A Case Report on Trastuzumab Emtansine (T-DM1) in a Patient With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer and Brain Metastases: Long-Term Treatment and Survival.

Breast cancer remains the most common cancer in women worldwide. Among women with breast cancer, brain metastases are very prevalent among HER2-positive and affect those in the advanced stages of the disease. Various factors, including molecular subtypes, performance status, extracranial disease status, leptomeningeal metastasis, and the number of lesions, significantly influence the prognosis of patients with brain metastases from breast cancer (BCBrM). Understanding and addressing the specific risks associated with different breast cancer subtypes is crucial for developing tailored and effective medical treatments. This report presents a case of a breast cancer patient with recurrent disease and brain metastases who achieved long-term survival following a treatment regimen that included radiotherapy and a T-DM1 biosimilar.

Large-Scale Proteomics in Early Pregnancy and Hypertensive Disorders of Pregnancy.

Importance: There is no consensus regarding the best method for prediction of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia. Objective: To determine predictive ability in early pregnancy of large-scale proteomics for prediction of HDP. Design, Setting, and Participants: This was a nested case-control study, conducted in 2022 to 2023, using clinical data and plasma samples collected between 2010 and 2013 during the first trimester, with follow-up until pregnancy outcome. This multicenter observational study took place at 8 academic medical centers in the US. Nulliparous individuals during first-trimester clinical visits were included. Participants with HDP were selected as cases; controls were selected from those who delivered at or after 37 weeks without any HDP, preterm birth, or small-for-gestational-age infant. Age, self-reported race and ethnicity, body mass index, diabetes, health insurance, and fetal sex were available covariates. Exposures: Proteomics using an aptamer-based assay that included 6481 unique human proteins was performed on stored plasma. Covariates were used in predictive models. Main Outcomes and Measures: Prediction models were developed using the elastic net, and analyses were performed on a randomly partitioned training dataset comprising 80% of study participants, with the remaining 20% used as an independent testing dataset. Primary measure of predictive performance was area under the receiver operating characteristic curve (AUC). Results: This study included 753 HDP cases and 1097 controls with a mean (SD) age of 26.9 (5.5) years. Maternal race and ethnicity were 51 Asian (2.8%), 275 non-Hispanic Black (14.9%), 275 Hispanic (14.9%), 1161 non-Hispanic White (62.8% ), and 88 recorded as other (4.8%), which included those who did not identify according to these designations. The elastic net model, allowing for forced inclusion of prespecified covariates, was used to adjust protein-based models for clinical and demographic variables. Under this approach, no proteins were selected to augment the clinical and demographic covariates. The predictive performance of the resulting model was modest, with a training set AUC of 0.64 (95% CI, 0.61-0.67) and a test set AUC of 0.62 (95% CI, 0.56-0.68). Further adjustment for study site yielded only minimal changes in AUCs. Conclusions and Relevance: In this case-control study with detailed clinical data and stored plasma samples available in the first trimester, an aptamer-based proteomics panel did not meaningfully add to predictive utility over and above clinical and demographic factors that are routinely available.

Nab-Paclitaxel-Based Systemic Approach to Achieving Complete Remission for Relapsed Stage III Endometrial Carcinoma: Insights From the Indian Subcontinent.

Endometrial adenocarcinoma (EC) is a common type of cancer in women that starts in the lining of the uterus. It usually affects women following menopause but can also occur in younger women. There are different types of EC based on how the cells look under a microscope and their molecular characteristics. EC is generally divided into two main groups: Type I, which is linked to estrogen and mainly consists of low-grade cells, is more common and usually has a better outcome; and Type II, which is not related to estrogen, consists of high-grade cells, is less common, and typically has a worse prognosis. This case report presents a comprehensive examination of the clinical course of a 65-year-old female patient who achieved complete remission following a relapse of high-risk EC through a unique therapeutic approach involving Taxonab 300mg/carboplatin 450mg. The case report underscores the significance of investigating nab-paclitaxel-based interventions as a promising strategy for improving outcomes in patients facing the challenging scenario of inoperable, high-risk EC relapses.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular disease.

Fixed-dose combination (FDC) therapy, also known as polypill therapy, targets risk factors for atherosclerotic cardiovascular disease (ASCVD) and has been proposed as a strategy to reduce global ASCVD burden. Here we conducted a systematic search for relevant studies from 2016-2022 to assess the effects of FDC therapy for prevention of ASCVD. The studies selected include randomized trials evaluating FDC therapy with at least one blood pressure-lowering drug and one lipid-lowering drug. The study data were independently extracted, the quality of evidence was appraised by multiple reviewers and effect estimates were pooled using a fixed-effect meta-analysis when statistical heterogeneity was low to moderate. The main outcomes of the analysis were all-cause mortality, fatal and nonfatal ASCVD events, adverse events, systolic blood pressure, low-density lipoprotein cholesterol and adherence. Among 26 trials (n = 27,317 participants, 43.2% female and mean age range 52.9-76.0), FDC therapy was associated with lower low-density lipoprotein cholesterol and systolic blood pressure, with higher rates of adherence and adverse events in both primary and mixed secondary prevention populations. For studies with a mostly primary prevention population, FDC therapy was associated with lower risk of all-cause mortality by 11% (5.6% versus 6.3%; relative risk (risk ratio) of 0.89; 95% confidence interval 0.78 to 1.00; I2 = 0%; four trials and 16,278 participants) and risk of fatal and nonfatal ASCVD events by 29% (6.1% versus 8.4%; relative risk (risk ratio) of 0.71; 95% confidence interval 0.63 to 0.79; I2 = 0%; five trials and 15,503 participants). One adequately powered trial in an exclusively secondary prevention population showed that FDC therapy reduced the risk of major adverse cardiovascular events by 24%. These findings support adoption and implementation of polypills to lower risk for all-cause mortality and ASCVD.

A Case Report on the Efficacy of Trastuzumab Emtansine in a Patient With Human Epidermal Growth Factor Receptor 2 Exon 20-Mutated Adenocarcinoma of the Lung.

Lung cancer is the foremost reason for cancer-related mortality among men and women. The ultimate goal of patient supervision post-diagnosis for advanced cases is to improve survival and quality of life with minimal treatment-associated side effects. With advancements in genomic medicine and a better understanding of cell signaling pathways, many actionable gene mutations have been identified in lung carcinoma, which drastically improve survival outcomes. Mutations in human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor together are observed in nearly 1-3% of cases and act as an oncogenic driver. In the case of HER2-mutant lung cancers, there are limited approved agents, and the treatment represents a critical unmet medical need because of the poorer survival outcomes compared to patients with additional oncogenic drivers. The recent standard of care of treatment is chemotherapy, but reports suggest that compared with cytotoxic chemotherapy, patients receiving HER2-directed therapies have relatively longer median survival duration. Here, we report a case of HER2 exon 20-mutated metastatic lung adenocarcinoma patient who received trastuzumab emtansine in the third-line setting and achieved durable disease control.

Addition of trastuzumab emtansine (T-DM1) in a human epidermal growth factor receptor 2-overexpressed metastatic carcinoma of the gallbladder patient to enhance survival: A case study.

Biliary tract cancers are clinically and genetically heterogeneous cancer type with a worst prognosis among gallbladder adenocarcinoma patients. Systemic therapeutic options for metastatic biliary tract cancers are fewer, and there are limited treatment choices for the patients who progress on first line apart from symptomatic treatment. Thus, a biomarker-guided personalized treatment approach needs to be explored among biliary tract cancer subtypes. We encountered a case of 53-year-old male patient with human epidermal growth factor receptor 2 (HER2, ERBB2) positive metastatic gallbladder cancer, treated with first-line gemcitabine and cisplatin combination-based chemotherapy along with trastuzumab followed by second-line treatment with mFOLFIRINOX. On progression in third line, treated with single agent ado-trastuzumab emtansine targeting human epidermal growth factor receptor 2 and got survival benefit of nearly 6 months. This is the first reported case from India that explored the possibility and impact of ado-trastuzumab emtansine in advanced gallbladder cancer after exhausting standard treatment options. It highlights the possibility of exploring ado-trastuzumab emtansine for treatment resilient, human epidermal growth factor receptor 2-positive and advanced gallbladder adenocarcinoma.

Neurohormonal Blockade During Left Ventricular Assist Device Support.

Neurohormonal blockade (NHB) is the mainstay of therapy for patients with systolic heart failure (HF). However, the efficacy in patients with left ventricular assist devices (LVADs) remains unknown. Of all, 114 LVAD patients (57 [48, 65] years old and 78% male) were enrolled and followed during the early period (6 months after index discharge), and 98 were followed during the late period (6-12 months following index discharge). Of them, 46% were on beta-blocker (BB), 49% on angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin II receptor blocker (ARB), and 51% on aldosterone antagonist at baseline. Prevalence of BB and ACEi/ARB use increased during the study period. During the early period, similar event rates were found irrespective of the NHB uses. During the late period, BB was associated with reduced HF readmission, and ACEi/ARB was associated with reduced HF readmission and gastrointestinal bleeding (p < 0.05 for all). In conclusion, BB and ACEi/ARB use during the late period was associated with a reduction in HF recurrence in LVAD patients. Further prospective randomized control trials are warranted to clarify the utility of NHB therapy in LVAD patients.

Combined Left Ventricular Assist Device and Coronary Artery Bypass Grafting Surgery: Should We Bypass the Bypass?

Left ventricular assist devices (LVADs) have become a mainstay of therapy for advanced heart failure. Although selected patients undergo concomitant coronary artery bypass grafting (CABG) at the time of LVAD implantation, the detailed implication of this combined surgical approach is not yet well studied. In this study, all ischemic cardiomyopathy patients who underwent concomitant CABG during LVAD implantation between 2010 and 2016 were enrolled. A control group matching for age, gender, and device type, were selected. Of 79 LVAD patients finally included, 28 patients underwent concomitant CABG (CABG group); whereas 51 did not (non-CABG group). There was no difference in the baseline characteristics between groups. There was a trend toward longer cardiopulmonary bypass time in the CABG group (169 vs. 147 min; p = 0.09). One month survival in the CABG group was significantly lower than the non-CABG group (75.0% vs. 94.1%; p = 0.014). No difference in the occurrence of ventricular arrhythmias was detected between the groups, nor was there a difference in the incidence or severity of right ventricular failure. Concomitant CABG surgery during LVAD implantation may carry significant perioperative mortality, and addition of CABG to LVAD surgery may be performed only in strictly selected cases.

A histopathologic schema to quantify the burden of cardiac amyloidosis: Relationship with survival and echocardiographic parameters.

BACKGROUND: Despite routine use of echocardiographic parameters to evaluate the severity of cardiac amyloidosis (CA), this methodology has not been well validated. We developed a histopathologic schema for quantifying CA burden and evaluated its relationship with clinical outcomes. Additionally, echocardiographic parameters were tested as potential noninvasive indices of CA burden. METHODS: We retrospectively studied 59 patients with CA (17 light chain, 42 transthyretin) who underwent endomyocardial biopsies. Light microscopy with staining was used to categorize CA burden as mild-to-moderate (<50%) or high (≥50%). Kaplan-Meier survival analysis was performed for the two groups. In 34 patients with good-quality echocardiograms, we measured left ventricular volumes, ejection fraction (EF), interventricular septal thickness (IVSt), posterior wall thickness (PWt), LV mass, lateral e'-velocity, and global longitudinal strain (GLS). These parameters were compared between the two groups. RESULTS: Thirty-five patients had mild-to-moderate and 24 severe amyloid burden. Kaplan-Meier curves demonstrated a trend toward worse mortality with high CA burden, which was more common and associated with higher mortality specifically in transthyretin-type patients. Echocardiography-derived IVSt, PWt, and LV mass were directly related to CA burden, while LV EF, e'-velocity, and GLS magnitude were inversely related to CA burden. CONCLUSIONS: Our findings provided a signal that CA burden is a clinically important entity with potentially valuable prognostic information. Echocardiographic parameters of LV anatomy and function correlate with histopathologic burden of CA, which is inversely related to survival. Further studies are needed to determine whether these parameters could be used as imaging biomarkers of treatment-related changes in CA burden.

Transcranial Doppler Identification of Neurologic Injury during Pediatric Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND: We used transcranial Doppler to examine changes in cerebral blood flow velocity in children treated with extracorporeal membrane oxygenation. We examined the association between those changes and radiologic, electroencephalographic, and clinical evidence of neurologic injury. METHODS: This was a retrospective review and prospective observational study of patients 18 years old and younger at a single university children's hospital. Transcranial Doppler studies were obtained every other day during the first 7 days of extracorporeal membrane oxygenation, and 1 additional study following decannulation, in conjunction with serial neurologic examinations, brain imaging, and 6- to 12-month follow-up. RESULTS: The study included 27 patients, the majority (26) receiving veno-arterial extracorporeal membrane oxygenation. Transcranial Doppler velocities during extracorporeal membrane oxygenation were significantly lower than published values for age-matched healthy and critically ill children across different cerebral arteries. Neonates younger than 10 days had higher velocities than expected. Blood flow velocity increased after extracorporeal membrane oxygenation decannulation and was comparable with age-matched critically ill children. There was no significant association between velocity measurements of individual arteries and acute neurologic injury as defined by either abnormal neurologic examination, seizures during admission, or poor pediatric cerebral performance category. However, case analysis identified several patients with regional and global increases in velocities that corresponded to neurologic injury including stroke and seizures. CONCLUSIONS: Cerebral blood flow velocities during extracorporeal membrane oxygenation deviate from age-specific normal values in all major cerebral vessels and across different age groups. Global or regional elevations and asymmetries in flow velocity may suggest impending neurologic injury.

Mealtime behavior among parents and their young children with food allergy.

BACKGROUND: Food allergies are increasingly prevalent in the pediatric population. Balancing allergen avoidance with the promotion of healthy eating behaviors can be challenging for families. OBJECTIVE: To characterize mealtime behaviors among parents of young children with food allergy. METHODS: Seventy-four parents of young children with food allergies (≤7 years of age) completed measures of mealtime behavior, perceptions of food allergy risk and severity, pediatric parenting stress, and food allergy-related quality of life. Mealtime behavior reports were compared with published data regarding typically developing children, young children with type 1 diabetes, and children with diagnosed feeding disorders (with or without related medical factors). RESULTS: Parents of young children with food allergies reported frequent mealtime concerns. Specifically, they reported significantly more mealtime behavioral concerns than typically developing peers, comparable mealtime behavioral concerns to young children with type 1 diabetes, and significantly fewer mealtime behavioral concerns than children with diagnosed feeding disorders. Parental mealtime concerns were positively correlated with other parent perceptions of food allergy, such as risk of allergen exposure, illness-related parenting stress, and food allergy-related quality of life. CONCLUSION: Young children with food allergy and their parents are more likely to exhibit mealtime behavioral concerns than typically developing peers and their parents. Future research should investigate the effect of food allergies and maladaptive mealtime behaviors on children's nutrition to provide clinical guidelines for parents who may benefit from psychosocial and/or nutritional support.

Use of Transcranial Doppler for Management of Central Nervous System Infections in Critically Ill Children.

BACKGROUND: The primary objective of this study was to characterize changes in cerebral blood flow measured using transcranial Doppler in children with central nervous system infections. We hypothesized that children with central nervous system infections have abnormal cerebral blood flow, associated with a greater frequency of complications and poor neurological outcome. METHODS: We conducted a single-center, retrospective study of children admitted to the neonatal or pediatric intensive care unit with central nervous system infection and undergoing transcranial Doppler as part of routine care between March 2011 and July 2015. RESULTS: A total of 20 children with central nervous system infection underwent 35 transcranial Dopplers. The mean age was 8.2 ± 6.3 years, including 12 boys and eight girls. The most common infection was meningitis (n = 11, 55%), with the remainder comprising encephalitis (15%), meningoencephalitis (20%), and abscess or empyema (10%). Bacterial (n = 10, 50%) and viral (n = 6) sources were common with only one (5%) fungal infection and three (15%) unknown but presumed viral etiology. The patients underwent transcranial Doppler 4 ± 9 days after intensive care unit admission. Mean cerebral blood flow velocities were overall increased compared with reference values for age (healthy children and critically ill children) mostly because of hyperemia (n = 21, 60%) and vasospasm (6%). Hypoperfusion (cerebral blood flow velocity <1 S.D. of normal value) in at least one vessel was associated with morbidity (intubation, vasoactive medications, neurosurgery, cardiac arrest) (P = 0.04) and mortality (P = 0.03). Two patients had increased intracranial pressure and hyperventilation was safely achieved with transcranial Doppler monitoring to avoid ischemia. Serial transcranial Dopplers were used to guide blood pressure management. CONCLUSIONS: Transcranial Doppler can be used in children with central nervous system infection as a tool to assess cerebral blood flow. In this retrospective study, cerebral hypoperfusion was associated with increased morbidity and mortality. If transcranial Doppler is to guide medical therapy and management of cerebral blood flow in children with central nervous system infections, these results will need to be validated in prospective studies with a more homogenous population of children with encephalitis or meningitis.

Primary Care Continuity Improves Diabetic Health Outcomes: From Free Clinics to Federally Qualified Health Centers.

INTRODUCTION: There are a number of well-established barriers to accessing primary care. The LINKED Study set out to improve primary care usage through 1-on-1 counseling and referrals for patients with diabetes being treated at local free clinics. We hypothesized that this educational intervention paired with expedited referral would increase the use of federally qualified health centers (FQHCs) as a source of health care and ultimately lead to improved diabetic health. METHODS: Medical student volunteers counseled participants on the importance of primary care. The participants then completed surveys about diabetic health, socioeconomic status, and general demographics. Participants were subsequently assigned to 1 of 2 FQHCs; designated care coordinators facilitated appointments. At the end of a 9-month action period, participants repeated the initial surveys, now including appointment history and health data (hemoglobin A1c (%) [HbA1c], body mass index). RESULTS: Sixty-eight participants were enrolled. The average time since a diagnosis of diabetes mellitus was 8.3 years (standard deviation [SD], 8.4 years), and 25% of participants used insulin. Mean baseline HbA1c for participants with a recorded value (n = 55) was 9.5 (SD, 2.5). FQHC appointments were scheduled by 68% of participants; 38% of the participants attended ≥2 appointments. The most common reported barriers to accessing primary care were no prior health insurance (85.3%) and cost of medical care (72.1%). In our follow-up assessment there was a statistically significant decrease in HbA1c for those linked to FQHCs (9.5 [SD, 2.3] to 8.3 [SD, 2.2]; n = 21). CONCLUSIONS: This study demonstrates the utility of a linkage program from free clinics to FQHCs. Those individuals with diabetes receiving health care from an FQHC demonstrated improved glycemic control.

Checking In: A Pilot of a Physician-Delivered Intervention to Increase Parent-Adolescent Communication About Blood Glucose Monitoring.

Low-cost, translatable interventions to promote adherence in adolescents with type 1 diabetes are needed. This study evaluated a brief physician-delivered intervention designed to increase parent-adolescent communication about blood glucose monitoring. Thirty adolescent-parent dyads completed baseline questionnaires and received the physician-delivered intervention. Participants completed follow-up questionnaires at 12 weeks; HbA1c and glucometer data were abstracted from medical charts. Parent-reported conflict surrounding diabetes management decreased from pre- to postintervention. Participants who reported adhering to the intervention plan (n = 15) demonstrated an increase in blood glucose monitoring frequency and trends in improved HbA1c and parental diabetes collaboration from pre- to postintervention. Participants and physicians reported overall satisfaction with the program. Results demonstrate initial feasibility as well as a trend toward improvement in diabetes-specific health indicators for parent-adolescent dyads who adhered to program components. Frequent joint review of glucometer data can be a useful strategy to improve type 1 diabetes-related health outcomes and parent-adolescent communication.

Feasibility of the SMART Project: A Text Message Program for Adolescents With Type 1 Diabetes.

This study investigated response rates to the Self-Management and Research Technology Project, a 6-week text message program for adolescents with type 1 diabetes designed to provide diabetes self-management reminders and education. The rate of response to texts was high, with 78% of texts responded to during the 6-week period. Girls and participants who self-reported sending a large number of personal daily texts had higher response rates; other demographic and medical variables were unrelated to text response rates. Inclusion of mobile health technologies such as text messages in clinical care may be a unique, relevant method of intervention for youths with type 1 diabetes, regardless of age, socioeconomic status, or glycemic control.

Pilot and feasibility study: prospective proteomic profiling of mammary epithelial cells from high-risk women provides evidence of activation of pro-survival pathways.

Normal mammary gland homeostasis requires the coordinated regulation of protein signaling networks. However, we have little prospective information on whether activation of protein signaling occurs in premalignant mammary epithelial cells, as represented by cells with cytological atypia from women who are at high risk for breast cancer. This information is critical for understanding the role of deregulated signaling pathways in the initiation of breast cancer and for developing targeted prevention and/or treatment strategies for breast cancer in the future. In this pilot and feasibility study, we examined the expression of 52 phosphorylated, total, and cleaved proteins in 31 microdissected Random Periareolar Fine Needle Aspiration (RPFNA) samples by high-throughput Reverse Phase Protein Microarray. Unsupervised hierarchical clustering analysis indicated the presence of four clusters of proteins that represent the following signaling pathways: (1) receptor tyrosine kinase/Akt/mammalian target of rapamycin (RTK/Akt/mTOR), (2) RTK/Akt/extracellular signal-regulated kinase (RTK/Akt/ERK), (3) mitochondrial apoptosis, and (4) indeterminate. Clusters 1 through 3 comprised moderately to highly expressed proteins, while Cluster 4 comprised proteins that are lowly expressed in a majority of RPFNA samples. Our exploratory study showed that the interlinked components of mitochondrial apoptosis pathway are highly expressed in all mammary epithelial cells obtained from high-risk women. In particular, the expression levels of anti-apoptotic Bcl-xL and pro-apoptotic Bad are positively correlated in both non-atypical and atypical samples (unadjusted P < 0.0001), suggesting a delicate balance between the pro-apoptotic and anti-apoptotic regulation of cell proliferation during the early steps of mammary carcinogenesis. Our feasibility study suggests that the activation of key proteins along the RTK/Akt pathway may tip this balance to cell survival. Taken together, our results demonstrate the feasibility of mapping proteomic signaling networks in limited RPFNA samples obtained from high-risk women and the promise of developing rational drug targets or preventative strategies for breast cancer in future proteomic studies with a larger cohort of high-risk women.

Protein microarray analysis of mammary epithelial cells from obese and nonobese women at high risk for breast cancer: feasibility data.

BACKGROUND: Obesity is a well-established risk factor for cancer, accounting for up to 20% of cancer deaths in women. Studies of women with breast cancer have shown obesity to be associated with an increased risk of dying from breast cancer and increased risk of developing distant metastasis. While previous studies have focused on differences in circulating hormone levels as a cause for increased breast cancer incidence in postmenopausal women, few studies have focused on potential differences in the protein expression patterns of mammary epithelial cells obtained from obese versus nonobese women. METHODS: Protein expression was assessed by reverse-phase protein microarray in mammary epithelial cells from 31 random periareolar fine needle aspirations performed on 26 high-risk women. RESULTS: In this pilot and exploratory study, vimentin (unadjusted P=0.028) expression was significantly different between obese and nonobese women. CONCLUSIONS: Vimentin is integral both to adipocyte structure and function and to the epithelial-to-mesenchymal transition needed for cancer cell metastasis. Further research is needed to confirm this finding and determine the possible effects of the adipocyte microenvironment on the initiation and progression of breast cancer in high-risk women. IMPACT: Differential protein expression patterns obtained from a future expanded study may serve to elaborate the underlying pathology of breast cancer initiation and progression in obese women and identify potential biomarkers of response to preventative interventions such as dietary changes and exercise.