, 25 were tissue positive and plasma negative, while 16 were plasma positive and tissue negative. Conclusions: "> This real-world study in Indian patients suggests that plasma testing for EGFR mutation analysis is a viable diagnostic option in newly diagnosed advanced/metastatic NSCLC patients. The noninvasive plasma procedure in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies by providing clinicians with valuable insights into the patient's tumor mutation status. ClinicalTrials.gov Identifier: NCT03562819.

Carboxy-Terminal Processing Protease Controls Production of Outer Membrane Vesicles and Biofilm in Acinetobacter baumannii.

Carboxy-terminal processing protease (Ctp) is a serine protease that controls multiple cellular processes through posttranslational modification of proteins. Acinetobacter baumannii ATCC 17978 ctp mutant, namely MR14, is known to cause cell wall defects and autolysis. The objective of this study was to investigate the role of ctp mutation-driven autolysis in regulating biofilms in A. baumannii and to evaluate the vesiculation caused by cell wall defects. We found that in A. baumannii, Ctp is localized in the cytoplasmic membrane, and loss of Ctp function enhances the biofilm-forming ability of A. baumannii. Quantification of the matrix components revealed that extracellular DNA (eDNA) and proteins were the chief constituents of MR14 biofilm, and the transmission electron microscopy further indicated the presence of numerous dead cells compared with ATCC 17978. The large number of MR14 dead cells is potentially the result of compromised outer membrane integrity, as demonstrated by its high sensitivity to sodium dodecyl sulfate (SDS) and ethylenediaminetetraacetic acid (EDTA). MR14 also exhibited the hypervesiculation phenotype, producing outer-membrane vesicles (OMVs) of large mean size. The MR14 OMVs were more cytotoxic toward A549 cells than ATCC 17978 OMVs. Our overall results indicate that A. baumanniictp negatively controls pathogenic traits through autolysis and OMV biogenesis.

Phage φAB6-Borne Depolymerase Combats Acinetobacter baumannii Biofilm Formation and Infection.

Biofilm formation is one of the main causes of increased antibiotic resistance in Acinetobacter baumannii infections. Bacteriophages and their derivatives, such as tail proteins with depolymerase activity, have shown considerable potential as antibacterial or antivirulence agents against bacterial infections. Here, we gained insights into the activity of a capsular polysaccharide (CPS) depolymerase, derived from the tailspike protein (TSP) of φAB6 phage, to degrade A. baumannii biofilm in vitro. Recombinant TSP showed enzymatic activity and was able to significantly inhibit biofilm formation and degrade formed biofilms; as low as 0.78 ng, the inhibition zone can still be formed on the bacterial lawn. Additionally, TSP inhibited the colonization of A. baumannii on the surface of Foley catheter sections, indicating that it can be used to prevent the adhesion of A. baumannii to medical device surfaces. Transmission and scanning electron microscopy demonstrated membrane leakage of bacterial cells treated with TSP, resulting in cell death. The therapeutic effect of TSP in zebrafish was also evaluated and the results showed that the survival rate was significantly improved (80%) compared with that of the untreated control group (10%). Altogether, we show that TSP derived from φAB6 is expected to become a new antibiotic against multi-drug resistant A. baumannii and a biocontrol agent that prevents the formation of biofilms on medical devices.

Barriers, Facilitators and Recommended Strategies for Implementing a Home-Based Palliative Care Intervention in Kolkata, India.

BACKGROUND: 40 million people in the world are in need of palliative care, but only one-seventh of that population receive services. Underuse of palliative care in low resource countries exacerbates suffering in patients with life limiting illnesses such as cancer. OBJECTIVES: The current study was conducted to identify barriers, facilitators and recommended strategies for informing development of a home-based palliative care intervention for poor and medically underserved rural patients in Kolkata, India. METHODS: Semi-structured interviews were conducted with 20 clinical and patient stakeholders in Kolkata, India. Questions queried current practices for delivering palliative care, along with barriers, facilitators and optimal strategies for implementing homebased palliative care. RESULTS: We identified some key barriers to palliative care delivery in rural areas: lack of access to palliative care till late stages; patients unaware of their cancer stage; lack of affordability of medication and treatment costs; transportation challenges to access care; strict morphine distribution regulations making it challenging for patients to obtain morphine; cultural factors discouraging patients from seeking palliative care; resistance from medical community to use "rural medical practitioners (RMPs)" to deliver care. We also identified important facilitators, including availability of existing palliative care infrastructure at the cancer center, network of RMPs to serve as CHWs to facilitate palliative care delivery, low morphine cost and family support system for patients. CONCLUSION: Our findings provide evidence that a palliative care intervention which leverages an existing CHW infrastructure may be a feasible model for expanding the reach of palliative care to rural underserved patients.

Configuration Flipping in Distal Pocket of Multidrug Transporter MexB Impacts the Efflux Inhibitory Mechanism.

MexAB-OprM efflux pumps, found in Pseudomonas aeruginosa, play a major role in drug resistance by extruding out drugs and antibiotic molecules from cells. Inhibitors are used to cease the potency of the efflux pumps. In this study, in-silico models are used to investigate the nature of the binding pocket of the MexAB-OprM efflux pump. First, we have performed classical molecular dynamics (MD) simulations to shed light on different aspects of protein-inhibitor interaction in the binding pocket of the pump. Using classical MD simulations, quantum mechanics/molecular mechanics (QM/MM), and various types of analyses, it is found that D13-9001 has a higher binding affinity towards the binding pocket compared to D1 and D2; the results are in sync with the experimental dat. Two stable configurations of D13-9001 are discovered inside the distal pocket which could be one of the primary reasons for the greater efficacy of D13-9001. The free energy barrier upon changing one state to another is calculated by employing umbrella sampling method. Finally, F178 is mutated to have the complete picture as it contributes significantly to the binding energy irrespective of the three inhibitors. Our results may help to design a new generation of inhibitors for such an efflux pump.

Mutation of the Carboxy-Terminal Processing Protease in Acinetobacter baumannii Affects Motility, Leads to Loss of Membrane Integrity, and Reduces Virulence.

Motility plays an essential role in the host-parasite relationship of pathogenic bacteria, and is often associated with virulence. While many pathogenic bacteria use flagella for locomotion, Acinetobacter baumannii strains do not have flagella, but have other features that aid in their motility. To study the genes involved in motility, transposon mutagenesis was performed to construct A. baumannii mutant strains. Mutant strain MR14 was found to have reduced motility, compared to wild-type ATCC 17978. NCBI BLAST analysis revealed that the Tn10 transposon in the MR14 genome is integrated into the gene that encodes for carboxy-terminal processing protease (Ctp). Additionally, MR14 exhibits a mucoidy, sticky phenotype as the result of increased extracellular DNA (eDNA) caused by bacterial autolysis. Transmission and scanning electron microscopy revealed cytoplasmic content leaving the cell and multiple cell membrane depressions, respectively. MR14 showed higher sensitivity to environmental stressors. Mutation of the ctp gene reduced invasion and adhesion of A. baumannii to airway epithelial cells, potentially due to increased hydrophobicity. In the zebrafish model of infection, MR14 increased the survival rate by 40% compared to the wild-type. Taken together, the ctp gene in A. baumannii has a pivotal role in maintaining membrane integrity, adaptation to environmental stress, and controlling virulence.

Role of Cresp® in the management of chemotherapy-induced anemia in cancer patients: A real-world clinical practice audit.

INTRODUCTION: Anemia is a common, underestimated problem in cancer patients receiving myelosuppressive chemotherapy and has significant adverse effect on the quality of life and outcome. Darbepoetin has been shown to be effective in this setting, but controversy surrounds it actual use. METHODS: We analyzed prospectively collected clinical practice data of patients receiving darbepoetin in a real-world setting for this retrospective audit. Patients with baseline hemoglobin (Hb) of <11 g/dl were included in this analysis. Their medical records were audited using a predetermined 35-point pro forma. RESULTS: There were a total of 274 patients with advanced cancer receiving myelosuppressive chemotherapy who had baseline Hb <11 g/dl and who were given darbepoetin. Head-and-neck squamous cell carcinoma, lung cancer, and breast cancer were the most common cancers. Their median baseline Hb was 8.9 g/dl which rose to 11.2 g/dl at the end of commenced therapy, along with improved symptomatology. There were no new toxicities, and only two patients required discontinuation of darbepoetin due to toxicity. CONCLUSION: Darbepoetin is safe and effective in the prevention and management of anemia among patients receiving myelosuppressive chemotherapy.

Practice patterns and outcomes with the use of regorafenib in metastatic colorectal cancer: Results from the Regorafenib in Metastatic colorectal cancer - An Indian exploratory analysis study.

BACKGROUND: Regorafenib is considered a standard of care as third-line therapy in metastatic colorectal cancers (mCRCs). MATERIALS AND METHODS: The study was based on a computerized clinical data form sent to oncologists across the country for entry of anonymized patient data. The data entry form was conceived and generated by the coordinating center's (Tata Memorial Hospital) gastrointestinal medical oncologists and disseminated through personal contacts at academic conferences as well as through E-mail to various oncologists across India. RESULTS: A total of 19 physicians contributed data resulting in 80 patients receiving regorafenib who were available for the evaluation of practice patterns. The median age was 55 years (range: 24-75). Majority had received oxaliplatin-based (97.5%), irinotecan-based (87.5%), and targeted therapy (65%), previously. Patients were primarily started on reduced doses of regorafenib upfront (160 mg - 28.8%, 120 mg - 58.8%, and 80 mg - 12.5%). The median duration of treatment (treatment duration) with regorafenib was 3.1 months (range: 0.5-18), while the median progression free survival was 3.48 months (range: 2.6-4.3). Forty-five percent of patients required dose modifications due to toxicities, and the most common were (all grades) hand-foot syndrome (68.8%), fatigue (46.3%), mucositis (37.6%), and diarrhea (31.3%). CONCLUSIONS: Majority of physicians in this collaborative study from India used a lower dose of regorafenib at the outset in patients with mCRC. Despite a lower dose, there was a significant requirement for dose reduction. Duration of treatment with regorafenib as an efficacy end point in this study is similar to available data from other regions as it is the side effect profile.

An Observational Study to Assess the Socioeconomic Status and Demographic Profile of Advanced Cancer Patients Receiving Palliative Care in a Tertiary-Level Cancer Hospital of Eastern India.

INTRODUCTION: Socioeconomic status (SES) comprises of not just gross income but also educational qualification, financial security and individual perceptions of social status and class. It has been observed that people with low SES have less access and utilization of palliative care services. With this background, this observational study was carried out at SGCCRI to assess and evaluate the SES of patients attending the palliative care department and analyse the major social concerns of patients in the last days of life. OBJECTIVES: Assessment of socio- economic status and demographic profile of patients with advanced cancer receiving palliative care. MATERIALS AND METHODS: From May 2017 to October 2017 we assessed the demographic features and socio-economic status of 80 advanced cancer patients receiving palliative care by interviewing them face to face with the help of a self designed social assessment sheet. RESULTS: A total of 80 patients consented to be interviewed with regards to assessment of their socio-economic conditions. Majority were male patients (64%) with the highest percentage in the age group of 60-70years (33%). 38% of the patients interviewed were from rural surroundings. Only 38% of the patients had completed their basic education. Approximately 30% of the patients interviewed had income less than 1lakh/month while majority (>60%) had income in the bracket of 1lakh- 2lakh. In 30% of cases, the patient was the sole earner in the family. CONCLUSION: It was observed that majority of patients and their family were constrained with regards to financial resources and large percentage of patients had social insecurity with respect to future of family members.

Primary Merkel cell carcinoma of the oral mucosa in a young adult male: report of a rare case.

Merkel cell carcinoma (MCC) is a highly aggressive neoplasm of skin with neuroendocrine differentiation. Primary MCC of the oral mucosa is exceedingly rare and even more unresponsive to therapy. A 15-year-old male presents with gradually increasing painless swelling in right side of the floor of mouth for 6 weeks. Computed tomography of head and neck region showed globular mass (4.6 cm × 1.7 cm) involving right side of the floor of mouth. Fine-needle aspiration from the upper deep cervical node suggested small round cell tumor. A trucut biopsy showed mass composed of trabeculae and nests of tumor cells with high N:C ratio, granular speckled chromatin, scanty to moderate amount of clear vacuolated cytoplasm. Cells were immunoreactive for cytokeratin-20, CD56, c-kit, CD99 and negative for p63, thyroid-transcription factor-1, CDX2, synaptophysin, neuron-specific enolase. Patient was started on chemotherapy with cyclophosphamide, doxorubicin and vincristine. The mass regressed in size and patient underwent wide local excision with pull-through approach. Patient is currently under combined chemoradiation regime and doing well.

A Rare Case of Cytokeratin-Positive Interstitial Reticulum Cell Sarcoma and Review of the Entity.

The tumors of dendritic/reticulum cells constitutes the rarest tumors affecting the lymphoid tissues. Among them tumors derived from fibroblastic reticular cells (FBRCs) are very rare, and those of cytokeratin (CK)-positive interstitial reticulum cells (CIRCs) origin are even more rare. These tumors can be easily misdiagnosed as tumors of other dendritic cells, myofibroblastic tumors or even metastatic poorly differentiated carcinomas. Less than twenty such cases have been reported in the literature till date. We present such a rare case of CIRC sarcoma in cervical lymph node of a 64-year-old man.