APOBEC3 mutagenesis drives therapy resistance in breast cancer.

Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer 1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.

Aversion of surgical exploration in patients with complex ovarian cysts secondary to overt hypothyroidism: A series of three cases.

Long-standing, overt hypothyroidism-induced bilateral multiloculated ovarian cysts represent an infrequent occurrence. Our first case, presented with bilateral complex ovarian masses, exhibited overt hypothyroidism symptoms, including lethargy, weight gain and subfertility, prompting consideration for surgical intervention. Similarly, in the second case, a girl aged 11 years with stunting, delayed bone age and academic challenges was referred for surgical exploration due to bilateral complex ovarian masses. Both cases revealed elevated thyroid-stimulating hormone levels during preoperative workup. Commencing levothyroxine replacement therapy resulted in complete regression of ovarian cysts and substantial symptom improvement within an 8-week timeframe. The third case, a previously diagnosed patient with Hashimoto's thyroiditis, benefited from the lessons gleaned in managing the initial cases, responding well to levothyroxine therapy, thereby averting the necessity for surgery in all three instances. These cases underscore the significance of considering thyroid function in the evaluation of ovarian masses and highlight the efficacy of levothyroxine replacement therapy in resolving both hypothyroidism and associated ovarian cysts, thereby obviating the need for surgical intervention.

Rise of Antibody-Drug Conjugates: The Present and Future.

Antibody-drug conjugates (ADCs) embody a simple, but elegant, vision for cancer therapy-the delivery of a potent cytotoxic agent to tumor cells with minimal damage to normal cells-so-called smart chemo. Although there were significant challenges in achieving this milestone culminating in the first Food and Drug Administration approval in 2000, subsequent advancements in technology have led to rapid drug development with regulatory approvals for ADCs targeting a variety of tumor types. The most successful application for solid tumors has been in breast cancer, with ADCs becoming the standard of care across traditional human epidermal growth factor receptor 2 (HER2)+, hormone receptor+ (HR+) and triple-negative disease subtypes. Moreover, the improved features and gains in potency with the development of ADCs have expanded the treatment-eligible population to those with low/heterogeneous expression of the target antigen on the tumor with trastuzumab deruxtecan or in the case of sacituzumab govitecan, agnostic to target expression. Despite their antibody-directed homing, these novel agents come with their share of toxicities obligating appropriate patient selection and vigilant monitoring while on treatment. As more ADCs are included in the treatment armamentarium, mechanisms of resistance need to be studied and understood for optimal sequencing. Modifying the payload to use immune-stimulating agents or combination therapies with immunotherapy and other effective targeted therapies may further extend the utility of these agents in the treatment of solid tumors.

Comparing the efficacy of oral labetalol with oral amlodipine in achieving blood pressure control in women with postpartum hypertension: randomized controlled trial (HIPPO study-Hypertension In Pregnancy & Postpartum Oral-antihypertensive therapy).

De novo - or as a continuum of antenatal hypertension -postpartum hypertension complicates ~2% of pregnancies. Many maternal complications, such as eclampsia and cerebrovascular accidents, occur in the postpartum period. Despite widespread use of antihypertensives during pregnancy and childbirth, there is a paucity of data on preferred medications in the postpartum period. This randomized controlled study enrolled 130 women who were started on antihypertensives. They were randomized to receive oral Labetalol(LAB, maximum 900 mg per day in three doses) or oral Amlodipine(AML, maximum 10 mg per day given in two doses). In the immediate postpartum, all women were closely monitored for neurological symptoms, blood pressure, heart rate, respiratory rate, urine output, and deep tendon reflex. The primary outcome was the time to achieve sustained blood pressure control for 12 h from the initiation of medication; secondary outcomes included side effects of both medications. Mean time to achieve sustained blood pressure control was lower in women who received AML than in those who received LAB-(mean difference 7.2 h; 38 95% CI 1.4, 12.9, p = 0.011). There were fewer severe hypertensive episodes among those with AML than in those who received LAB. However, the proportion of women who continued to require antihypertensives at discharge was higher in the AML group than in the LAB group (55.4% versus 32.3%, p = 0.008). None of the participants developed drug-related side effects. Among women with postpartum persistence or new-onset hypertension, oral AML achieved sustained blood pressure control in a shorter duration, with fewer hypertensive emergencies than oral LAB. (CTRI/2020/02/023236).Trial Registration details: The study protocol was registered with Clinical Trial Registry of India with CTRI Number CTRI/2020/02/023236 dated 11.02.2020. Protocol can be accessed at https://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=40435&EncHid=&modid=&compid=%27,%2740435det%27 .

ADCs or: How I Learned to Stop Worrying and Love Chemotherapy.

Antibody-drug conjugates are transforming cancer treatment, and payload characteristics are emerging as crucial determinants of clinical activity. As exemplified by Weng and colleagues, advancements in the linker and payload chemistry may provide the next evolutionary step in enabling this class of drugs to overcome chemoresistance and deliver even more profound responses. See related article by Weng et al., p. 950 (2).

Maternal and perinatal outcome in pregnancies complicated with portal hypertension: a systematic review and meta-analysis.

BACKGROUND: Portal hypertension is secondary to either cirrhotic or non-cirrhotic causes, and complicating pregnancy poses a challenge to the treating team. A systematic review was performed to determine maternal and perinatal outcomes in women with portal hypertension. Outcomes were compared among those with cirrhotic (CPH) with non-cirrhotic portal hypertension (NCPH) as well as non-cirrhotic portal fibrosis (NCPF) with extra-hepatic portal vein obstruction (EHPVO). METHODS: Medline and EMBASE databases were searched for studies reporting outcomes among pregnant women with portal hypertension. Reference lists from relevant papers and reviews were hand-searched for appropriate citations. Data were extracted to describe maternal complications, obstetric and neonatal outcomes. A random-effects model was used to derive pooled estimates of various outcomes, and final estimates were reported as percentages with a 95% confidence interval (CI). Cumulative, sequential and sensitivity analysis was studied to assess the temporal trends of outcomes over the period. RESULTS: Information on 895 pregnancies among 581 patients with portal hypertension was included from 26 studies. Portal hypertension was diagnosed during pregnancy in 10% (95% CI 4-24%). There were 22 maternal deaths (0%, 95% CI 0-1%), mostly following complications from variceal bleeding or hepatic decompensation. Variceal bleeding complicated in 14% (95% CI 9-20%), and endoscopic interventions were performed in 12% (95% CI 8-17%) during pregnancy. Decompensation of liver function occurred in 7% (95% CI 3-12%). Thrombocytopenia was the most common complication (41%, 95% CI 23-60%). Miscarriages occurred in 14% (95% CI 8-20%), preterm birth in 27% (95% CI 19-37%), and low birth weights in 22% (95% CI 15-30%). Risk of postpartum hemorrhage was higher (RR 5.09, 95% CI 1.84-14.12), and variceal bleeding was lower (RR 0.51, 95% CI 0.30-0.86) among those with CPH compared to NCPH. Risk of various outcomes was comparable between NCPF and EHPVO. CONCLUSION: One in ten pregnancies complicated with portal hypertension is diagnosed during pregnancy, and thrombocytopenia is the most common complication. Hepatic decompensation and variceal bleeding remain the most common cause of maternal deaths, with reduced rates of bleeding and its complications reported following the introduction of endoscopic procedures during pregnancy. CPH increases the risk of postpartum hemorrhage, whereas variceal bleeding is higher among NCPH.

Vaginal mesh erosion - a challenging entity.

Pelvic reconstructive surgery with mesh for pelvic organ prolapse (POP) has been reported to have a superior anatomical cure rate compared with traditional repair methods. Mesh-related adverse events are increasing worldwide. We describe a case of excision of mesh erosion following vaginal hysterectomy. A 45yr old lady presented with 3 × 2 cm infected mesh erosion on the anterior vaginal wall following a vaginal hysterectomy a year earlier in a camp setting. Cystoscopy was normal. Under anesthesia, the mesh was dissected from the vagina and excised. The vaginal edges were freshened, and approximated Postoperative period was uneventful, and she was discharged home the next day. Surgical revision is indicated for large or multiple erosions. Mesh excision can be a challenging procedure with difficulty in gaining access and increased risk of surgical bleeding. A multidisciplinary approach in conjunction with a urologist will help optimise outcomes.

Preparedness of healthcare facilities of manipur in the management of noncommunicable diseases: A cross-sectional study.

Background: India is experiencing a rapid health transition with a rising burden of noncommunicable diseases (NCDs), causing significant morbidity and mortality. Cost-effective interventions for comprehensive NCD management can only be designed after assessing the readiness of various health facilities. Objectives: This study aimed to assess the preparedness of healthcare facilities of Manipur in the management of NCDs and to assess the knowledge of doctors regarding NCDs. Methods: A cross-sectional study was conducted in 21 public healthcare facilities in seven districts of Manipur during October 2021. Readiness of these facilities was assessed through observation and interview of doctors and nurses using a checklist adapted from the WHO Package of Essential NCDs. Knowledge of 153 doctors was also assessed using a self-administered, structured questionnaire. Data were entered in SPSS-26 and expressed using descriptive statistics. Results: General readiness index of primary health centers (PHCs), community health centers (CHCs), district hospitals (DHs), and tertiary care centers (TCCs) was 47%, 66.3%, 73.2%, and 70%, respectively. CHCs were ready in the domains of patient care services (80%), human resources (75%), and advocacy (91.7%). DHs and TCCs were ready in terms of patient care services, human resources, record maintenance, referral system, and advocacy. PHCs were not ready in any of the nine domains. Majority of the doctors (88%) had inadequate knowledge regarding NCDs. Conclusion: PHCs and CHCs were not adequately prepared, but DHs and TCCs were ready to manage NCDs. More than four-fifth of the doctors had inadequate knowledge. Strengthening PHCs and CHCs and training of healthcare workers are needed for integrated NCD management.

Clinical Presentation and Management of Peripartum Pubic Diastasis.

Background: Symphysis pubis diastasis (SPD) is an uncommon peripartum complication which can have short-term morbidities secondary to pain and restricted movements as well as long-term complications. It is important to diagnose this condition as it causes significant discomfort to the nursing mothers. We present our experience in five patients with SPD who were managed successfully. Methods: Present study is an observation of five cases of SPD managed in a single unit in a tertiary care center over three years from January 2017 to December 2019. All women with symptoms of SPD with inter-pubic distance of more than 10 mm were selected for the study. The demographic profile, clinical details, diagnostic imaging findings, and treatment provided for such patients were noted down from the individual case records. Follow-up of each patient for improvement in the symptoms and X-ray findings was available till 3 months for each case. Results: Mean age of the women with SPD was 29.8 ± 5.4 years. Four women had vaginal delivery and one had vacuum delivery. Average birth weight is 3.26 ± 0.85 kg. Mean duration of first stage of labor is 6.6 ± 0.89 h and median of second stage is 35 min. Average inter-pubic distance at the time of diagnosis on X-ray was 1.84 ± 0.2 cm. All women were managed conservatively with bed rest, analgesics, pelvic binder and physiotherapy. Improvement in the range of movement was noted over average of 21.8 ± 3.7 days and symptoms resolved over 14.4 ± 2.6 weeks. Conclusion: Treating obstetrician should be aware of this condition as simple treatment measures can avoid the long-term morbidities and complications.

COVID-19 Vaccine hesitancy among pregnant women: A facility-based cross-sectional study in Imphal, Manipur.

Background: Vaccine hesitancy has been recognized as a public health issue which needs to be addressed urgently. Pregnant women with COVID-19 are at increased risk of adverse pregnancy outcomes. An assessment of the determinants of vaccine hesitancy will aid in the acceleration of vaccine administration among pregnant women. Objectives: The present study aimed to determine COVID-19 vaccine hesitancy among pregnant women in Imphal, Manipur and assess associated factors. Methods: Across-sectional study was conducted among pregnant women attending Obstetrics and Gynecology Department of a Tertiary Care Institute in Imphal, Manipur during August 2021. One hundred and sixty-three pregnant women were interviewed using a structured questionnaire over phone calls. Univariate analysis was carried out using the Chi-square test and multivariable logistic regression was performed to determine the factors significantly associated with vaccine acceptance. Results: The mean age of the participants was 28.3 ± 5.5 years and majority, 102 (62.6%) were multigravida and 27 (16.6%) had comorbidities. Vaccine hesitancy was found in 127 (77.9%) participants. Logistic regression analysis indicated that awareness on COVID-19 vaccine eligibility (P = 0.002), disagreement of vaccine being unsafe during pregnancy (P = 0.005), and agreement on vaccine benefiting the baby (P = 0.003) were the significant predictors of vaccine acceptance. Conclusion: Nearly four out of every five pregnant women had COVID-19 vaccine hesitancy. Pregnant women should be informed about the benefits and encouraged to take COVID-19 vaccine.

Quality of life assessment in women with spontaneous premature insufficiency: A comparative cross-sectional study.

OBJECTIVE: Premature ovarian insufficiency is cessation of ovarian function prior to 40 years of age. It is known to have varied short and long-term implications on the health of the women. The quality of life is affected in various domanins. The objective of this study is to evaluate QOL of women with POI and the factors associated with it, using WHO QOL-BREF scale. METHODS: This is a cross sectional comparative study. Women with premature ovarian insufficiency with normal karyotype were included before initiation of hormone replacement therapy as cases and age matched women without any menstrual irregularity, infertility or any chronic illness were included as controls. Written informed consent was obtained from all patients. The pre-validated Tamil version of the WHOQOL-BREF (26 items, 4 domains) was filled through face-to-face interview. The score of each domain was transformed into 0-100 as per the guideline provided by WHOQOL-BREF. Statistical analysis was done using SPSS version 19. RESULTS: A total of 100 (50 women with POI and 50 control women) completed the WHOQOL-BREF questionnaire. The mean age of the women who participated in the study was 29.6 ± 6.5 years. Among the cases, 72% were nulliparous. There was statistically significant difference in the median scores of overall QOL, physical, psychological and social domains between the two groups. Univariate analysis showed that nulliparity and infertility were the factors responsible for poor QOL, however, these were not independently associated with poor QOL after applying bivariate linear regression analysis. CONCLUSION: The scores of overall QOL, physical, psychological and social domains were poorer in women with POI as compared to healthy controls.

Evaluation of T-piece resuscitator in the delivery room management of pre-term neonates with respiratory distress syndrome in resource-limited settings: A pre-post intervention study.

The aim of our study was to evaluate the impact of the T-piece resuscitator in the delivery room management of pre-term neonates in a resource-limited setting. We compared the incidence rates of delivery room intubation, surfactant replacement therapy, pulmonary air leak syndrome, and pre-term very low birth weight infant mortality, before and after T-piece use. Bi-monthly neonatal resuscitation training sessions were conducted for healthcare providers during the study period. We emphasized hands-on experience with the T-piece resuscitator and delivery room early respiratory care practices during the post-intervention epoch. Our pre- and post-intervention data recorded statistically significant decline in delivery room intubations, a 32% decrease in surfactant replacement therapy, and a 57% decrease in air leaks in pre-term neonates. However, the use of T-piece resuscitator did not have a statistically significant effect on pre-term very low birth weight infant mortality.

Risk factors for posterior reversible encephalopathy syndrome in hypertensive pregnant women presenting with seizures.

Pregnant women developing generalised tonic-clonic seizures in the absence of a prior neurological disorder are often diagnosed as eclamptic. Posterior reversible encephalopathy syndrome (PRES) is a distinct neuroimaging condition associated with long-term sequelae, which may occur in pregnancy. Some reports suggested PRES to be the pathophysiological process leading to eclampsia, whereas others observed PRES and eclampsia to have varying clinical severity and risk factors. In this case-control study, risk factors associated with PRES were compared to those for eclampsia in women with hypertension presenting with seizures who had undergone neuroimaging. PRES was noted to occur in 22.5% (51/227) hypertensive pregnant women presenting with seizures that otherwise would have been classified as eclampsia. An additional 51 women with eclampsia underwent neuroimaging. Women who had PRES had higher systolic (155.3 vs 144.5, p = 0.04), diastolic (99.2 vs 93.4, p = 0.006) and mean (117.9 vs 110.4, p = 0.001) blood pressure at admission compared to those with eclampsia. Eclampsia and PRES may occur through a similar pathophysiological mechanism, resulting in the same spectrum of neurological complications of preeclampsia, with PRES being the severest form of the disease process. PRES is difficult to differentiate from eclampsia based on clinical and laboratory investigation, except for high blood pressures, without adjunctive MRI/CT neuroimaging. Future studies should assess the role of biomarkers as well as long-term neurological sequelae in pregnant women with a diagnosis of PRES.

Migration of Ventriculoperitoneal Shunt to the Uterus in a Child: A Case Report.

BACKGROUND: A ventriculoperitoneal shunt (VPS) is usually placed inside the peritoneal cavity for cerebrospinal fluid drainage. Rarely, it can migrate to various pelvic visceral organs. Inside the pelvis, the distal end of the shunt can perforate anywhere from the uterus or adnexa to the vulva, and migration through the uterus is extremely rare. CASE: A three-and-a-half-year-old girl presented with a cerebrospinal fluid leak through the vagina after uterine perforation by a VPS. The diagnosis was made with an ultrasound. Her symptoms resolved after revision surgery. CONCLUSION: In a patient with a VPS in situ, presenting with a watery fluid leak through the vagina, perforation of the fornix or uterus must always be kept in mind. Timely diagnosis and intervention can result in the prevention of complications.