Outcomes of upfront plerixafor use for mobilization in germ cell tumor patients.

High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) improved 5-year overall survival rates in relapsed/refractory germ cell tumors (GCTs) from 10% to 52%. Nearly 30% of GCT patients are deemed poor mobilizers after receiving several lines of prior therapy. There is limited data available regarding upfront plerixafor use in GCT patients. We predicted upfront plerixafor use would increase the amount of stem cells collected preventing subsequent mobilizations and improve time to curative therapy. A retrospective, single center, chart review of adult GCT patients who received plerixafor upfront for mobilization at a single center between January 1, 2013 and August 31, 2021 was performed. The primary objective was to evaluate the rate of successful peripheral blood CD34+ cell collections. Secondary objectives consisted of describing the impact of plerixafor use on mobilization and assessing auto-HSCT related outcomes. Sixteen patients received plerixafor upfront after an average of three prior lines of therapy (range: 2-5 lines). Successful collection (≥4 × 106 CD34+ cells/Kg collected within four days) was achieved in 15 (94%) patients in a median of one apheresis day (interquartile range: 1-2 days). All patients proceeded to an initial auto-HSCT and 12 patients (75%) completed both transplants as planned. Survival at 12 months was 50%. The significantly higher amount of CD34+ cells collected over less apheresis days demonstrated the clinical utility of upfront plerixafor and its potential to facilitate more efficient stem cell mobilization. There is a need for larger randomized studies with upfront plerixafor use in this unique patient population.

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.

Breakthrough invasive fungal infections on isavuconazole prophylaxis in hematologic malignancy & hematopoietic stem cell transplant patients.

BACKGROUND: Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. METHODS: In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. RESULTS: We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 µg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. CONCLUSION: ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

Genome-wide identification and characterization of ABC transporter superfamily in the legume Cajanus cajan.

Plant ATP-binding cassette (ABC) protein family is the largest multifunctional highly conserved protein superfamily that transports diverse substrates across biological membranes by the hydrolysis of ATP and is also the part of the several other biological processes like cellular detoxification, growth and development, stress biology, and signaling processes. In the agriculturally important legume crop Cajanus cajan, a genome-wide identification and characterization of the ABC gene family was carried out. A total of 159 ABC genes were identified that belong to eight canonical classes CcABCA to CcABCG and CcABCI based on the phylogenetic analysis. The number of genes was highest in CcABCG followed by CcABCC and CcABCB class. A total of 85 CcABC genes were found on 11 chromosomes and 74 were found on scaffold. Tandem duplication was the major driver of CcABC gene family expansion. The dN/dS ratio revealed the purifying selection. The phylogenetic analysis revealed class-specific eight superclades which reflect their functional importance. The largest clade was found to be CcABCG which reflects their functional significance. CcABC proteins were mainly basic in nature and found to be localized in the plasma membrane. The secondary structure prediction revealed the dominance of α-helix. The canonical transmembrane and nucleotide binding domain, signature motif LSSGQ, Walker A, Walker B region, and Q loop were also identified. A class-specific exon-intron pattern was also observed. In addition to core elements, different cis-acting regulatory elements like stress, hormone, and cellular responsive were also identified. Expression profiling of CcABC genes at various developmental stages of different anatomical tissues was performed and it was noticed that CcABCF3, CcABCF4, CcABCF5, CcABCG66, and CcABCI3 had the highest expression. The results of the current study endow us with the further functional analysis of Cajanus ABC in the future.

Perspectives on the Intersection of Electronic Health Records and Health Care Team Communication, Function, and Well-being.

Importance: Understanding of the interplay between the electronic health record (EHR), health care team relations, and physician well-being is currently lacking. Approaches to cultivate interpersonal interactions may be necessary to complement advancements in health information technology with high-quality team function. Objective: To examine ways in which the EHR, health care team functioning, and physician well-being intersect and interact. Design, Setting, and Participants: Secondary qualitative analysis of semistructured interview data from 2 studies used keyword-in-context approaches to identify excerpts related to teams. Thematic analysis was conducted using pattern coding, then organized using the relationship-centered organization model. Two health care organizations in California from March 16 to October 13, 2017, and February 28 to April 21, 2022, participated, with respondents including attending and resident physicians. Main Outcome and Measures: Across data sets, themes centered around the interactions between the EHR, health care team functioning, and physician well-being. The first study data focused on EHR-related distressing events and their role in attending physician and resident physician emotions and actions. The second study focused on EHR use and daily EHR irritants. Results: The 73 respondents included attending physicians (53 [73%]) and resident physicians (20 [27%]). Demographic data were not collected. Participants worked in ambulatory specialties (33 [45%]), hospital medicine (10 [14%]), and surgery (10 [14%]). The EHR was reported to be the dominant communication modality among all teams. Interviewees indicated that the EHR facilitates task-related communication and is well suited to completing simple, uncomplicated tasks. However, EHR-based communication limited the rich communication and social connection required for building relationships and navigating conflict. The EHR was found to negatively impact team function by promoting disagreement and introducing areas of conflict into team relationships related to medical-legal pressures, role confusion, and undefined norms around EHR-related communication. In addition, interviewees expressed that physician EHR-related distress affects interactions within the team, eroding team well-being. Conclusions and Relevance: In this study, the EHR supported task-oriented and efficient communication among team members to get work done and care for patients; however, participants felt that the technology shifts attention away from the human needs of the care team that are necessary for developing relationships, building trust, and resolving conflicts. Interventions to cultivate interpersonal interactions and team function are necessary to complement the efficiency benefits of health information technology.

Slit-lamp assisted TORic Marker (STORM): A novel corneal axis marker.

Background: Toric Intraocular lenses (IOLs) are supposed to be aligned at a particular axis for spectacle-free vision for distance. The evolution of topographers and optical biometers has made it quite achievable for us to aim the target. However, the result sometimes remains unpredictable. A big aspect of this depends on the preop axis marking for toric IOL alignment. Errors in axis marking have been reduced recently with the array of different toric markers in the market, but still we see postoperative refractive surprises due to faulty marking. Purpose: In this video, we present a novel slit lamp-based toric marker innovation, STORM, which gives us a hands-free approach to a reliable and accurate axis marking on the cornea. The axis marker is a simple modification to our age-old marker, with the advantage of no touch and slit-lamp assistance, which will make it error free and easy to use. Synopsis: The present innovation answers the problem statement of stable, economical, and accurate marking solution. Many a times, hand-holding devices create inaccurate and stressed condition while marking the cornea before corneal surgery. Highlights: The invention can be used for marking of accurate and easy astigmatic axis of a toric IOL preoperatively, that is, before the surgery. If the appropriate device is used to mark the cornea, it would impact the outcome of surgery. This device also makes the patient and the surgeon comfortable to mark the cornea with accuracy and without hesitation. Video link: https://youtu.be/4MVM7HRwz70.

Melphalan on day -1 versus day -2 in patients with plasma cell disorders undergoing autologous stem cell transplant.

High-dose melphalan-based autologous stem cell transplant (ASCT) remains a standard of care for plasma cell disorders (PCDs). Currently, there is variability in the literature surrounding the timing of melphalan administration to avoid potential cytotoxic effects, although the administration has been safely proposed when given at least 8 hours prior to stem cell infusion. The objectives of this study were to assess differences in safety and efficacy outcomes between day -1 and day -2 single-dose melphalan administration in patients undergoing ASCT for PCDs. A retrospective chart review was performed at our institution comparing patients receiving melphalan on day -1 to an equal number of patients receiving melphalan on day -2. The primary endpoint was time to neutrophil engraftment from stem cell infusion. Univariate analyses were performed. Mean time to neutrophil engraftment from stem cell infusion was identical at 10.7 days for both cohorts (p = 0.88). Mean time to platelet engraftment from stem cell infusion was shorter with day -1 administration (17.4 vs. 18.6 days, p = 0.06). Mean time to neutrophil and platelet engraftment from melphalan infusion were significantly shorter with day -1 administration. Similar outcomes were observed for length of hospitalization, infection- and mucositis-related toxicities, hematologic response, transplant-related mortality, and overall survival. Our findings show no difference in time to neutrophil engraftment from stem cell infusion and a trend toward shorter time to platelet engraftment with day -1 administration. Based on our study, day -1 melphalan administration is an acceptable and safe practice.

Incidental Appendiceal Tumors During Appendectomy: A Nineteen-Year Retrospective Review at a Municipal Hospital.

Non-operative management of appendicitis (NOMA) has recently gained popularity, but a concern is that NOMA might miss appendiceal neoplasms. We conducted a retrospective review of 1694 appendectomies done for acute appendicitis at our institution between January 2001 and December 2019 to study the incidence and distribution of appendiceal tumors. We identified 24 appendiceal neoplasms (1.43%), including 9 Low Grade Appendiceal Mucinous Neoplasms (LAMNs), 6 neuroendocrine tumors (NETs), 6 mucoceles, and one each of adenocarcinoma, endometrioma, and neurofibroma. Tumor occurrence had two age peaks, with LAMNs prominent in the 5th and 6th decades of life and NETs in the 2nd and 3rd decades. All patients under age 40 had benign disease. Presence of appendicoliths was independent of the presence of neoplasms. All cases were managed per National Comprehensive Cancer Network (NCCN) guidelines, with twenty cases cured by appendectomy alone. Given these, we conclude that NOMA is safe for patients under 40.

Deciphering the enigma of astigmatism in cataract surgery.

Background: With about 87% of patients with cataracts having astigmatism, management of astigmatism in cataract surgery not only yields an improved unaided visual acuity and image quality but also higher patient satisfaction. The video will give a step-wise guide to cataract surgeons to manage astigmatism with cataracts. Purpose: To hit the bull's eye as far as target refraction is concerned, it is necessary to understand the benefits and limitations of currently available cutting-edge technology and formulae and apply them to the cataract surgery practice. The purpose of the video is to make sure that we have no surprises in our Toric intraocular lens (IOL) planning. Synopsis: After a brief introduction to available modalities for the treatment of astigmatism, a step-wise approach to diagnostics is discussed, which will include the role of corneal topography and aberrometers and their application to planning Toric IOLs. Appropriate planning, implementation, and execution in form of preoperative and intraoperative pearls of using Toric IOLs are shown in the video. This will be followed by troubleshooting and case-based discussions and future perspectives including the possible role of corneal biomechanics. Highlights: What this video adds new is the importance of topography, interpretation of Belin‒Ambrosio display map and the equivalent keratometry reading (EKR) map, aberrometry, and higher order aberration (HOA) analysis and role of biomechanics in Toric IOL planning. Video also highlights the importance of posterior corneal astigmatism and accurate axis marking. With a case-based approach and relevant examples, we are trying to decipher the enigma of astigmatism by giving a step-wise approach for the same. Online Video Link: https://youtu.be/5VuEY_6NdQA.

#CosmeticsTwitter: Predicting Public Interest in Nonsurgical Cosmetic Procedures Using Twitter Data.

BACKGROUND: The utilization of social media in plastic surgery is expanding. The Twitter Academic Research Product Tract (TARPT) database provides plastic surgeons the opportunity to monitor public interest in plastic surgery procedures. Previously, TARPT was shown to be effective in tracking public interest in surgical cosmetic facial and body procedures. OBJECTIVES: The authors sought to determine the ability of the TARPT tool to track and predict public interest in nonsurgical cosmetic procedures and to examine temporal public interest trends in nonsurgical cosmetic procedures. METHODS: The authors employed the TARPT tool to calculate the total number of tweets containing keywords related to 15 nonsurgical cosmetic procedures from 2010 to 2020. Annual case volumes were obtained for each of the 15 procedures from annual reports provided by the American Society of Plastic Surgeons. Univariate linear regression was employed to compare tweet volumes and procedure volumes, with P < 0.05 as a threshold for significance. RESULTS: Univariate linear regression revealed significant positive correlations between tweet volumes and American Society of Plastic Surgeons procedure volumes for 10 search terms representing 6 nonsurgical cosmetic procedures: "xeomin," "microdermabrasion," "facial filler," "fat filler," "fat injections," "fat transfer," "hyaluronic acid filler," "hyaluronic acid injection," "HA filler," and "PRP filler." Thirty-two search terms did not demonstrate a significant relationship. CONCLUSIONS: The TARPT tool is an informative data source for plastic surgeons with the potential to guide marketing and advertising strategies, and monitor public interest in nonsurgical cosmetic procedures, helping surgeons respond to patients' evolving needs.

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.

Clinical profile and outcome of ocular manifestation in Marfans syndrome in India.

PURPOSE: Marfan syndrome (MFS) is a genetic disorder associated with considerable morbidity and mortality. Presently, well-documented information on this condition is not available in India. METHODS: In this retrospective cohort study, we recruited patients with clinically diagnosed MFS who presented to the outpatient department using revised Ghent nosology. We retrieved complete ophthalmic information, including vision, anterior and posterior segments, exported from electronic medical records, and relevant investigations, surgical details, and follow-up data were obtained in a specific, pretested format. RESULTS: Our cohort consisted of 86 eyes of 43 patients and had a male preponderance. The prevalence was 20.5 per 100,000 individuals. The mean age of the patients was 23.9 years. All eyes were treated either optically with refraction or surgically using lensectomy and vitrectomy with suture supported scleral fixated intraocular lens (IOL), which significantly affected the visual outcome (P = 0.000). CONCLUSION: Although considered a rare disease, MFS is commonly found in the ophthalmological setting. Refraction and surgery (lensectomy with scleral fixated IOL) may improve the vision significantly.

Anesthesia Considerations for Cataract Surgery in Patients with Schizophrenia: A Narrative Review.

Schizophrenia is ranked among the top 10 global burdens of disease. About 1% of people meet the diagnostic criteria for this disorder over their lifetime. Schizophrenic patients can develop cataract, particularly related to age and medications, requiring surgery and anesthesia. Many concerning factors, including cognitive function, anxiety, behavioral issues, poor cooperation and paroxysmal movements, may lead to general anesthesia as the default method. Antipsychotic agents should be continued during the perioperative period if possible. Topical/regional anesthesia is suitable in most schizophrenic patients undergoing cataract surgery. It reduces potential drug interactions and many postoperative complications; however, appropriate patient selection is paramount to its success. General anesthesia remains the primary technique for patients who are considered unsuitable for the topical/regional technique. Early involvement of a psychiatrist in the perioperative period, especially for patients requiring general anesthesia, is beneficial but often under-utilized. This narrative review summarizes the anesthetic considerations for cataract surgery in patients with schizophrenia.

Anesthesia Challenges in the Management of Freeman-Sheldon Syndrome: Report of Two Cases and Literature Review.

Freeman-Sheldon syndrome is a congenital myopathy with a reported prevalence of less than 1 per 1 million. Also known as craniocarpotarsal dysplasia, this syndrome is characterized by muscle contractures and soft-tissue dysplasia of the face, hands, and feet. The resulting musculoskeletal deformities may require multiple orthopedic, ocular, and plastic reconstructive surgeries. The anesthetic challenges include a potentially difficult airway and intravenous access, susceptibility to malignant hyperthermia, and an unpredictable response to muscle relaxants. This report of the anesthetic management of 2 children with Freeman-Sheldon syndrome emphasizes the anesthetic considerations for the successful management of patients with this syndrome.

Liposomal delivery of hydrophobic RAMBAs provides good bioavailability and significant enhancement of retinoic acid signalling in neuroblastoma tumour cells.

Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. In vivo, retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid (RA) pharmacokinetics in pre-clinical neuroblastoma models. Here, we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance RA action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here, we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signalling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans.

A Common Outer Retinal Change in Retinal Degeneration by Optical Coherence Tomography Can Be Used to Assess Outcomes of Gene Therapy.

Identifying early disease hallmarks in animal models with slow disease progression may expedite disease detection and assessment of treatment outcomes. Using optical coherence tomography, a widely applied noninvasive method for monitoring retinal structure changes, we analyzed retinal optical sections from six mouse lines with retinal degeneration caused by mutations in different disease-causing genes. While images from wild-type mice revealed four well-separated hyper-reflective bands in the outer retina (designated as outer retina reflective bands, ORRBs) at all ages, the second band (ORRB2) and the third band (ORRB3) were merged in retinas of five mutant mouse lines at early ages, suggesting the pathological nature of this alteration. This ORRB change appeared to be degenerating photoreceptor related, and occurred before obvious morphological changes that can be identified on both hematoxylin and eosin-stained sections and electron microscopic sections. Importantly, the merging of ORRB2 and ORRB3 was reversed by treatment with adeno-associated viral vector-mediated gene replacement therapies, and this restoration occurred much earlier than measurable functional or structural improvement. Our data suggest that the ORRB change could be a common hallmark of early retinal degeneration and its restoration could be used for rapid and noninvasive assessment of therapeutic effects following gene therapy or other treatment interventions.

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.