Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors.

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

A US-Based Multicenter Retrospective Report of Perioperative Anaphylaxis, 2010-2021.

BACKGROUND: US-based perioperative anaphylaxis (POA) studies are limited to single-center experiences. A recent report found that a serum acute tryptase (sAT) >9.8 ng/mL or mast cell activation (MCA) can predict POA causal agent identification. Urinary mast cell mediator metabolites (uMC) have not been studied in POA. OBJECTIVE: To analyze the epidemiologic data of POA, to determine if sAT or MCA can predict suspected causal agent identification, and to evaluate uMC utility in POA. METHODS: This study is a retrospective multicenter review of POA cases that were subcategorized by suspected causal agent identification status. sAT, MCA (defined as sAT >2 + 1.2 × serum baseline tryptase), and uMC (N-methylhistamine [N-MH], 11ß-prostaglandin-F2α [11ß-PGF2α], leukotriene E4 [LTE4]) were recorded. RESULTS: Of 100 patients (mean age 52 [standard deviation 17] years, 94% adult, 50% female, 90% White, and 2% Hispanic) with POA, 73% had an sAT available, 41% had MCA, 16% had uMC available, and 50% had an identifiable suspected cause. POA cases with an identifiable suspected cause had a positive MCA status (100% vs 78%; P = .01) compared with POA with an unidentifiable cause. An elevated median sAT did not predict causal agent identification. Positive uMC were not associated with suspected causal agent identification during POA. Patients with positive uMC had a higher median sAT (30 vs 6.45 ng/mL; P = .001) and MCA status (96% vs 12%; P = .001) compared with negative uMC patients. Patients with POA had an elevated acute/baseline uMC ratios: 11ß-PGF2α ratio > 1.6, N-MH ratio >1.7, and LTE4 ratio >1.8. CONCLUSIONS: The presence of MCA in POA is associated with suspected causal agent identification. Positive uMC possibly correlate with a higher sAT level and MCA status but require further study. The authors suggest applying an acute/baseline uMC ratio (11ß-PGF2α ratio >1.6, N-MH ratio >1.7, and LTE4 ratio >1.87) in patients with POA for MCA when a tryptase level is inconclusive during POA evaluations.

Non-functional Pituitary Adenomas: Analysis of Delayed Diagnosis in Mexico.

BACKGROUND:  Although tumors of the central nervous system (CNS) are rare, they can cause significant morbidity and mortality. The clinical presentation of patients with non-functional pituitary adenomas (NFPA) ranges from being completely asymptomatic to causing pituitary, hypothalamic, or visual dysfunction due to their large size. Patients usually arrive with large tumors at the time of diagnosis.  Objectives: Try to describe the characteristics of NFPA and explain the causes of delayed diagnosis.  Methods: We carried out a retrospective study including 58 patients with NFPA and analyzed the tumor volume at the time of diagnosis and its relationship with sociodemographic and health sector variables.  Results: Low socioeconomic status (SES) was associated with high tumor volume (SES 1-2 of 17.4 cm3 vs 3-6 of 11.7 cm3, p=0.018), and the time between first consultation and diagnosis was longer in the public sector than in the private sector (13.5 months vs 5.1 months). The time between the first symptom and the first consultation was shorter when they had visual impairment than when they did not (4.1 vs 18.4 months, p=0.006). CONCLUSIONS: On the one hand, citizens should be made aware that a visual deficit should make them go to a medical check-up, and on the other hand, strengthen the health system so that they have the NFPA as a differential diagnosis in patients with some visual alteration. Socioeconomic inequality in our country undoubtedly puts the underprivileged at greater risk.

One- versus 2-day aspirin desensitization in aspirin exacerbated respiratory disease: A quality improvement project.

Background: Current aspirin desensitization protocols for aspirin-exacerbated respiratory disease (AERD) require from 1 to 3 days to complete. Objective: Our aim was to assess the implementation of a 1-day versus 2-day aspirin desensitization protocol in patients with aspirin-exacerbated respiratory disease. Methods: We used a preintervention-postintervention quality improvement design to compare the completion rates, reaction rates, and estimated costs of a 2-day versus 1-day aspirin desensitization. The cost for each desensitization was estimated on the basis of 2017-2020 US Medicare standards. We included the predesensitization variables for FEV1 value, urinary leukotriene E4 level, absolute eosinophil count (AEC), and total IgE level for each group. Results: A total of 15 patients underwent a 2-day aspirin desensitization in the 4-year (2017-2020) preintervention period and were compared with 8 patients who underwent a 1-day aspirin desensitization in the 1-year (2021) postintervention period. The desensitization completion rate (93% vs 100% [P = 1]) and the mean number of reactions requiring intervention during the desensitization protocols (0.26 vs 0.8 [P = .14]) were similar between groups. The average time frame between last polypectomy and desensitization was longer in the 2-day group (1946 vs 39.2 days [P = .03]). The mean values for FEV1 level, urinary leukotriene E4 level, absolute eosinophil count, and total IgE level were 76% vs 83% (P = .6), 1084 vs 385 pg/mg (P = .2), 686 vs 306 cells/µL (P = .74), and 735 vs 278 kU/L (P = .5), respectively. The estimated direct cost reduction was $762 per aspirin desensitization for using 1-day vs 2-day aspirin desensitization. Conclusion: Compared with a 2-day protocol, the implementation of a 1-day aspirin desensitization was characterized by similar completion and reaction rates as well as lower costs.

Prevention of Recurrent Attacks of Hereditary Angioedema (HAE): Berotralstat and Its Oral Bioavailability.

Hereditary angioedema (HAE) is a condition characterized by episodes of cutaneous and submucosal edema. Angioedema of the extremities and abdominal attacks are the most common manifestations of the disease. It can also affect the upper airways with the potential of becoming life-threatening. The two most common causes of HAE are a deficiency of C1 inhibitor (classified as type 1 HAE) or a dysfunction of C1 inhibitor (type 2 HAE). A malfunction or deficiency of C1 inhibitor leads to an overactivated plasma kallikrein (an inflammatory vasoactive peptide), that increases bradykinin, mediating the angioedema episodes in patients with HAE. To minimize the difficulties of this pathology and to improve patients' quality of life, prevention of this condition is essential. Berotralstat is a unique option for oral administration for routine prophylaxis. This drug acts by binding to kallikrein and reducing its plasma activity, lowering bradykinin levels. Open-label studies have demonstrated the effectiveness of a single daily dose of berotralstat 150 mg in preventing HAE attacks. This review aims to examine studies performed to elucidate the efficacy, safety, and tolerability of berotralstat.

The Nonirritating Concentrations of Neuromuscular Blocking Agents and Related Compounds.

BACKGROUND: Skin testing (ST) concentrations of neuromuscular blocking agents (NMBAs), NMBA-reversal agents, and the sugammadex-rocuronium inclusion complex (S-R-Cx) vary widely among reports. OBJECTIVE: To determine maximal ST nonirritant concentrations (NICs) of NMBAs (cisatracurium, rocuronium, succinylcholine, and vecuronium), NMBA-reversal agents (neostigmine and sugammadex), and S-R-Cx in NMBA-tolerant and NMBA-naïve participants. METHODS: A single-center, prospective study between October 2019 and November 2021 of adult participants with or without a planned surgical procedure. The reference standard was tolerance of medication tested during a procedure (NMBA-tolerant group) before ST. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at 5-7 increasing concentrations of 1 or more medications. All medications were reconstituted according to package insert instructions and diluted with 0.9% saline. A concentration was considered irritant when more than 5% of participants had a positive test per ST positivity criteria (wheal ≥3 mm than initial wheal and associated erythema of the same size or greater than wheal). We also compared our results with current guidelines. RESULTS: A total of 187 participants (78% NMBA-tolerant) underwent 7812 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT NICs (mg/mL): cisatracurium (0.02), rocuronium (0.05), succinylcholine (0.8), vecuronium (0.01), neostigmine (0.2), sugammadex (50), and S-R-Cx (sugammadex 7.14 + rocuronium 2). CONCLUSION: Our results suggest that SPT may be performed with undiluted stock concentrations. We confirm maximal IDT NICs for cisatracurium and rocuronium. We also propose that currently recommended maximal IDT NICs of succinylcholine, neostigmine, sugammadex, and S-R-Cx could be increased, whereas the maximal IDT NIC of vecuronium could be decreased compared with current guidelines and prior reports.

Pregnancy hypothyroidism incidence and complications using the 2011 and 2017 ATA cutoff values. Experience at a maternity hospital in a densely populated area in Mexico City.

OBJECTIVES: Normal thyroid activity has an essential role in fetal development, its deficiency may hamper fetal neurodevelopment and neonatal growth. The quantitation of thyroid hormones although useful, still exposes differences on cut off levels to diagnose thyroid deficit accurately that can elicit under or over diagnosis of thyroid dysfuntion. METHODS: A total of 839 pregnant patients were studied for thyroidal clinical assessment through quantitation of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) circulating levels. Patients evaluated for prenatal and neonatal outcomes. Thyroid function deficiencies were determined with the American Thyroid Association (ATA) 2011 and 2017 values. Statistical analysis searched for associations between variables, odds ratios (OR) and correlations were calculated to evaluate the reliability of the cutoff values recommended by the ATA. RESULTS: Mean age of our cases was 27.5 + 5.83 years at diagnosis, mean gestational age at first consultation was 23.8 + 10.5 weeks. Mean TSH levels detected were: 2.5 + 1.89 mIU/L, total T3: 3.55 + 4.1 ng/dL, FT4: 3.14 + 4.4 ng/dL. The ATA 2011 values yielded 332 hypothyroidism cases vs. 507 euthyroid patients, a total incidence of 39.6% vs. the ATA 2017 values, diagnosing 100 hypothyroidism cases and 739 euthyroid patients, total incidence of 11.9%. Association with complications were not significant. CONCLUSIONS: Using ATA 2017 values showed a decreased population with gestational hypothyroidism, hence preventing overdiagnosis and over-treatment. No significant complications were associated, requiring the determination of new regional values. Education and sensibilization of our population is needed to comply with early prenatal consultation and thyroid function testing.

Bosutinib-Induced Stevens-Johnson Syndrome and Evidence of Tolerance to a Structurally Dissimilar Tyrosine Kinase Inhibitor.

Bosutinib is a breakpoint cluster region-Abelson gene (BCR-ABL) tyrosine kinase inhibitor (TKI) used for the treatment of chronic myeloid leukemia (CML). Patients on TKIs may develop severe cutaneous adverse reactions (SCARs). A 73-year-old female with CML treated with a second-generation TKI (bosutinib) was evaluated after developing fever and a maculopapular exanthema with skin-peeling affecting her lips, oral mucosa, and genitals 10 days after starting the medication. She required hospitalization, bosutinib discontinuation, and management with intravenous corticosteroids and antibiotics. Patch testing was contraindicated due to the severity of the reaction. The patient was subsequently challenged with first-generation TKI along with careful observation without any adverse reactions. She has not reported any adverse reactions while on therapy in the last two years. In patients who have suffered from SCARs, the suspected triggers must be avoided in all instances. In some cases, the underlying condition limits the use of alternative agents, but low-concentration patch testing may help guide alternative therapies within the same medication group. There appears to be a low cross-reactivity among generational TKIs, and our patient benefited from treatment with a structurally dissimilar alternative TKI for her CML.

Carrier screening in the Mexican Jewish community using a pan-ethnic expanded carrier screening NGS panel.

PURPOSE: The Mexican Jewish community (MJC) is a previously uncharacterized, genetically isolated group composed of Ashkenazi and Sephardi-Mizrahi Jews who migrated in the early 1900s. We aimed to determine the heterozygote frequency of disease-causing variants in 302 genes in this population. METHODS: We conducted a cross-sectional study of the MJC involving individuals representing Ashkenazi Jews, Sephardi-Mizrahi Jews, or mixed-ancestry Jews. We offered saliva-based preconception pan-ethnic expanded carrier screening, which examined 302 genes. We analyzed heterozygote frequencies of pathogenic/likely pathogenic variants and compared them with those in the Genome Aggregation Database (gnomAD). RESULTS: We recruited 208 participants. The carrier screening results showed that 72.1% were heterozygous for at least 1 severe disease-causing variant in 1 of the genes analyzed. The most common genes with severe disease-causing variants were CFTR (16.8% of participants), MEFV (11.5%), WNT10A (6.7%), and GBA (6.7%). The allele frequencies were compared with those in the gnomAD; 85% of variant frequencies were statistically different from those found in gnomAD (P <.05). Finally, 6% of couples were at risk of having a child with a severe disorder. CONCLUSION: The heterozygote frequency of at least 1 severe disease-causing variant in the MJC was 72.1%. The use of carrier screening in the MJC and other understudied populations could help parents make more informed decisions.

An App-Based Telemedicine Program for Primary Care and Specialist Video Consultations During the COVID-19 Pandemic in Mexico.

Background:The coronavirus disease 2019 (COVID-19) pandemic has disrupted the health care system in various ways, one of which is the implementation of telemedicine as a part of the daily clinical practice for many physicians. Sofía is a Mexican health care and technology startup that implemented an app-based telemedicine program during this pandemic in Mexico.Materials and Methods:The telemedicine program included on-demand video consultations with internal medicine specialists from March to September 2020. In the following study, we present a descriptive analysis of all the patients in the telemedicine program, called Coronaid. Results:2,585 video consultations were conducted for a total of 1,545 patients and 44.4% of these were associated with respiratory symptoms. Of all patients, 46% were female and the mean age was 34 years, 52.2% were overweight or obese, and 25% presented at least one comorbid condition. Aside from respiratory complaints, the most common chief complaints were associated with gastrointestinal, psychiatric, and genitourinary symptoms. Patient satisfaction after video consultation services was >80%.Discussion:During the COVID-19 pandemic, an application-based telemedicine program had a high patient satisfaction rate in a significant sample of young patients, which can be attributed to the accessibility of the medical services and widespread use of smartphones in this patient demographic.Conclusion:Telemedicine has proven to be a useful, safe, and effective tool to improve patients' health, which has been boosted by the COVID-19 pandemic. The use of mobile applications and video consultation services can encourage patients to improve their health and prevent complications in the short and long terms.

Delayed Vesicular Urticarial Dermatosis Due to Apixaban.

Cutaneous adverse drug reactions (cADR) are delayed hypersensitivity reactions that are T-cell mediated. Novel oral anticoagulants, including Factor Xa inhibitors, are increasingly used as therapeutic or prophylactic management of thrombosis and atrial fibrillation. We introduce the case of a 78-year-old woman with no known allergies and a history of atrial fibrillation who was started on apixaban for cerebrovascular accident prophylaxis. Approximately nine days after starting apixaban, she developed a vesicular-urticated erythematous rash initially located on her right upper extremity, progressing to her face. She was evaluated after two weeks for the persistence of symptoms and improved with hydroxyzine and prednisone. Subsequently, she was advised to discontinue and evade all Factor Xa inhibitors, including apixaban, and was switched to warfarin. Naranjo score scale was 5-6. The patient declined skin biopsy and drug challenge. After a month of discontinuation of systemic steroids, patch testing was performed with apixaban, rivaroxaban, and edoxaban, with a negative result. Since this episode, the patient has not had a recurrence of the rash. As far as we know, this is the first case report of a non-severe cADR to apixaban. Even though there are no standardized protocols for diagnosing drug reactions to Factor Xa inhibitors, patch testing at increasing non-irritant concentrations with re-challenge of alternative agents and the suspected offending agent, if possible, should be included in the evaluation of a cADR.

Risk factors for hospitalization and mortality due to dengue fever in a Mexican population: a retrospective cohort study.

OBJECTIVES: Identify risk factors associated with increased hospital admission and mortality due to dengue fever (DF), and estimate the risk magnitude associated with each individual variable. METHODS: Records of patients diagnosed with dengue were obtained from the Mexican National Epidemiological Surveillance System. Descriptive statistics were performed in all variables. Demographic characteristics and comorbidities were compared between patients based on type of care and mortality. Multivariable analysis was done with a logistic regression model, using two different outcomes: hospitalization and mortality. RESULTS: A total of 24,495 patients were included in the analysis, with a DF case fatality rate of 0.58%. Patients younger than 10 and older than 60, were found to have a greater risk of both hospitalization and mortality due to DF. Comorbidities associated with a higher risk for hospital admission include cirrhosis, CKD, immunosuppression, diabetes, and hypertension. For mortality, CKD, diabetes, and hypertension were identified as risk factors, along with pregnancy. CONCLUSION: Identification of risk factors associated with increased hospitalization and mortality due to DF can help categorize patients that require close monitoring and inpatient care. Early identification of warning signs and patients at increased risk is key to avoiding delay of supportive care.

Lessons from the COVID-19 pandemic: knowledge and preventive actions among a mexican population sample / Lecciones de la pandemia de COVID-19: conocimiento y acciones preventivas de una muestra de población mexicana

Objective: to evaluate the knowledge of the general population about the COVID-19 pandemic, including the disease and the preventive measures to reduce spreading of the virus undertaken by participants. Materials and methods: a cross-sectional study on a Mexican population sample was conducted during the period of March 20th to March 27th in Mexico, via a computer-based survey. General knowledge about COVID-19 and the adherence to recommendations were evaluated. Results: a total of 2,577 participants completed the survey. The results revealed an overall proper knowledge about the disease, with 76.2% having the proper knowledge about the disease, which was significantly correlated with age (r=0.15, p<0.001), socioeconomic status (r=0.06, p<0.003) and maximum academic level achieved by the study subjects (r=0.12, p<0.001). Conclusions: overall, people have good knowledge of COVID-19 and know about the specific public health recommendations, but a large proportion of people do not strictly follow these recommendations..Au

Objetivo: evaluar el conocimiento de la población general acerca de la pandemia de COVID-19, incluyendo datos sobre la enfermedad y las medidas preventivas para reducir la propagación del virus. Materiales y métodos: se realizó un estudio transversal en una muestra de la población mexicana durante el periodo del 20 al 27 de marzo del 2020 por medio de una encuesta electrónica. Se evaluó el conocimiento general sobre COVID-19 y el apego a las recomendaciones de salud pública Resultados: 2,577 participantes completaron la encuesta. Los resultados muestran un adecuado conocimiento sobre la enfermedad en la población general (76.2% de la muestra), el cual está levemente correlacionado con la edad (r=0.15, p<0.001), estado socioeconómico (r=0.06, p<0.003) y grado académico (r=0.12, p<0.001). Conclusiones: en general, la población conoce la información acerca del COVID-19 y conoce las recomendaciones de salud pública, pero una gran proporción de la gente no sigue estrictamente estas recomendaciones..Au

The Coronaid Program: An App-Based Telemedicine Tool for Triaging, Testing, Treating and Monitoring COVID-19 Patients in Mexico.

OBJECTIVE: To describe the results of a Mexican telemedicine program for patients with coronavirus disease 2019 (COVID-19). METHODS: An observational retrospective study was conducted to analyze and describe the baseline demographic and clinical characteristics of patients who received medical video consultations for respiratory symptoms. RESULTS: A total of 1,148 video consultations were given from March to September 2020 via Sofía's mobile app. A total of 580 patients sought medical consultation regarding respiratory symptoms. Of the patients, 51% were male and the mean age was 36 years (SD = 13). Of the patients, 35% had comorbidities such as diabetes, hypertension, and obesity, and 1.2% were sent to the ED. Fifty-seven polymerase chain reaction (PCR) tests for COVID-19 were requested and we detected a 53% positivity rate with a mean follow-up of 4.6 consultations. CONCLUSION: Telemedicine has proven to be a safe and effective tool for triaging, testing, treating, and remote monitoring of patients with mild COVID-19. Patients triaged by Sofía had good overall outcomes and reduced the risks of in-person consultation in the pandemic.

U-shaped-aggressiveness of SARS-CoV-2: Period between initial symptoms and clinical progression to COVID-19 suspicion. A population-based cohort study.

BACKGROUND: Early identification of different COVID-19 clinical presentations may depict distinct pathophysiological mechanisms and guide management strategies. OBJECTIVE: To determine the aggressiveness of SARS-CoV-2 using symptom progression in COVID-19 patients. DESIGN: Historic cohort study of Mexican patients. Data from January-April 2020 were provided by the Health Ministry. SETTING: Population-based. Patients registered in the Epidemiologic Surveillance System in Mexico. PARTICIPANTS: Subjects who sought medical attention for clinical suspicion of COVID-19. All patients were subjected to RT-PCR testing for SARS-CoV-2. MEASUREMENTS: We measured the Period between initial symptoms and clinical progression to COVID-19 suspicion (PISYCS) and compared it to the primary outcomes (mortality and pneumonia). RESULTS: 65,500 patients were included. Reported fatalities and pneumonia were 2176 (3.32%), and 11568 (17.66%), respectively. According to the PISYCS, patients were distributed as follows: 14.89% in <24 hours, 43.25% between 1-3 days, 31.87% between 4-7 days and 9.97% >7 days. The distribution for mortality and pneumonia was 5.2% and 22.5% in <24 hours, 2.5% and 14% between 1-3 days, 3.6% and 19.5% between 4-7 days, 4.1% and 20.6% >7 days, respectively (p<0.001). Adjusted-risk of mortality was (OR [95% CI], p-value): <24 hours = 1.75 [1.55-1.98], p<0.001; 1-3 days = 1 (reference value); 4-7 days = 1.53 [1.37-1.70], p<0.001; >7 days = 1.67 [1.44-1.94], p<0.001. For pneumonia: <24 hours = 1.49 [1.39-1.58], p<0.001; 1-3 days = 1; 4-7 days = 1.48 [1.41-1.56], p<0.001; >7 days = 1.57 [1.46-1.69], p<0.001. LIMITATIONS: Using a database fed by large numbers of people carries the risk of data inaccuracy. However, this imprecision is expected to be random and data are consistent with previous studies. CONCLUSION: The PISYCS shows a U-shaped SARS-CoV-2 aggressiveness pattern. Further studies are needed to corroborate the time-related pathophysiology behind these findings.