Prospects of liquid biopsy in the prognosis and clinical management of gastrointestinal cancers.

Gastrointestinal (GI) cancers account for one-fourth of the global cancer incidence and are incriminated to cause one-third of cancer-related deaths. GI cancer includes esophageal, gastric, liver, pancreatic, and colorectal cancers, mostly diagnosed at advanced stages due to a lack of accurate markers for early stages. The invasiveness of diagnostic methods like colonoscopy for solid biopsy reduces patient compliance as it cannot be frequently used to screen patients. Therefore, minimally invasive approaches like liquid biopsy may be explored for screening and early identification of gastrointestinal cancers. Liquid biopsy involves the qualitative and quantitative determination of certain cancer-specific biomarkers in body fluids such as blood, serum, saliva, and urine to predict disease progression, therapeutic tolerance, toxicities, and recurrence by evaluating minimal residual disease and its correlation with other clinical features. In this review, we deliberate upon various tumor-specific cellular and molecular entities such as circulating tumor cells (CTCs), tumor-educated platelets (TEPs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), exosomes, and exosome-derived biomolecules and cite recent advances pertaining to their use in predicting disease progression, therapy response, or risk of relapse. We also discuss the technical challenges associated with translating liquid biopsy into clinical settings for various clinical applications in gastrointestinal cancers.

THE ROLE OF INTRAVITREAL METHOTREXATE AS AN ADJUNCT TO LOCAL OR SYSTEMIC CORTICOSTEROIDS IN VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT AND CHOROIDAL DETACHMENT: A Pilot Study.

PURPOSE: To evaluate the role of repeated intravitreal methotrexate as an adjunct to pars plana vitrectomy in the management of rhegmatogenous retinal detachment with choroidal detachment. METHOD: The authors compared anatomical and visual outcomes of rhegmatogenous retinal detachment with choroidal detachment eyes that underwent pars plana vitrectomy with (Group B) or without repeated intravitreal methotrexate (Group A). RESULTS: The study included 25 eyes of 25 patients, 16 eyes in Group A and nine in Group B. Both groups had similar baseline characteristics. In Group A, successful retinal attachment was achieved in 50% as compared with 89% in Group B; however, the difference was not statistically significant ( P = 0.08). Also, Group B had a significantly greater change in visual acuity from baseline to the last follow-up visit (1.6 + 1.5 logMAR units) compared with Group A (1.18 + 1 logMAR units) ( P = 0.05). There were no significant safety concerns with the use of intravitreal methotrexate. CONCLUSION: Repeated intravitreal methotrexate after vitrectomy for rhegmatogenous retinal detachment with choroidal detachment improves outcomes without posing major safety concerns. Nonetheless, further investigation is necessary to establish the optimal intravitreal methotrexate dosage and duration to prevent recurrence effectively.

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment.

T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.

Diagnostic significance of dysregulated miRNAs in T-cell malignancies and their metabolic roles.

T-cell malignancy is a broad term used for a diverse group of disease subtypes representing dysfunctional malignant T cells transformed at various stages of their clonal evolution. Despite having similar clinical manifestations, these disease groups have different disease progressions and diagnostic parameters. The effective diagnosis and prognosis of such a diverse disease group demands testing of molecular entities that capture footprints of the disease physiology in its entirety. MicroRNAs (miRNAs) are a group of noncoding RNA molecules that regulate the expression of genes and, while doing so, leave behind specific miRNA signatures corresponding to cellular expression status in an altered stage of a disease. Using miRNAs as a diagnostic tool is justified, as they can effectively distinguish expressional diversity between various tumors and within subtypes of T-cell malignancies. As global attention for cancer diagnosis shifts toward liquid biopsy, diagnosis using miRNAs is more relevant in blood cancers than in solid tumors. We also lay forward the diagnostic significance of miRNAs that are indicative of subtype, progression, severity, therapy response, and relapse. This review discusses the potential use and the role of miRNAs, miRNA signatures, or classifiers in the diagnosis of major groups of T-cell malignancies like T-cell acute lymphoblastic lymphoma (T-ALL), peripheral T-cell lymphoma (PTCL), extranodal NK/T-cell lymphoma (ENKTCL), and cutaneous T-cell lymphoma (CTCL). The review also briefly discusses major diagnostic miRNAs having prominent metabolic roles in these malignancies to highlight their importance among other dysregulated miRNAs.

Orchestral role of lipid metabolic reprogramming in T-cell malignancy.

The immune function of normal T cells partially depends on the maneuvering of lipid metabolism through various stages and subsets. Interestingly, T-cell malignancies also reprogram their lipid metabolism to fulfill bioenergetic demand for rapid division. The rewiring of lipid metabolism in T-cell malignancies not only provides survival benefits but also contributes to their stemness, invasion, metastasis, and angiogenesis. Owing to distinctive lipid metabolic programming in T-cell cancer, quantitative, qualitative, and spatial enrichment of specific lipid molecules occur. The formation of lipid rafts rich in cholesterol confers physical strength and sustains survival signals. The accumulation of lipids through de novo synthesis and uptake of free lipids contribute to the bioenergetic reserve required for robust demand during migration and metastasis. Lipid storage in cells leads to the formation of specialized structures known as lipid droplets. The inimitable changes in fatty acid synthesis (FAS) and fatty acid oxidation (FAO) are in dynamic balance in T-cell malignancies. FAO fuels the molecular pumps causing chemoresistance, while FAS offers structural and signaling lipids for rapid division. Lipid metabolism in T-cell cancer provides molecules having immunosuppressive abilities. Moreover, the distinctive composition of membrane lipids has implications for immune evasion by malignant cells of T-cell origin. Lipid droplets and lipid rafts are contributors to maintaining hallmarks of cancer in malignancies of T cells. In preclinical settings, molecular targeting of lipid metabolism in T-cell cancer potentiates the antitumor immunity and chemotherapeutic response. Thus, the direct and adjunct benefit of lipid metabolic targeting is expected to improve the clinical management of T-cell malignancies.

MEDIUM-TERM PERFLUORO-N-OCTANE AS RESCUE POSTOPERATIVE TAMPONADE FOR VERY COMPLEX RETINAL DETACHMENTS: ANATOMICAL AND FUNCTIONAL OUTCOMES.

PURPOSE: To report the anatomical and functional outcomes of medium-term perfluoro-n-octane (PFO) tamponade as a rescue procedure in very complex retinal detachments (RDs). METHODS: We reviewed the case records of 35 consecutive patients who underwent vitrectomy for very complex RDs due to diverse etiologies. The surgical complexity was so graded because of the intraoperative failure to ascertain complete retinal reattachment; perfluoro-n-octane was used as rescue tamponade for 2 to 4 weeks. The second intervention included additional membrane peeling, retinectomy, endophotocoagulation, and gas/silicone oil tamponade. The minimum follow-up was 3 months after the final intervention: the primary outcome was retinal reattachment and the secondary outcome was change in best-corrected visual acuity (BCVA). RESULTS: The most common presentations were severe trauma with retinal incarceration, preretinal and subretinal hemorrhage, or chronic/recurrent RDs with anterior proliferative vitreoretinopathy. Preoperative BCVA was ≤counting fingers in 31 (88.6%) patients. Complete retinal attachment without any tamponade was achieved in 33 (94.3%) eyes. best-corrected visual acuity improved in 30 (85.7%) eyes: 16 (45.7%) had BCVA ≥20/200 and 21 (60%) regained ambulatory vision (≥5/200). Two eyes developed keratopathy, and four needed antiglaucoma medications. CONCLUSION: We achieved excellent anatomical outcomes and acceptable functional outcomes in nearly inoperable RDs with few side effects. Medium-term perfluoro-n-octane tamponade can be used as a salvage procedure in very complex RDs where intraoperative reattachment cannot be ensured.

SARS-CoV-2 Mutations and Their Impact on Diagnostics, Therapeutics and Vaccines.

With the high rate of COVID-19 infections worldwide, the emergence of SARS-CoV-2 variants was inevitable. Several mutations have been identified in the SARS-CoV-2 genome, with the spike protein as one of the mutational hot spots. Specific amino acid substitutions such as D614G and N501Y were found to alter the transmissibility and virulence of the virus. The WHO has classified the variants identified with fitness-enhancing mutations as variants of concern (VOC), variants of interest (VOI) or variants under monitoring (VUM). The VOCs pose an imminent threat as they exhibit higher transmissibility, disease severity and ability to evade vaccine-induced and natural immunity. Here we review the mutational landscape on the SARS-CoV-2 structural and non-structural proteins and their impact on diagnostics, therapeutics and vaccines. We also look at the effectiveness of approved vaccines, antibody therapy and convalescent plasma on the currently prevalent VOCs, which are B.1.17, B.1.351, P.1, B.1.617.2 and B.1.1.529. We further discuss the possible factors influencing mutation rates and future directions.

Association of VEGFA promoter polymorphisms rs699947 and rs35569394 with diabetic retinopathy among North-Central Indian subjects: a case-control study.

BACKGROUND: Diabetes mellitus type 2 is often described as the global pandemic of the 21st century with India emerging as its capital. Microvascular complications such as retinopathy associated with diabetes are a serious world health problem, leading to the already existing burden of blindness. The aim of this study was to determine whether VEGF gene polymorphisms rs35569394 and rs699947 are associated with DR in North Indians. MATERIALS AND METHODS: North Indian subjects, diabetic controls with no retinopathy (DR I, n = 51), subjects with diabetes with mild-moderate retinal changes (DR II, n = 50), and subjects with diabetes with severe retinopathy with/without retinal neovascularization (DR III, n = 55) were recruited for this study. Genotyping of the VEGF gene I/D polymorphism was done by PCR and C/A polymorphism by PCR-RFLP method. RESULTS: DD-genotype was 2.73 times over expressed among DR III category (p = .02; OR: 2.73; 95% CI: 1.20-6.19) as compared to DR I category among male subgroup. C-allele (rs699947) had 1.66-times more exposure among DR III as compared to DR I (C vs. A allele; p = .063; OR: 1.66; 95% CI: 0.97-2.84), probably due to high linkage disequilibrium between both the polymorphisms. CONCLUSIONS: Results of our study support the hypothesis that D-allele and DD-genotype of rs35569394 have deleterious effect on the progression of DR. C-allele had skewed frequency towards DR III subjects owing to strong linkage disequilibrium between C-allele (rs699947) and D-allele (rs35569394).

Internal limiting membrane peeling for large macular hole: Tailoring the rhexis to the shape of the hole.

PURPOSE: To report a simple modification of internal limiting membrane (ILM) peeling tailored to the shape of the macular hole to improve the closure rates. METHODS: This is a single-center interventional case series. conducted between 2016 and 2020. The minimum follow-up was 4 months. All surgeries were performed by one surgeon. Twenty consecutive patients (21 eyes) with large idiopathic macular holes (horizontal diameter: ≥600 µm) were enrolled; vertical hole diameters were also measured using spectral-domain optical coherence tomography (OCT). Following vitrectomy, ILM peeling was performed over a horizontally oval area (additional 1 disc-diameter temporally); perfluoropropane gas (C3F8, 15%) tamponade was used. Hole closure and change in best-corrected visual acuity (BCVA) were monitored after absorption of the gas. Preoperative and postoperative visual acuities were compared using paired t-test. IBM SPSS (ver. 26) was used for analysis. RESULTS: The macular holes were horizontally oval rather than circular without exception: mean horizontal and vertical diameters were 714 µm (range: 600-1020 µm) and 602 µm (490-844 µm), respectively. Following vitrectomy, macular hole closure was obtained in 20/21 eyes by the last follow-up (mean: 28 months, median: 34 months; range 4-48 months). Mean Snellen BCVA improved from 20/200 to 20/63 (P < 0.0001). CONCLUSION: All the macular holes in the study were observed to be horizontally oval. A corresponding horizontal enlargement of the ILM rhexis yielded excellent anatomical and satisfactory visual outcomes.

Advanced Coats' disease: Treating the effect before the cause.

An 8-year-old child with Stage 3A Coats' disease and severe submacular lipid exudation was initially treated with intravitreal injections of bevacizumab followed by triamcinolone. The exudative retinal detachment was then treated by scleral buckling, cryotherapy of persistent telangiectasia, and subretinal fluid drainage. The residual telangiectasia on the reattached retina was finally ablated by photocoagulation. The patient had a near-total resolution of submacular hard exudates without macular fibrosis. The peripheral telangiectasia and exudative detachment also regressed, with the sustained recovery of excellent visual acuity.

Evolution and successful management of a large postvitrectomy macular hole.

We report the successful closure of a large postvitrectomy macular hole by temporal extension of internal limiting membrane (ILM) peeling. A 25-year-old man underwent pars plana vitrectomy, ILM peeling, and perfluoropropane gas tamponade for optic pit with chronic macular schisis and outer lamellar hole. The macular schisis deroofed into a large, full-thickness macular hole postoperatively. Optical coherence tomography revealed the horizontally oval shape of the secondary macular hole (658 × 824 µ). The best-corrected visual acuity (BCVA) was 20/200. Since ILM had already been peeled and the macular hole was widest horizontally, we combined a repeat gas tamponade with temporal extension of the ILM rhexis. Closure of the large macular hole with no central defect was observed and documented after the gas fill of the vitreous cavity was reduced sufficiently. BCVA remained unchanged for the initial months but gradually improved to 20/63 by the final follow-up visit at 5 years. A simple horizontal extension of ILM peel - in line with the shape of the hole - with repeat gas tamponade successfully closed a large secondary macular hole with progressive visual improvement.

Tubercular Retinal Vasculitis: Diagnostic Dilemma and Management Strategies.

Ocular tuberculosis (OTB) is a rare, extrapulmonary manifestation of systemic TB, which has been a global etiology of uveitis for centuries, though concentrated in the developing world. OTB remains difficult to diagnose clinically despite a plethora of conventional and modern investigations. Tubercular retinal vasculitis (TRV) is a common and specific presentation of OTB but is variably defined in the literature in terms of clinical profile and the investigations essential for diagnosis and treatment. Ironically, the need and duration of antitubercular treatment is uncertain for this manifestation of ocular TB. The rationale and utility for corticosteroids is similarly equivocal for TRV. This review attempts to tease out a commonsense approach from the best available evidence and consensus in the literature to suspect, investigate and diagnose TRV with reasonable certainty, and institute appropriate treatment with due ethnic and geographic considerations.