Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity.

POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMB in 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high ≥10 mutations/Mb (mut/Mb) or TMB-low <10 mut/Mb. TMB was significantly highest in tumors with "POLE ExoD driver plus POLE Variant" (colorectal cancer and endometrial cancer, P < 0.001; ovarian cancer, P < 0.05). TMB increased with additional POLE variants (P < 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the "POLE ExoD driver plus POLE Variant" tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes. SIGNIFICANCE: Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.

Comparative study of visual outcome of newly designed scleral tuck lens and suture-fixated lens for rehabilitation of aphakia in various aetiologies.

Purpose: Visual rehabilitation in aphakia can be performed using several modalities. However, these modalities could be either technically difficult or expensive. Herein, we developed a scleral tuck lens to provide a simple and cost-effective solution for aphakia and compared its outcome with standard methods. Methods: A specially designed posterior chamber self-sustaining lens was implanted in patients with aphakia without capsular support because of different primary etiologies. The visual outcomes, as well as intraoperative and postoperative complications, were examined. The data were retrieved from electronic medical records, and visual outcome and complication rates were compared. The outcomes were also compared according to the etiology and age groups (pediatric and adults). Results: We found significant improvement in preoperative and postoperative visual outcome. We did not find any significant difference in visual outcome amongst suture-supported scleral fixated lens with scleral tuck lens. Conclusion: Satisfactory visual outcomes were noted with minimal complications; and comparable with gold standard suture fixated lens, however long-term follow-up is required.

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.

DNA repair vulnerabilities are present in a significant proportion of cancers. Specifically, germline alterations in DNA repair not only increase cancer risk but are associated with treatment response and clinical outcomes. The therapeutic landscape of cancer has rapidly evolved with the FDA approval of therapies that specifically target DNA repair vulnerabilities. The clinical success of synthetic lethality between BRCA deficiency and poly(ADP-ribose) polymerase (PARP) inhibition has been truly revolutionary. Defective mismatch repair has been validated as a predictor of response to immune checkpoint blockade associated with durable responses and long-term benefit in many cancer patients. Advances in next generation sequencing technologies and their decreasing cost have supported increased genetic profiling of tumors coupled with germline testing of cancer risk genes in patients. The clinical adoption of panel testing for germline assessment in high-risk individuals has generated a plethora of genetic data, particularly on DNA repair genes. Here, we highlight the therapeutic relevance of germline aberrations in DNA repair to identify patients eligible for precision treatments such as PARP inhibitors (PARPis), immune checkpoint blockade, chemotherapy, radiation therapy and combined treatment. We also discuss emerging mechanisms that regulate DNA repair.

A prospective cohort study on the epidemiology of ocular trauma associated with closed-globe injuries in pediatric age group.

Purpose: To study the epidemiology of mechanical ocular trauma and closed globe injury using the Birmingham Eye Trauma Terminology System in patients belonging to the pediatric age group. Methods: This work involved a prospective cohort study of all ocular trauma patients (pediatric age group) registered between 2002 and 2017 at the ocular trauma care center. The data were collected using the international ocular trauma society form through our online MIS data and exported to the Excel sheet. The statistical analyses including the univariate analysis and cross tabulation were carried out using SPSS 22 software. Results: Our cohort consisted of 12687 patients with mechanical ocular trauma. There were 7546 (59.4%) eyes with open globe ocular injuries and 5328 (41.9%) with closed globe injuries. Of all closed globe injury patients, 1010 (19.0%) belonged to the pediatric age group (0-18 years), including 690 males (68.3%) and 320 females (31.7%). The mean age of the patients was 10.2 ± 5.1 years. Of all closed globe injuries, 692 (68.5%) were closed globe contusion and 318 (31.5%) were lamellar laceration. Conclusion: Closed globe injury is an important in cause of vision loss in children (24% <1/60). The condition is more prevalent in males and >51.7% in children under 10 years of age. The treatment has significant impact on the visual outcome in patients belonging to the pediatric age group.

Innovative cost-effective method to repair lacrimal cannaliculi laceration - finding proximal end and stent.

Purpose: To explore a new technique to find out the proximal end of lacerated canaliculi and a new material for the stent. Methods: Surgery was performed on 9 eyes of 9 patients using a 5/0 prolene suture needle as a modified probe. Prolene suture was inserted as a stent and left in place for two months. All the data were analyzed. Results: The surgery was successful in all cases and the prolene were removed after two months. The mean follow-up time after the tube removal was 3.8 months (range 3-6 months). No other complications associated with the prolene sutures were noticed except for epiphora and corneal irritation in three cases. All the tubes were removed successfully without any difficulty. No iatrogenic injuries occurred during prolene removal. Conclusions: The reported surgical technique is a very cost-effective option for lacrimal canalicular laceration repair.

Comparative study of visual outcome between open- and closed-globe injuries following surgical treatment of traumatic cataract in children.

OBJECTIVE: To compare final visual outcomes of surgically treated traumatic cataract between open-globe and closed-globe injuries in children, as classified by the Birmingham Eye Trauma Terminology system. METHODS: This is an observational cohort study with permission from Hospital Ethical Committee. We enrolled children meeting specific inclusion criteria, examined their eyes to review any co-morbidities due to trauma, performed surgery for traumatic cataracts, and implanted lenses. The patients were re-examined postoperatively. We classified the cases of traumatic cataract as either open-globe (Group 1) or closed-globe (Group 2) according to the Birmingham Eye Trauma Terminology system and compared visual acuity. RESULT: Our study cohort of 1076 eyes with traumatic cataracts included 405 eyes in Group 1 and 671 in Group 2. Postoperatively, the visual acuity was >20/60 in 223 (55.3%) and 377 (56.3%) operated eyes in Groups 1 and 2, respectively ( p < 0.001, analysis of variance). With further follow-up, >20/60 vision was significantly higher in Group 2 as compared to Group 1 (odds ratio = 1.61; 95% confidence interval = 0.85-3.02). Overall, 600 eyes (55.7%) regained final visual acuity >20/60. CONCLUSION: Closed-globe injury has more favourable prognosis for the satisfactory (>20/60) visual recovery after effective management of traumatic cataracts in children.

Pediatric ocular trauma score as a prognostic tool in the management of pediatric traumatic cataracts.

OBJECTIVE: To introduce and validate the pediatric ocular trauma score (POTS) - a mathematical model to predict visual outcome trauma in children with traumatic cataract METHODS: In this retrospective cohort study, medical records of consecutive children with traumatic cataracts aged 18 and below were retrieved and analysed. Data collected included age, gender, visual acuity, anterior segment and posterior segment findings, nature of surgery, treatment for amblyopia, follow-up, and final outcome was recorded on a precoded data information sheet. POTS was derived based on the ocular trauma score (OTS), adjusting for age of patient and location of the injury. Visual outcome was predicted using the OTS and the POTS and using receiver operating characteristic (ROC) curves. RESULTS: POTS predicted outcomes were more accurate compared to that of OTS (p = 0.014). CONCLUSION: POTS is a more sensitive and specific score with more accurate predicted outcomes compared to OTS, and is a viable tool to predict visual outcomes of pediatric ocular trauma with traumatic cataract.

Spontaneous dislocation of lens bag with acrylic lens after uneventful cataract surgery - unusual complication of cataract surgery.

INTRODUCTION: Spontaneous dislocation of intraocular lens with bag is rare. METHODS: We report a case of a 56-year-old male who presented with spontaneous anterior dislocation of an in-the-bag intraocular lens 3 years after manual small incision cataract surgery. He had undergone manual small incision cataract surgery with foldable acrylic intraocular lens implantation, and 18 months after cataract surgery ND: YAG capsulotomy with uneventful post capsulotomy follow-up. 17 months after capsulotomy, the patient presented with sudden decrease of vision. On anterior segment examination, the intraocular lens with bag was dislocated into the anterior chamber. RESULT: It was managed with intraocular lens explantation with bag, anterior vitrectomy and sclera fixated intraocular lens. CONCLUSION: Spontaneous intraocular lens dislocation with bag is possible after 1.5 years of uneventful surgery which may be managed using different techniques.

Lens siderosis resulting from a small intralenticular metallic foreign body.

We report a rare case of lens siderosis with an undetectable intraocular foreign body by imaging. An 8-year-old boy presented with diminution of vision in the left eye since 3 months. His parents gave a preceding uncertain history of a foreign body injury to his left eye 3 months ago while playing. Presenting visual acuity in the left eye was perception of hand movements. Slit-lamp examination revealed a total white cataract with brownish-pigmented spots on the anterior capsule of the lens, but no intraocular foreign body was found. There was also no evidence of an intraocular foreign body on ultrasonography. Patient underwent cataract extraction with intraocular lens implantation. During the operation, a small (2×1×1 mm in size) intralenticular foreign body of metal material was found and removed carefully with a magnet. The patient regained 20/30 vision after surgery.

Maximizing the visual outcome in traumatic cataract cases: The value of a primary posterior capsulotomy and anterior vitrectomy.

Objective: The objective was to provide evidence-based care for patients with traumatic cataracts, we assessed whether a posterior capsulotomy and anterior vitrectomy, as part of the primary surgical procedure, could be a positive predictor of final visual outcome. Materials and Methods: This is a prospective randomized control trial. Patients presenting at our hospital between January 2010 and December 2012 having ocular trauma and traumatic cataracts were enrolled, according to the inclusion criteria. We enrolled two groups: Those with and without primary posterior capsulotomy and vitrectomy. Information regarding demographic and ocular trauma were collected using the World Eye Trauma Registry form at the first visit and follow-up, and specific information was collected for both the group who underwent posterior capsulectomies and vitrectomies as a part of the primary procedure, and the control group. Data were analyzed to evaluate the predictive value of primary posterior capsulectomy and anterior vitrectomy. Results: We enrolled 120 cases, 60 in each group, comprising 31 females and 89 males. When all other variables were controlled for, the visual outcome (best corrected visual acuity) differed significantly (P < 0.001) between the groups. Conclusion: Performance of posterior capsulectomy and anterior vitrectomy as part of the primary procedure improves the final visual outcome.

Visual outcome of cataract in pediatric age group: does etiology have a role.

PURPOSE: To compare visual outcome results among traumatic and nontraumatic groups of eyes with cataract in the pediatric age group. METHOD: This is a retrospective cohort study. This study comprised a consecutive series of pediatric patients under 5 years of age with unilateral congenital, developing, or traumatic cataract who underwent surgery between January 1999 and April 2012 at Drashti Netralaya, Dahod. Records were retrieved from the medical record department. Patients were grouped as traumatic or nontraumatic and their demographics, cataract type, presenting symptoms, surgical intervention, and postoperative visual acuity follow-up refractive changes were recorded and compared. RESULTS: A total of 128 eyes of 128 children under 5 years of age were included with unilateral cataract. A total of 85 (66.4%) were traumatic and 43 (33.3%) nontraumatic. The age at surgery ranged from 1 to 60 months. Eyes were grouped by etiology: group 1- traumatic 85 (66.4%) eyes that had traumatic cataracts. Group 2 non-traumatic 43 (33.3%) eyes that had congenital, developmental or complicated cataracts. The mean follow-up time was 117 days. Finally, 22 (51.1%) group 1 patients and 40 (47.1%) group 2 patients achieved visual acuity better than 20/200 (p = 0.000). CONCLUSIONS: Surgical treatment with intraocular lens implantation for children with congenital, developmental, or traumatic cataract is an effective treatment for visual rehabilitation. Visual outcome is significantly better (p = 0.005) in case of nontraumatic cataracts than traumatic cataracts.

Cannula dacryocystorhinostomy: a simple, innovative and cost-effective method of lacrimal surgery.

To compare our innovative, cost-effective method of lacrimal surgery with other methods. A prospective cohort study. The study included 80 eyes of 80 consecutive patients who presented to our clinic between January 2009 and December 2011. The patients underwent surgery using a new technique with a specially designed cannula and were followed according to our protocol. Patency on irrigation. Of the 80 cases enrolled, the procedure was successful in 52.5 % with a mean follow-up of 247.2 days. The success rate was significantly affected by the preoperative conditions (p = 0.001) and follow-up duration (p = 0.006). This simple innovative technique was cost-effective and the results were comparable with those of other techniques.

Ocular Trauma Score as a predictor of final visual outcomes in traumatic cataract cases in pediatric patients.

PURPOSE: To validate the predictive value of the Ocular Trauma Score (OTS) in children with traumatic cataract. DESIGN: Retrospective cohort study. SETTING: Tertiary eye care center at nexus of Gujarat, Madhya Pradesh, and Rajasthan states, central Western India. METHODS: After meeting inclusion criteria, eyes with traumatic cataract were enrolled and examined to review comorbidities caused by trauma. Surgery was performed for traumatic cataract, intraocular lenses were implanted, and patients were treated for amblyopia, as applicable. Patients were reexamined 6 weeks postoperatively. Based on ocular trauma described according to the Birmingham Eye Trauma Terminology System, the patients were divided into 2 traumatic cataract groups: open-globe injury and closed-globe injury. The relationship between final corrected distance visual acuity (CDVA) and demographic and clinical variables was analyzed. Visual outcomes were predicted using the OTS, and the predictions were compared with actual outcomes using statistical tests. RESULTS: The study enrolled 354 children. Six weeks postoperatively, the CDVA was better than 20/200 in 181 eyes (63.0%) and 20/40 or better in 110 eyes (38.4%) in the open-globe group and better than 20/200 in 36 eyes (53%) and 20/40 or better in 15 eyes (22.4%) in the closed-globe group. The differences between the groups were not significant (P=.143). Of all eyes, 214 (61.3%) achieved a final CDVA of better than 20/200 and 123 eyes (35.3%), of 20/40 or better. CONCLUSION: The OTS was a reliable predictor of the final visual outcome in cases of pediatric traumatic cataract.

OcularTrauma Score: a useful predictor of visual outcome at six weeks in patients with traumatic cataract.

OBJECTIVE: To validate the predictive value of the Ocular Trauma Score (OTS) in injury cases with traumatic cataracts. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 787 eyes. METHODS: A total of 787 eyes of 787 subjects with traumatic cataracts were enrolled using specific inclusion criteria. The eyes were examined to review comorbidities caused by trauma. Surgery was performed for traumatic cataracts, lenses were implanted, and patients were treated for amblyopia, as applicable. The patients were reexamined 6 weeks postoperatively. On the basis of ocular trauma described according to the Birmingham Eye Trauma Terminology System, the patients were divided into 2 traumatic cataract groups: open globe injury and closed globe injury. The relationship of visual acuity (VA) with demographic and clinical variables was analyzed. The visual outcomes were predicted using the OTS, and the predictions were compared with the actual outcomes using statistical tests. MAIN OUTCOME MEASURES: Visual acuity. RESULTS: At 6 weeks postoperatively, 245 eyes (31%) had a VA ≥ 20/40 and 480 eyes (61.0%) had a VA >20/200. The OTS prediction was not significantly different when compared with actual visual outcome at 6 weeks postoperatively in all OTS categories. CONCLUSIONS: The relationship of VA at 6 weeks with demographic and clinical variables was analyzed. In this study, the OTS was found as a reliable tool to predict visual outcome in cases of traumatic cataracts 6 weeks postoperatively.

Visual outcome of traumatic cataract in pediatric age group.

PURPOSE: To review results of traumatic cataracts in children. METHODS: This is a retrospective cohort study done at a tertiary eye care center at the junction of Gujarat, Madhya Pradesh, and Rajasthan states in central western India. We enrolled children with specific inclusion criteria, examined their eyes to review the comorbidities due to trauma, performed surgery for traumatic cataracts, and implanted a lens, treating amblyopia if applicable. The patients were re-examined 6 weeks postoperatively. We divided the traumatic cataract cases into open-globe (group 1) and closed-globe (group 2) groups according to the ocular trauma based on the Birmingham Eye Trauma Terminology System and compared the determinants of visual acuity. RESULT: Our cohort of 354 eyes with traumatic cataracts in children included 287 eyes in group 1 and 67 in group 2. Six weeks postoperatively, the visual acuity in the operated eye was >20/200 in 181 (63%) and =20/40 in 109 (38%) eyes in the open-globe group and >20/200 in 36 (53%) and =20/40 in 16 (22.4%) eyes in the closed-globe group (p = 0.143), and the difference between the groups was not significant in children. Overall, 125 (35.3%) eyes gained a visual acuity at 6 weeks of =20/40 and >20/200 in 214 (61.3%) cases. CONCLUSIONS: Satisfactory visual outcome can be achieved in children with traumatic cataracts, with no significant difference found among open- and closed-globe injuries in the pediatric age group.