Acute keratoconjunctivitis associated with tisotumab vedotin-tftv for metastatic cervical cancer.

Purpose: Tisotumab vedotin-tftv, an antibody-drug conjugate, was recently FDA-approved for metastatic or treatment-resistant cervical cancer. A high rate of ocular comorbidities was seen in pivotal clinical trials. We present a case of a 46-year-old woman who experienced prolonged ocular surface adverse effects associated with use of the drug. Observations: Our patient was initiated on tri-weekly 2mg/kg infusions of tisotumab for metastatic cervical cancer. Baseline ophthalmic exam was unremarkable. One week after the second infusion, she developed bilateral eyelid edema and chalazia managed with initiation of lid hygiene measures. Preceding the fourth infusion, she developed unilateral pseudomembranous conjunctivitis and bilateral meibomitis that improved with topical corticosteroids. The fifth infusion was subsequently given at a reduced dosage. Despite this, she experienced decreased vision, bilateral diffuse punctate epitheliopathy, and subepithelial haze. The patient was subsequently referred to the cornea service. Symptomatic and clinical improvement was initially achieved with the addition of bandage contact lenses (BCLs). As the keratitis improved, topical steroids were tapered and BCLs removed. She is currently maintained on a regimen that includes eyelid hygiene, preservative-free artificial tears, punctal plugs, autologous serum tears, and lifitegrast. Given the severity of the ophthalmic adverse effects, however, further tisotumab infusions were held. Conclusions and importance: This is a report of a patient with prolonged ocular surface disease following the initiation of tisotumab, significant enough to lead to discontinuation. Antibody-drug conjugates are an emerging class of therapeutics across oncology, and ophthalmologists should be aware of their potential effects on ocular health.

Ophthalmology Residency Match in the Covid-19 Era: Applicant and Program Director Perceptions of the 2020-2021 Application Cycle.

OBJECTIVE: To evaluate the experiences and preferences of ophthalmology residency applicants and program directors (PDs), with emphasis on the effect of COVID-19 as well as recent changes on the application process. DESIGN: Cross-sectional, online survey. PARTICIPANTS: All applicants to the Bascom Palmer Eye Institute ophthalmology residency program, and all United States ophthalmology residency PDs, during the 2020-2021 application cycle. METHODS: An online survey was distributed to applicants and program directors of the 2020-2021 ophthalmology residency application cycle.Main Outcome Measures: Applicant demographics, application submissions, interview experiences, financial considerations, match results, and suggestions for improvement of the application process. RESULTS: Responses were obtained from 205 applicants (34.9% response rate) and 37 PDs (30.3%). A successful match into an ophthalmology residency was achieved by 144 (83.7%) applicants. Applicants applied to (mean ± SD) 79.7 ± 22.8 ophthalmology residency programs, received 13.1 ± 8.9 invitations to interview, and attended 11.1 ± 5.8 interviews. Most applicants (N = 126; 71.2%) and PDs (N = 22; 78.6%) expressed a preference for in-person interviews over virtual interviews. If given a choice regarding the future direction for interviews, most applicants were unsure (N = 68; 38.4%) or would prefer to hold interviews virtually (N = 62; 35.0%); PDs felt that interviews should go back to being in-person (39.3%) or were unsure (28.6%). Most PDs (N = 21; 72.4%) reported an increased number of applications received by their respective programs this year compared to previous years. While applicants (N = 108; 61.0%) mostly felt that there should not be a cap on the number of applications, 19 (67.9%) PDs supported a limit on application numbers. Applicants spent an average (SD) of $2320.96 ($1172.86) on the application process this year, which is significantly less than 2018-2019 data. CONCLUSIONS: The ophthalmology residency application process was especially complex during the COVID-19 pandemic. Although many applicants and PDs were glad that interviews were held virtually this year, they were less certain regarding future years. The virtual format led to a significantly lower financial burden for applicants and may lead some to prefer this format in the future; if a hybrid model is offered for virtual/in-person interviews, these two interview modes should be compared equally.

Transparency in the Ophthalmology Residency Match: Background, Study, and Implications.

Background Medical students are applying to dramatically more ophthalmology residency programs than in the past, causing an increased administrative burden for programs and financial harm to students. This study considers the background of this situation and looks at how a lack of transparency surrounding potential residency match filters contributes. Furthermore, this study raises several potential solutions to this lack of transparency that may increase the functionality of the ophthalmology residency match. Objective The purpose of this study was to determine the availability and consistency of potential ophthalmology residency match filters through training program websites and the American Medical Association's (AMA) Residency & Fellowship Database (FREIDA). Methods This study was a cross-sectional observational study of ophthalmology residency program websites and AMA's FREIDA database entries. For 119 ophthalmology residency programs, five potential filters were evaluated for both availability and consistency on individual residency websites and FREIDA. These filters were: (1) whether a program required a minimum United States Medical Licensing Examination (USMLE) Step 1 score; (2) minimum number of letters of recommendation required; 3) whether a minimum USMLE Step 2 score was required; (4) if the program accepts the Comprehensive Osteopathic Medical Licensing Examination (COMLEX) sequence in lieu of the USMLE; and (5) ability of the residency to sponsor a visa (J-1, H-1B, or F-1). Each program's website and FREIDA entry were independently evaluated by two authors to increase validity, with a third author brought in to break the tie in case of a disagreement. Results Only two ophthalmology residency programs had information about all five filters both available and consistent on their website and FREIDA. Inter-reviewer reliability was 92.5%. Conclusions Information about potential filters used in the ophthalmology residency match is neither publicly available nor consistent. This lack of transparency may contribute to the phenomenon of medical students applying to dramatically more ophthalmology residency programs. A standardized database of these filters is needed to increase transparency to applicants, which may reduce the expenses of medical students and the workload of program directors.

POSITIVE RESULTS BIAS AND IMPACT FACTOR IN RETINA CLINICAL TRIALS 2016 to 2019.

PURPOSE: To assess for a positive results bias in recently published randomized controlled trials in the field of vitreoretinal disease. METHODS: A bibliometric analysis was conducted examining randomized controlled trials published in the field of retina between January 1, 2016, and December 31, 2019. Studies were classified as positive result or negative result based on the statistical significance of their primary outcome. Publication date and sample size were documented. These variables were compared against Journal Citation Reports Impact Factor in the year of publication. RESULTS: Two hundred and eighty-eight randomized controlled trials from 64 unique journals were included and analyzed. One hundred and eighty-five (64.2%) studies were classified as positive result, and 103 (35.8%) studies were classified as negative result. There was no association between impact factor and positive result. Studies classified as positive result had larger sample sizes, and higher sample size was associated with higher impact factor. CONCLUSION: These results do not support the presence of a recent positive results bias in retina randomized controlled trials. This is reassuring, although several factors could be contributing to this finding including studies that were conducted but never submitted and selective reporting of outcomes. Thus, it will be important to remain cognizant of potential publication biases moving forward.

Perceptions of a Virtual Interview Exercise for Ophthalmology Residency Applicants.

Importance In-person interviews have traditionally been considered a crucial component of the residency application process. Virtual interviews (VIs) became the standard format for the 2020 to 2021 application cycle due to the novel coronavirus disease 2019 (COVID-19) pandemic. VIs offer a new perspective and challenge to this process which warrants unique considerations and further understanding of effects on applicants. Objective This study aimed to assess the perceived efficacy of a VI preparedness exercise for ophthalmology residency applicants in the 2021 residency application cycle. Design, Setting, and Participants A cross-sectional survey was distributed online. All participants in a mock VI exercise conducted via video-telecommunication technology were invited to complete the survey. Data collection occurred from October 12, 2020, to November 2, 2020. A follow-up survey after a match results released was distributed to all participants and data collection occurred from February 18, 2021, to February 25, 2021. Main Outcome and Measures Applicant demographics, comfort, and attitudes toward VIs and VI practice were the primary measurements of this study. Results Responses to the initial survey were received from all 35 participants (100%) in the VI mock interviews. There was a statistically significant difference between the pre- and postinterview responses for "How prepared do you feel for virtual interviews with residency programs?" ( p = 0.0003) and "How likely are you to practice virtual interviews with someone you know?" ( p = 0.0023). Participants reported feeling more prepared for VIs with residency programs after the mock interview ( p = 0.002). A greater proportion of participants responded with "Very Likely" after the mock interview in comparison to before the interview to the questions "How likely are you to practice interviews with someone you know?" ( p = 0.039) and "How likely are you to practice virtual interviews in the same room/area as you will during the official interview season?" ( p = 0.021). Of the 35 original participants, 20 completed the follow-up survey. There were an equal number of participants who responded either "Helped Somewhat" ( n = 9) or "Helped Greatly" ( n = 9) to "How much did the VI mock exercise help you for the actual interview season?" in the follow-up survey. The majority of follow-up survey respondents (17/20) reported that they had additional practice in the virtual environment for interviews after the VI mock exercise. There was no significant difference in perceived helpfulness of the VI mock exercise during the actual interview season between matched and unmatched participants. Conclusion and Relevance As residency applicants prepare for future VIs, practice and adequate preparation will be essential. In this study, implementation of a VI preparedness exercise had a positive impact on applicants' perception of their preparedness and intention to practice the format in the future.

COVID-19 and the Ophthalmology Residency Match: Data from Applicants' Perspectives.

Background The coronavirus disease 2019 (COVID-19) pandemic has had a profound impact on medical education, particularly for those applying to residency programs in 2020 to 2021. This study describes the challenges for potential ophthalmology residency applicants so that residency leadership can make informed decisions about changes to the process. Methods A survey was distributed electronically via social media and medical school ophthalmology interest groups from June 18, 2020 to July 2, 2020 to individuals interested in applying to ophthalmology residency in the United States. Survey questions included demographics and perceived impacts of COVID-19 on ability, confidence, intention to apply, and perceptions toward changes in the application process for the 2020 to 2021 ophthalmology residency application cycle. Results One-hundred sixteen total responses were received. Eighty-six responses (74%) were from individuals intending to apply in the 2020 to 2021 application cycle. Most respondents (86%) felt that their application would be affected by COVID-19 with 51% feeling less confident. Only four (5%) felt that they could adequately compile a rank list following a video interview, and over half (51%) anticipated applying to more programs than they originally intended. Academic plans of seven (8%) respondents were significantly altered via deferral of application or cancellation of a research year. Thirty-nine (45%) students reported delayed ophthalmology electives, with less than half (41%) feeling that they had adequate clinical exposure to be prepared for residency. Conclusion The COVID-19 pandemic has had a substantial impact on the 2020 to 2021 ophthalmology residency application cycle. As stakeholders begin to approach this cycle, these findings will help them make effective and informed decisions to create the best overall experience for all involved.

FACE COVERING ADHERENCE IN AN OUTPATIENT OPHTHALMOLOGY CLINIC DURING COVID-19.

Purpose: The purpose of this report is to examine the proper use of face coverings by patients entering one of several outpatient ophthalmology clinics during the coronavirus disease 19 (COVID-19) global pandemic.Methods: Proper face-covering use was documented for all patients entering thirteen different outpatient ophthalmology clinics in Western Pennsylvania in July 2020. Gender and age of all patients were collected. Patients who were not wearing or improperly wearing a face covering were provided one with instructions on proper use.Results: Over 5 days, 43 of 2286 patients (2%) that entered one of the participating clinics were observed not or incorrectly wearing face coverings. The average age of patients who were not correctly wearing a face covering was significantly higher. There was no association between gender and face-covering use.Conclusion: As case counts continue to rise, effective use of face coverings in healthcare settings remains essential. The high percentage of adherence presented in this report is reassuring. However, the elderly, a high-risk population, may require additional, targeted educational measures to increase face-covering adherence.

Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by cytopenia and a propensity to develop acute myeloid leukemia (AML). The management of lower-risk (LR) MDS with persistent cytopenias remains suboptimal. Eltrombopag (EPAG), a thrombopoietin receptor agonist, can improve platelet counts in LR-MDS and tri-lineage hematopoiesis in aplastic anemia (AA). We conducted a phase 2 dose modification study to investigate the safety and efficacy of EPAG in LR-MDS. EPAG dose was escalated from 50 mg/day, to a maximum of 150 mg/day over a period of 16 weeks. The primary efficacy endpoint was hematologic response at 16-20 weeks. Eleven of 25 (44%) patients responded; five and six patients had uni- or bi-lineage hematologic responses, respectively. The predictors of response were presence of a PNH clone, marrow hypocellularity, thrombocytopenia with or without other cytopenia, and elevated plasma thrombopoietin levels at study entry. The safety profile was consistent with previous EPAG studies in AA; no patients discontinued drug due to adverse events. Three patients developed reversible grade-3 liver toxicity and one patient had increased reticulin fibrosis. Ten patients discontinued EPAG after achieving a robust response (median time 16 months); four of them reinitiated EPAG due to declining counts, and all attained a second robust response. Six patients had disease progression not associated with expansion of mutated clones and no patient progressed to AML on study. In conclusion, EPAG was well-tolerated and effective in restoring hematopoiesis in patients with low to intermediate-1 risk MDS. This study was registered at clinicaltrials.gov as #NCT00932156.

Lung Cancer Genomics.

The landscape of lung cancer treatment is rapidly evolving with the use of genomic testing which helps identify specific mutations or resistance mutations for these heterogenous tumors. Advanced lung cancer has a very poor prognosis but identifying other treatment options based on genomic profiling of the tumor can lead to improved outcomes. Evidence of benefit for genomic testing in lung cancer has now resulted in this test becoming part of national guidelines. There are challenges with genomic testing which need to be understood as well as understanding how to apply test results. These results can help identify treatment options or may serve as predictors to respond to specific therapies. CONCLUSION: In the current era of precision medicine, it is imperative clinicians be familiar with genomic testing and be able to offer it to their cancer patients, specifically those with advanced lung cancer.

Evaluation of Functional Outcome of Arthroscopic Rotator Cuff Repair Using Southern California Orthopedic Institute Technique.

BACKGROUND: The number of anchors and modality of fixation to be used has been a point of debate in the arthroscopic management of rotator cuff repair. Southern California Orthopedic Institute (SCOI) technique has shown better anatomical healing of tendons using single-row anchors. In this study, we evaluated the functional outcomes of arthroscopic rotator cuff repair using the SCOI technique, in Indian population. MATERIALS AND METHODS: Thirty two patients (16 males and 16 females) were included in the study, and underwent an arthroscopic repair of small-to-medium-sized rotator cuff tear, at a single institution, for 12 months. Postoperatively, patients were evaluated using UCLA score and Constant-Murley score, and range of motion was analyzed and documented using photographs. RESULTS: Mean age was 57.06 years, and the most common cause of cuff tear was a traumatic degeneration. Mean UCLA score improved from preoperative 8.75 to postoperative 31.79, at 12 months, with the P < 0.001. Similarly, mean Constant-Murley score improved from preoperative 20.66 to postoperative 81.31, at 12 months, with P < 0.001. CONCLUSION: We conclude that the SCOI single-row technique proves to be a good and effective modality of treatment in the arthroscopic management of small-to-medium-sized rotator cuff tears. In Indian population, considering cost-effectiveness, single-row repair of rotator cuff tears using SCOI technique can be an interesting option in its management.

Response to rapamycin analogs but not PD-1 inhibitors in PTEN-mutated metastatic non-small-cell lung cancer with high tumor mutational burden.

In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor. Even in the event of failure of treatment with checkpoint inhibitors in the background of a case with a higher tumor mutational burden and PD-L1 positivity, targeting specific genomic alterations may still result in patient benefit.

Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients.

BACKGROUND: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients. METHODS: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America(®) regional hospitals between November 2012 and November 2014. RESULTS: We identified a total of 341 patients including 217 (59%) estrogen receptor (ER)+, 177 (48%) progesterone receptor (PR)+, 30 (8%) hormone receptor+/HER2 positive, and 119 (32%) triple negative patients. ESR1 mutation was noted in 27/222 (12.1%) ER+ or PR+ breast cancer patients. All ER+ patients received at least one line of an aromatase inhibitor. All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). In this cohort, 19 (67.9%) patients carried three or more, seven (25%) patients had one or two additional genomic alterations and one (3.6%) patient had an ESR1 mutation only. Of 28 patients, three patients were treated with fulvestrant immediately before and two patients were treated after next-generation sequencing testing; only one patient achieved stable disease for 8 months and the other four patients had progression of disease. In all, 3/3 (100%) patients before testing and 2/4 (50%) after testing treated with exemestane and everolimus achieved stable disease for at least 6 months. CONCLUSION: ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings.

Network analysis of breast cancer progression and reversal using a tree-evolving network algorithm.

The HMT3522 progression series of human breast cells have been used to discover how tissue architecture, microenvironment and signaling molecules affect breast cell growth and behaviors. However, much remains to be elucidated about malignant and phenotypic reversion behaviors of the HMT3522-T4-2 cells of this series. We employed a "pan-cell-state" strategy, and analyzed jointly microarray profiles obtained from different state-specific cell populations from this progression and reversion model of the breast cells using a tree-lineage multi-network inference algorithm, Treegl. We found that different breast cell states contain distinct gene networks. The network specific to non-malignant HMT3522-S1 cells is dominated by genes involved in normal processes, whereas the T4-2-specific network is enriched with cancer-related genes. The networks specific to various conditions of the reverted T4-2 cells are enriched with pathways suggestive of compensatory effects, consistent with clinical data showing patient resistance to anticancer drugs. We validated the findings using an external dataset, and showed that aberrant expression values of certain hubs in the identified networks are associated with poor clinical outcomes. Thus, analysis of various reversion conditions (including non-reverted) of HMT3522 cells using Treegl can be a good model system to study drug effects on breast cancer.

Robust reverse engineering of dynamic gene networks under sample size heterogeneity.

Simultaneously reverse engineering a collection of condition-specific gene networks from gene expression microarray data to uncover dynamic mechanisms is a key challenge in systems biology. However, existing methods for this task are very sensitive to variations in the size of the microarray samples across different biological conditions (which we term sample size heterogeneity in network reconstruction), and can potentially produce misleading results that can lead to incorrect biological interpretation. In this work, we develop a more robust framework that addresses this novel problem. Just like microarray measurements across conditions must undergo proper normalization on their magnitudes before entering subsequent analysis, we argue that networks across conditions also need to be "normalized" on their density when they are constructed, and we provide an algorithm that allows such normalization to be facilitated while estimating the networks. We show the quantitative advantages of our approach on synthetic and real data. Our analysis of a hematopoietic stem cell dataset reveals interesting results, some of which are confirmed by previously validated results.

Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug.

About a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy. We have previously demonstrated that eltrombopag has efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. We now report safety and efficacy data on a further 18 patients and long-term follow-up on the entire cohort of 43 patients. The overall response rate was 17 of 43 patients (40%) at 3 to 4 months, including tri- and bilineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. Eltrombopag is efficacious in a subset of patients with aplastic anemia refractory to immunosuppressive therapy, with frequent multilineage responses and maintenance of normalized hematopoiesis off treatment. This study is registered at www.clinicaltrials.gov as #NCT00922883.

Imaging of hepatocellular carcinoma: current concepts.

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, and usually develops in the setting of liver cirrhosis. The early diagnosis of HCC is essential as curative treatment (including surgical resection and liver transplantation) improves survival. While screening and surveillance are traditionally performed with ultrasound, reported accuracies of ultrasound vary greatly, and poor sensitivity for small nodules is a uniformly recognized concern. Advances in computed tomography (CT) and magnetic resonance imaging (MRI), including multidetector technology and fast breath hold sequences now allow dynamic multiphasic enhanced imaging of the liver with excellent spatial and temporal resolution, holding much promise for improved HCC detection.

Immunomodulatory treatment of myelodysplastic syndromes: antithymocyte globulin, cyclosporine, and alemtuzumab.

It is now well accepted that a subgroup of patients with myelodysplastic syndromes (MDS) can recover from pancytopenia following immunosuppressive treatment (IST). For many years immunosuppression with antilymphocyte antibodies has been a standard treatment approach for patients with severe aplastic anemia (SAA). The initial concept of using immunosuppression to treat pancytopenic patients with MDS was based on the premise that MDS might share with SAA an autoimmune basis for the bone marrow failure common to both conditions. The idea was supported by reports of favorable outcomes in occasional cases of MDS treated with antithymocyte globulin (ATG). Today, various forms of IST have been successfully used to restore hematopoiesis in MDS in many centers worldwide. In this review we outline the rationale for use of IST in MDS, and describe studies which help to define the patients with MDS likely to respond to IST. We summarize 18 published clinical trials using IST for MDS and discuss how these studies have helped to define the MDS subgroups likely to respond to treatment, the nature and durability of the response, the impact of IST on long-term outcome, and the best treatment approach.