Healing responses at the angle after micro-invasive glaucoma surgery-an AS-OCT study.

PURPOSE: To evaluate structural alterations and healing responses in the trabecular meshwork region with optical coherence tomography (AS-OCT) following after gonioscopy assisted transluminal trabeculotomy (GATT) and microincisional trabeculectomy (MIT). METHODS: 73 eyes of 67 patients (M:F = 45:22) with ≥6 months of follow-up after MIT (n = 41) or GATT (n = 32) with or without combined cataract surgery were included for this prospective study. The angle as seen on AS-OCT at 1, 3, 6 months after surgery were evaluated for structural alterations like peripheral anterior synechiae (PAS), hyphema, and hyperreflective scarring responses. The scarring was graded according to the linear extent measured from the centre of the trabecular meshwork (TM) gutter to the sclera/cornea as mild (<250µ), moderate (250-500µ), and severe(˃500µ), while the pattern of scarring was graded as open saucer/gutter, closed gutter, and trench pattern. The association of the need for medication or surgical outcome and clinical variables and AS-OCT parameters including the pattern and severity of scarring were analysed using multivariate regression. RESULTS: All eyes achieved significant reduction of IOP and number of medications with a final IOP of 15±3.2mm Hg at a mean follow-up of 8±32. months. While mild scarring was seen more common in MIT, severe scarring was seen in >65% of GATT eyes compared to 31% of MIT eye, p<0.001. An open saucer was equally seen in MIT and GATT while the trench pattern was more commonly seen in GATT eyes (>50%). Severe scarring in a trench pattern seemed to predict the need for medications for IOP control, though they independently did not seem to influence the final IOP or surgical outcome. CONCLUSION: A severe form of scarring in a trench pattern on AS-OCT predicted the need for glaucoma medications after MIGS surgery. Regular monitoring of the scarring responses by AS-OCT and clinical examination are necessary to identify those at need for medications after MIGS.

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

Outcomes of Ahmed glaucoma valve surgery performed by glaucoma fellows - A large retrospective study from Eastern India.

PURPOSE: Teaching and training of glaucoma fellows on the technique of Ahmed glaucoma valve (AGV) implantation surgery is very important. The purpose of this study was to describe the clinical outcomes and complications of AGV surgery performed by glaucoma fellows of a tertiary eye center from eastern India. METHODS: This was a retrospective study based on electronic medical records. Thirty-five eyes operated with AGV by five glaucoma fellows from January 2016 to November 2020 were included. Best-corrected visual acuity, intraocular pressure (IOP), and number of antiglaucoma medications (AGMs) were the study outcome measures. RESULTS: The mean (±standard deviation) age of the patients was 40.5 (±19.7) years. The follow-up period was 24.37 (±13.01) months. Both complete success (IOP <21 mmHg without additional AGM) and qualified success (IOP <21 mmHg with an additional AGM) were achieved in eight eyes each (22.8%). Failure of the surgery was noted in 19 eyes (54.3%) as there was a need for repeat surgery for IOP control in 12 eyes and a persistent IOP spike (IOP >21 mmHg with AGM beyond 3 months) in seven eyes. Despite a high rate of failure of the primary surgery, with the consultants' intervention, there was statistically significant improvement in vision and IOP in all patients ( P < 0.01) at the last follow-up. CONCLUSION: AGV implantation is a challenging surgical skill to be acquired by the glaucoma fellows.

Real-world health-related quality of life outcomes for patients with resected stage III/IV melanoma treated with adjuvant anti-PD1 therapy.

BACKGROUND: While adjuvant therapy with anti-programmed cell death protein-1 (anti-PD1) for patients with resected stage III/IV melanoma has been shown to improve recurrence-free survival, the overall survival benefit remains uncertain. This study aims to evaluate the impact of adjuvant anti-PD1 therapy on the health-related quality of life (HRQOL) of patients with resected stage III/IV melanoma METHODS: Data was used from two melanoma registries in Australia and the Netherlands. Patients with resected stage III/IV melanoma treated with adjuvant anti-PD1 who completed a baseline and at least one post-baseline HRQOL assessment were included. HRQOL was assessed using the EORTC QLQ-C30 at baseline, 3, 6, and 12 months. Established thresholds were used for interpreting changes in QLQ-C30 scores. RESULTS: 92 patients were included. Mean symptom and functioning scores improved or remained stable at 12 months compared to baseline. However, a substantial proportion of patients experienced a clinically significant decline in role (39%, µ = -50.8), social (41%, µ = -32.7), or emotional (50%, µ = -25.1) functioning at 12 months compared to baseline. Younger patients were more likely to experience clinically significant deteriorations in role (OR=1.07, 95% CI: 1.02-1.13, p < 0.01) and social (OR=1.06, 95% CI: 1.01-1.11, p = 0.013) functioning. CONCLUSION: A significant proportion of patients with resected stage III/IV melanoma who received adjuvant anti-PD1 experienced clinically significant declines in role, social and emotional functioning at 12 months compared to baseline. This highlights the HRQOL issues that may arise during adjuvant anti-PD1 therapy which may require supportive care intervention.

Rare Immune-Related Adverse Events (irAEs): Approach to Diagnosis and Management.

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment landscape across many solid organ malignancies and form part of routine clinical practice in many tumours. As indications for monotherapy, doublet therapy and combination approaches with chemotherapy and targeted agents expand, clinicians must be aware of the wide range of possible immune-related adverse events (irAEs). Common toxicities, including rash, colitis, hepatitis and pneumonitis are well described in the literature, and have established diagnostic and management algorithms. Rarer toxicities, often with an incidence of less than 1%, are less defined. These syndromes can be poorly recognised, may take on a fulminant course and do not have established or evidence-based diagnostic and management strategies. As such, patients may experience increased morbidity, mortality and poorer outcomes, related both to these irAEs as well as how the treatment of these may affect the management of their underlying malignancy. In this review, we aim to explore the incidence, potential biomarkers, pathogenesis, diagnostic work-up and clinical sequelae of a selection of uncommon irAEs, with a focus on myocarditis, neurological and haematologic syndromes. Further prospective research is required to accurately define the incidence and pathogenesis of these conditions, with the aim of increasing clinician awareness of rare irAEs and to assist with a more personalised and mechanism-based approach to these syndromes.

Histopathologic correlates of trabecular meshwork in microincisional trabeculectomy.

PURPOSE: To report the histopathologic correlates of trabecular meshwork (TM) specimens procured by microincisional trabeculectomy (MIT) for different severities of glaucoma (early glaucoma: visual field mean deviation [MD] <-6 dB, moderate glaucoma: MD from - 6 to - 12 dB, and advanced glaucoma: MD <-12 dB). METHODS: TM specimens from four patients undergoing MIT with or without cataract surgery were analyzed by routine histopathology for structural changes. The number of cells, the number of cells with spindle-shaped nuclei suggestive of epithelial-mesenchymal transformation (EMT), and the distance between the trabecular beams were calculated using different tools on freely available ImageJ software using the line or pint/count tool. RESULTS: The TM specimens procured from two early and two advanced glaucoma cases showed decreasing cellularity and decreased compact arrangement of the trabecular beams in severe disease stages. The number of cells and preserved architecture in all four specimens were evident, with > 50 cells being present per section in all four cases despite the glaucoma being of advanced disease stage in two patients. CONCLUSION: The TM specimens obtained from MIT can be utilized for downstream analysis using different molecular methods for studying the molecular events in the tissue from early to severe glaucoma.

Trabeculectomy with concurrent intravitreal bevacizumab in neovascular glaucoma.

PURPOSE: To evaluate the clinical efficacy of concurrent intravitreal bevacizumab (IVB) injection with trabeculectomy with mitomycin-C (MMC) in neovascular glaucoma (NVG). METHODS: Patients with NVG who underwent trabeculectomy with concurrent IVB (group 1) and those who underwent IVB sequentially, followed by trabeculectomy with MMC (group 2) in 1-2 weeks between January 2021 and August 2022, were included in this retrospective hospital-based study. The need for medications for intraocular pressure (IOP) control at 6 months in the two groups was the primary outcome measured and compared between the groups. The association of the need for medications postoperatively with clinical variables was assessed using stepwise multivariate regression statistics. RESULTS: We finally included 40 patients ( n = 12 in group 1, n = 28 in group 2) with no significant differences in presenting age between groups. The IOP at 1 day and 1 week were not significantly different between groups though the IOP at 1, 3, and 6 months. IOP was lower in group 1 eyes with the 6-month IOP, being significantly lower in group 1, P = 0.05. Three eyes in group 1 and 11 eyes in group 2 required anti-glaucoma medications in the postoperative period. Multivariate regression identified preoperative IVB >3 (ß =0.7, P < 0.001) and recurrent vitreous hemorrhage (ß = 0.7, P = 0.004) as prognostic factors ( R2 = 40.6%) determining the need for anti-glaucoma medication (AGM) postoperatively in both groups. CONCLUSION: Concurrent IVB with trabeculectomy with mitomycin-C is a feasible alternative in patients with NVG with refractory high-presenting IOP. This may serve to address raised IOP as well as retinal ischemia, thereby improving surgical success rates in the most challenging NVG cases.

'Intraoperative predictors for clinical outcomes after microinvasive glaucoma surgery".

PURPOSE: To evaluate the clinical applicability of intraoperative predictors for surgical outcomes after gonioscopy-assisted transluminal trabeculotomy (GATT) and microincisional trabeculectomy (MIT). METHODS: Consecutive patients with primary, or secondary glaucoma (trauma, aphakic, or status post-retinal surgeries) with uncontrolled IOP>21mm Hg, who were scheduled to undergo GATT or MIT with or without significant cataract surgery, at a tertiary eye centre in East India between September 2021 to March 2023, were included. All surgeries were done by a single surgeon. Blanching and Trypan blue (0.4%) staining after intracameral injection using a 25 canula, were analysed in each video. The extent/pattern of blanching and blue staining in each eye was analysed objectively using an overlay of a circle with 12 sectors and a protractor tool to quantify the degrees or quadrants of blanching/staining. Multivariate regression was used to identify predictors for surgical success or the need for medications after surgery. RESULT: Of 167 eyes that were included (male: female- 134: 33), 49 eyes and 118 eyes underwent GATT and MIT, respectively, with 81 of 167 eyes undergoing concurrent cataract surgery. All eyes had a significant reduction in the number of medications after surgery. Blanching was seen in 154 of 167 eyes in a mean of 2±1.8 quadrants with 41% of eyes showing a blanching effect in >3 quadrants. Of 99 of 167 eyes where Trypan blue staining was assessed, staining in a venular, diffuse haze, or reticular pattern of staining was seen in 73 eyes, 26 eyes showed blue staining in >2 quadrants, with 16% staining in >3 quadrants. Surgical success was not predicted by the quadrants of blanching, blue staining, or other clinical variables (age, visual field, baseline intraocular pressure, type of surgery). The variables significantly predicting the need for medications included blanch (r = -0.1, p = 0.03), and blue staining (r = -0.1, p = 0.04) in <2 quadrants. CONCLUSIONS: Blanching and Trypan blue staining in >2 quadrants after GATT or MIT can serve as surrogate predictors for the need for medications. However more studies are mandated to find predictors for surgical success after GATT or MIT.

Visual Field Progression After Glaucoma Surgery in Pseudoexfoliation versus Primary Glaucoma.

Purpose: To compare visual field progression in severity-matched pseudoexfoliation glaucoma (XFG) and primary glaucoma after intraocular pressure (IOP) reduction by filtering surgery. Methods: Patients with XFG (n=32), primary open-angle glaucoma (POAG, n=33) or primary angle closure glaucoma (PACG, n=28) that underwent routine cataract and glaucoma filtering surgery by the same surgeon (APR) between May 2017 and September 2021, were included for this prospective study. Rate of progression (ROP) was determined using guided progression analysis and compared between XFG and primary glaucoma. Multivariate regression was done to analyse the factors responsible for progression in each group. Results: Visual field progression after surgery was noted in 48 eyes (n=11 XFG, 18 POAG and 19 PACG eyes) at a mean follow-up of 10±5.6 months after surgery with RVI seen in 18 of 48 eyes. The final IOP (p=0.8) and mean ROP (p=0.09) were not significantly different between XFG and primary glaucoma. The XFG eyes had a greater number of eyes (36%) showing an ROP worse than -5dB/yr, with 45% of eyes showing an IOP spike >5mm Hg, and a higher mean IOP spike between visits. The ROP in eyes with RVO and >5mm Hg IOP spikes was greater in XFG than in POAG or PACG. In the multivariate analysis, higher IOP fluctuations >5mm Hg, and associated retinal vein occlusions (RVO) were significant factors for visual progression greater than -5dB/year (R2=53.5%) in POAG and XFG eyes. Age, gender, baseline MD, and number of medications before surgery or at final follow-up did not influence visual progression rates in either group. Conclusion: A higher IOP fluctuation >5mm Hg and associated RVO were the significant factors predicting visual field progression after filtering surgery in XFG and POAG eyes. Control of both IOP-dependent and -independent mechanisms of VF progression is therefore essential in these eyes.

Outcomes of "Complex" Cataract Surgeries Performed by Long-Term Glaucoma Fellows in a Tertiary Eye Centre from Eastern India.

Purpose: To evaluate the outcomes of operating on "complex cataracts" by the glaucoma fellows. Patients and Methods: This was a retrospective study done at a tertiary referral eye care centre in eastern India. After obtaining IRB approval, a retrospective chart review of all patients who underwent "complex" cataract surgery by one of four long-term (2 years) glaucoma fellows between January 2016 and November 2020 was conducted. 'Complex' was defined as cataracts complicated with pseudoexfoliation syndrome, phacodonesis with or without blunt ocular trauma, posterior polar cataract, small pupil, co-existent corneal opacity or uveal coloboma, post-glaucoma filtering surgery, post-vitreoretinal surgery, co-existent glaucoma or post-laser iridotomy and monocular patients. Results: Out of a total of 677 eyes done by the glaucoma fellows during the study period, 83 eyes had complex cataract surgery and completed the six-week post-operative follow-up. Intraoperative surgical complications like posterior capsular rent or vitreous loss were noted in 36 of the cases. Thirty of the eyes were left aphakic. Despite a high rate of complications, the LogMAR best-corrected visual acuity (mean ± standard deviation) improved from the preoperative level of 1.7 (±0.5) to 1.0 (± 0.8) at post-operative six weeks, significant at p < 0.001. As far as the surgeon's experience was concerned-less than or more than a year since joining the fellowship-there was statistically no difference in the final visual acuity. The group with greater experience had shorter surgical time and lesser complications though this difference was not statistically significant. Conclusion: This is the first study in the literature reporting the outcomes of "complex" cataract surgery performed by glaucoma fellows. Though high rates of postoperative complications were noted in this study, the mean best-corrected visual acuity improved significantly in all eyes after the surgery.

'Microincisional trabeculectomy for glaucoma".

PURPOSE: To evaluate the short-term clinical outcomes of microincisional trabeculectomy (MIT), a new technique of ab-interno trabeculectomy. METHODS: Consecutive patients with open-angle glaucoma identified from the hospital database that underwent MIT with or without cataract surgery between September 2021 to June 2022 at a tertiary eye centre in East India, were screened. Those with a follow-up of < 6 months or with incomplete data were excluded. MIT was done ab-interno using microscissors and microforceps in 2-4 clock hours of the nasal angle via a temporal incision. The intraocular pressure (IOP) reduction at 6 months, and reduction in the number of medications after surgery were analysed. Surgical success (IOP>6 and <22 mm Hg), complications, angle features on anterior segment optical coherence tomography (ASOCT), and the need for additional surgeries were analysed. RESULTS: We included thirty-two eyes of 32 patients with open-angle glaucoma (including n = 9 eyes that underwent concurrent cataract surgery) with a preoperative mean IOP of 22 ±11.1 mm Hg and visual field index of 47±37.9%. All eyes achieved >30% IOP reduction, with a final IOP of 14±6.9 mm Hg at 6 months. Surgical success in 31 of 32 eyes with complete success seen in 28 eyes with none of the eyes requiring >1 medication for IOP control. Hyphema was seen in 4 eyes, while transient IOP spikes at 1 day-1 month were seen in 5 eyes, none of which required any additional interventions. One eye with persistent raised IOP at 1 month required incisional trabeculectomy for uncontrolled IOP with 2 medications. CONCLUSION: MIT, a new technique of ab-interno trabeculectomy, is effective in terms of IOP control and reduction in the number of medications while having fewer complications. Long-term studies comparing the efficacy of MIT with incisional trabeculectomy, or other procedures are warranted in the future.

Cataract versus combined surgery in pseudoexfoliation glaucoma.

Purpose: Pseudoexfoliation glaucoma (XFG) is often associated with a higher rate of intraoperative complications and failure. This study aims to compare the long-term clinical and surgical outcomes of cataract surgery alone versus combined surgery in XFG. This was a retrospective: comparative case series. Methods: All patients with XFG who underwent either cataract surgery alone [group 1: either phacoemulsification, PHACO/small-incision cataract surgery (SICS), n = 35] or combined surgery (group 2: phacotrabeculectomy, PHACOT or SICS + trabeculectomy, n = 46) from 2013 to 2018 by a single trained surgeon were screened and recalled for a detailed clinical examination, including Humphrey visual field analysis at 3-monthly intervals for a minimum of 3 years. Surgical success (intraocular pressure, IOP, <21 mm Hg and >6 mm Hg with (qualified success) or without medicines, complete success, survival rates, visual field changes, and need for additional procedures/medicines for IOP control were compared between groups. Results: A total of 81 eyes of 68 patients with XFG were included in this study (groups 1-35 eyes and groups 2-46 eyes each). Both groups achieved 27-40% IOP reduction from preoperative IOP levels, P < 0.001. Surgical success rates were similar in both groups (complete success 66% vs 55%, P = 0.4), qualified success 17% vs 24%, P = 0.8, in groups 1 and 2). Kaplan-Meier analysis showed a marginally better survival rate for group 1, 75% (55-87%), than group 2, 66% (50-78%), at 3 and 5 years which was not significantly different. The number of eyes that progressed at 5 years after surgery (5-6%) was similar in both groups. Conclusion: Cataract surgery can be as effective as combined surgery in XFG eyes with regards to final visual acuity, long-term IOP profile, and visual field progression, and complications/survival rates are comparable between the two procedures.

Causes of Immediate and Early IOP Spikes After Circumferential Gonioscopy-Assisted Transluminal Trabeculotomy Using ASOCT.

Purpose: To report the early postoperative causes of intraocular pressure (IOP) spikes after complete circumferential gonioscopy-assisted transluminal trabeculotomy (GATT) using anterior segment optical coherence tomography (ASOCT). Methods: This was retrospective interventional case series of patients who underwent circumferential GATT by a single surgeon (APR) from 2021 to 2022 at a tertiary eye care in East India and who developed IOP spikes at 1 day-2 weeks (immediate) or early (>2 weeks-2 months) after GATT. The intraocular pressure (IOP), glaucoma medications, and angle evaluation by ASOCT at 1 week, and 1 month were compared between the two groups. Results: Thirty-two eyes of 32 consecutive patients, aged 40±20.1 years (20 exfoliation glaucoma, 9 juvenile open-angle, and 3 developmental glaucoma), that developed IOP spikes between immediate (n=20) or early (n=12) IOP spikes after GATT, were included. Immediate postoperative spikes were seen in 20 eyes due to retained viscoelastic (n=8), hyphema (n=8) in uncontrolled hypertension, and peripheral anterior synechiae (PAS) (n=6) of which only one eye required medication at 2 months. Causes of immediate IOP spikes on ASOCT included an inverted/reattached trabecular shelf, iris strands in eyes with abnormal iris in developmental glaucoma, and PAS in 1-2 quadrants. Causes of early IOP spikes included PAS >3 quadrants (n=8), and hyperreflective fibrotic tissue over TM (n=4) with 50% requiring medications at 2 months. The ASOCT features predicting the need for medications were PAS >3 quadrants (OR=8.4[2.2-14.3], p=0.03) and fibrotic TM closure (OR=5.4, [3.6-10.2], p=0.003). One eye with macrohyphema 3 days after surgery owing to uncontrolled hypertension (owing to the stoppage of medicines), required additional incisional trabeculectomy within 1 month of surgery. Conclusion: Immediate IOP spikes are mostly self-resolving as opposed to early IOP spikes >2 weeks that require medications after GATT. Gonioscopic PAS >3 quadrants, and fibrotic TM closure were the main identifiable ASOCT causes predicting the need for medications after GATT.

Secondary glaucoma following vitreo-retinal surgeries.

Vitreoretinal surgeries either in the form of external compression by buckles or by increasing the intraocular volume by tamponades can cause a significant rise in intraocular pressure (IOP), causing glaucoma to be one of the most common consequences of vitreoretinal surgeries despite improved surgical techniques. Identifying the mechanism that causes the raised IOP is crucial as the management of glaucoma can differ accordingly. Intravitreal (IVT) injections in the form of IVT steroids or anti-vascular endothelial growth factor (anti-VEGF) injections can also cause a significant rise in the IOP and effect, especially the glaucomatous eyes, which are already predisposed. Not just the overlapping clinical features make the diagnosis confusing but also associated scarring of the conjunctiva, and the presence of episcleral hardware in some cases due to scleral buckle make the surgical management of glaucoma in these eyes very challenging. In this review, we describe in detail the various mechanisms causing secondary glaucoma post vitreoretinal surgeries with a focus on how to distinguish between them. We also discuss the possible consequences of anti-VEGF agents on IOP, various surgical challenges, and modifications with newer surgical options in the management of this refractory glaucoma.

'Progressive peripheral anterior synechiae in iridocorneoendothelial syndrome- a crawling disaster'.

Purpose: Iridocorneal endothelial (ICE) syndrome is well known to cause refractory glaucoma in young adults. Commonly acclaimed mechanism for trabeculectomy failure in these cases include accelerated subconjunctival fibrosis, abnormal endothelial proliferation, and closure of ostium. In the following article, we present a case of Iridocorneal endothelial syndrome that presented with refractory glaucoma after trabeculectomy due to rapidly progressive peripheral anterior synechiae causing angle closure and corneal decompensation that mandated a tailored surgical approach of management. Methods: This is a descriptive case report based on electronic medical records, patient observation, surgical intervention, and follow-ups. Case description: A thirty-eight-year-old-male presented to us with signs suggestive of iridocorneal endothelial syndrome with gonioscopy revealing peripheral anterior synechiae (PAS) over four clock-hours temporally. Uncontrolled intraocular pressure (IOP) despite maximal medical therapy mandated augmented trabeculectomy with anti-fibrotics. The bleb failed within 3 weeks of trabeculectomy, with evidence of progressive crawling PAS causing endothelial decompensation and raised IOP. He underwent Ahmed glaucoma valve (AGV) implant surgery with viscosynechiolysis and sectoral iridectomy under antiviral cover. This helped control IOP and retain corneal clarity, with no recurrence of PAS in the affected area. Conclusion: Progressive peripheral synechiae in ICE syndrome can cause early bleb failure and refractory glaucoma. Careful viscosynechiolysis and sectoral iridectomy alongside a second implant surgery can help salvage visual functions and preserve corneal clarity while preventing further progression of PAS in these eyes.

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma.

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.

Trabeculectomy: Does It Have a Future?

The trabeculectomy (TRAB) procedure has undergone various modifications to increase the long-term surgical success and safety profiles. The main issues with TRAB include short and long-term complications, that are more common with the concomitant use of anti-fibrotic agents. While many surgeons have predicted the demise of trabeculectomy amidst newer non-penetrating glaucoma surgeries, it is still the gold standard procedure for patients with an advanced or rapidly progressing disease and for those patients who need very low intraocular pressures. This review article is unique in summarizing the evolution of trabeculectomy and its efficacy compared to neoteric shunt procedures while trying to predict if trabeculectomy has a future in the modern surgical world. We have compared the outcomes and complications of trabeculectomy to all the surgical procedures available to date and have tried to evolve an algorithm to help surgeons to decide on their preferred technique.

In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.

In mice and humans with cancer, intravenous 13C-glucose infusion results in 13C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD+ by the ETC. However, 13C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD+ independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13C labeling from multiple nutrients.

Role of Mitochondrial Mutations in Ocular Aggregopathy.

Background Mitochondria are essential cellular organelles that are responsible for oxidative stress-induced damage in age-dependent neurodegenerations such as glaucoma. Previous studies have linked mitochondrial DNA (mtDNA) mutations to cellular energy shortages that result in eye degeneration. Methodology To look for nucleotide variations in mtDNA in exfoliation syndrome/glaucoma (XFS/XFG), we performed a polymerase chain reaction (PCR) to amplify the entire coding region of the mitochondrial genome from peripheral blood of XFS/XFG (n = 25) patients and controls (n = 25). Results This study identified a total of 65 variations in XFS/XFG patients, of which 25 (38%) variations were non-synonymous single-nucleotide polymorphism (nsSNPs). Out of 25 nsSNPs, seven (five nsSNP in MT-ND4 and two in MT-ATP6 gene) were predicted as pathogenic using four different software, namely, SIFT, Polyphene2, mutation taster, and MutPred2. The pathogenic nsSNPs were then subjected to structural change analysis using online tools. Conclusions The pathogenic nsSNPs were found in both proteins' transmembrane domains and were expected to be conserved, but with lower protein stability (ΔΔG <- 0.5), indicating a possibly harmful effect in exfoliation. However, three-dimensional protein analysis indicated that the predicted mutations in MT-ND4 and MT-ATP6 were unlikely to alter the protein function.

Targeting the translational machinery in gastrointestinal stromal tumors (GIST): a new therapeutic vulnerability.

Although KIT-mutant GISTs can be effectively treated with tyrosine kinase inhibitors (TKIs), many patients develop resistance to imatinib mesylate (IM) as well as the FDA-approved later-line agents sunitinib, regorafenib and ripretinib. Resistance mechanisms mainly involve secondary mutations in the KIT receptor tyrosine kinase gene indicating continued dependency on the KIT signaling pathway. The fact that the type of secondary mutation confers either sensitivity or resistance towards TKIs and the notion that secondary mutations exhibit intra- and intertumoral heterogeneity complicates the optimal choice of treatment in the imatinib-resistant setting. Therefore, new strategies that target KIT independently of its underlying mutations are urgently needed. Homoharringtonine (HHT) is a first-in-class inhibitor of protein biosynthesis and is FDA-approved for the treatment of chronic myeloid leukemia (CML) that is resistant to at least two TKIs. HHT has also shown activity in KIT-mutant mastocytosis models, which are intrinsically resistant to imatinib and most other TKIs. We hypothesized that HHT could be effective in GIST through downregulation of KIT expression and subsequent decrease of KIT activation and downstream signaling. Testing several GIST cell line models, HHT led to a significant reduction in nascent protein synthesis and was highly effective in the nanomolar range in IM-sensitive and IM-resistant GIST cell lines. HHT treatment resulted in a rapid and complete abolishment of KIT expression and activation, while KIT mRNA levels were minimally affected. The response to HHT involved induction of apoptosis as well as cell cycle arrest. The antitumor activity of HHT was confirmed in a GIST xenograft model. Taken together, inhibition of protein biosynthesis is a promising strategy to overcome TKI resistance in GIST.