Initial Diagnosis and Treatment of Low-Risk Gestational Trophoblastic Neoplasia.

Gestational trophoblastic neoplasia (GTN) is a rare form of cancer that is treated according to the World Health Organization (WHO) risk score, which predicts responsiveness to single-agent chemotherapy. Patients with WHO risk scores ≤6 have low-risk GTN, for which cure rates near 100%. Most women with low-risk GTN will respond to single-agent chemotherapy, which is given with either methotrexate or dactinomycin, and allows women to retain their fertility. This article also discusses less common treatment paradigms including second dilation and curettage and hysterectomy, as well as the emerging role of immunotherapy in managing low-risk GTN.

Ultra High-risk Gestational Trophoblastic Neoplasia.

Ultra high-risk gestational trophoblastic neoplasia (GTN) refers to patients with World Health Organization prognostic risk scores of at least 13. The mortality risk for these patients averages 30%. Ultra high-risk GTN more frequently presents with higher tumor volume, liver and/or brain metastases, and very high human chorionic gonadotropin levels. The diagnostic evaluation must include a thorough evaluation for central nervous system disease. Prompt initiation of cisplatin - etoposide induction chemotherapy reduces the risks of early death. Collaborative services such as neurosurgery, radiation oncology, and interventional radiology may be required to manage hemorrhagic lesions.

Treatment of High-Risk Gestational Trophoblastic Neoplasia.

High-risk gestational trophoblastic neoplasia encompasses patients with high volumes of disease or diffuse metastatic involvement who are unlikely to achieve remission with single-agent chemotherapy. Etoposide-based multi-drug regimens form the core of high-risk therapy. Second-line therapy includes platinum-based regimens. Increasingly, third-line therapy uses immunotherapy. Surgical intervention may be required to resect foci of resistant disease or manage complications. Treatment should continue until the hCG is less that the reference range for normal, followed by at least 3 cycles of consolidation therapy. At least 2 years of hCG surveillance are advisable for most patients requiring multiagent therapy to encompass 95% of relapses.

Placental Site Trophoblastic Tumors and Epithelioid Trophoblastic Tumors.

Placental site trophoblastic disease (PSTT) and epithelioid trophoblastic tumor (ETT) are the rarest forms of gestational trophoblastic neoplasia (GTN) with unique clinical features and treatment considerations. Unlike other GTN, human chorionic gonadotropin (hCG) is minimally, if at all, elevated. Additionally, unlike other GTN, WHO risk scores are not applied to PSTT/ETT. Management of PSTT/ETT is predominately surgical with hysterectomy and possible lymphadenectomy. There are case reports of fertility sparing surgery for uterine confined disease. Multi-agent chemotherapy ± pembrolizumab is added for those with high risk features defined as advanced stage disease and those diagnosed ≥48 months from the antecedent pregnancy. Survival for early stage, low risk disease remains quite good but the prognosis for high-risk disease is poor and an scenario for which novel treatments are needed.

Identifying biochemical changes in the kidney using proton nuclear magnetic resonance in an adenine diet chronic kidney disease mouse model.

This study aimed to investigate the metabolic changes in the kidneys in a murine adenine-diet model of chronic kidney disease (CKD). Kidney fibrosis is the common pathological manifestation across CKD aetiologies. Sustained inflammation and fibrosis cause changes in preferred energy metabolic pathways in the cells of the kidney. Kidney cortical tissue from mice receiving a control or adenine-supplemented diet for 8 weeks (late inflammation and fibrosis) and 12 weeks (8 weeks of treatment followed by 4 weeks recovery) were analysed by 2D-correlated nuclear magnetic resonance spectroscopy and compared with histopathology and biomarkers of kidney damage. Tissue metabolite and lipid levels were assessed using the MestreNova software. Expression of genes related to inflammation, fibrosis, and metabolism were measured using quantitative polymerase chain reaction. Animals showed indicators of severely impaired kidney function at 8 and 12 weeks. Significantly increased fibrosis was present at 8 weeks but not in the recovery group suggesting some reversal of fibrosis and amelioration of inflammation. At 8 weeks, metabolites associated with glycolysis were increased, while lipid signatures were decreased. Genes involved in fatty acid oxidation were decreased at 8 weeks but not 12 weeks while genes associated with glycolysis were significantly increased at 8 weeks but not at 12 weeks. In this murine model of CKD, kidney fibrosis was associated with the accumulation of triglyceride and free lactate. There was an up-regulation of glycolytic enzymes and down-regulation of lipolytic enzymes. These metabolic changes reflect the energy demands associated with progressive kidney disease where there is a switch from fatty acid oxidation to that of glycolysis.

Atypical placental site nodules: Clinicopathologic features, management and patient outcomes in an institutional series.

OBJECTIVE: To report the New England Trophoblastic Disease Center (NETDC) experience with atypical placental site nodules (APSN). METHODS: The NETDC registry was reviewed from 2005 to 2022 and clinical data abstracted. Expert pathologists in GTD reviewed available slides with concurrent immunohistochemical analysis. Targeted deep sequencing was performed for four cases. RESULTS: Among 35 cases of APSN identified, 29 had clinical and demographic data available. Abnormal uterine bleeding (59.3%) was the most common presenting symptom. Most women (79.3%) had an antecedent live birth. Two cases were incidentally diagnosed after hysterectomy for other indications, and one case lost to follow-up. Among the remaining 26 cases, 11 (42.3%) opted for hysterectomy and 15 for re-sampling (57.7%), among whom 3 later underwent hysterectomy for persistent APSN. Subsequent obstetrical outcomes included 3 spontaneous abortions, 1 therapeutic abortion, 1 ectopic pregnancy, 2 cesarean sections, 1 cesarean hysterectomy, and 1 spontaneous vaginal delivery. Subsequent pathology was available for 26 cases: 4 epithelioid trophoblastic tumors (15.4%), 9 APSN (34.6%), 3 PSN (11.5%), and 10 without abnormalities (38.4%). Histopathologic characteristics of APSN included moderate to severe cytologic atypia, median Ki-67 proliferation index of 8%, and typical immunohistochemical profiles (diffuse or multifocal positivity for p63 and GATA-3 and absent or focal CD146). No histopathologic feature predicted ETT. Among 4 sequenced cases, no recurrent genomic features were identified. CONCLUSIONS: APSN is a rare form of gestational trophoblastic proliferation with uncertain malignant potential. While normal obstetric outcomes are possible, the persistence rate is high, and definitive management remains hysterectomy.

Diagnosis and Management of Molar Pregnancies.

Complete and partial molar pregnancies arise from abnormal fertilization with marked proliferation of syncytiotrophoblasts. Earlier diagnosis has reduced the frequency of severe medical complications at presentation; however, the risk of progression to gestational trophoblastic neoplasia (GTN) has remained unchanged. Initial assessment should include serum hCG measurement after physical examination, laboratory testing for organ dysfunction, and Doppler ultrasound. Following uterine evacuation, pathologic assessment can distinguish complete from partial moles or non-molar gestations. Close surveillance is essential for the timely diagnosis of GTN. Cure rates and subsequent obstetrics outcomes are excellent, but all patients should be referred for psychologic support and expert level care.

Surgical Management of Gestational Trophoblastic Neoplasia.

Gestational trophoblastic neoplasia (GTN) is primarily treated with chemotherapy, but surgery plays a key role at different steps in disease management, including initial diagnosis, primary therapy, and salvage options. Initial diagnosis is usually made by electric or manual vacuum aspiration for molar pregancy or uterine curettage for other forms of GTN. Excisional procedures of localized disease, whether second curettage or hysterectomy, can obviate chemotherapy, but patients still require monitoring for relapse. Resection remains a useful adjunct for either the management of isolated foci of chemoresistant disease or the management of bleeding complications.

Impact of tendon transfer on scapulothoracic and glenohumeral motion in children with brachial plexus birth injuries.

BACKGROUND: Tendon transfers are often utilized to improve shoulder external rotation and abduction in children with brachial plexus birth injuries and are designed to improve glenohumeral (GH) joint motion. However, changes in scapulothoracic (ST) and glenohumeral (GH) joint function after tendon transfer are not well defined. The purpose of this study was to quantify changes in GH, ST, and humerothoracic (HT) joint function before and after tendon transfer, and we hypothesized that tendon transfers would reorient the arc of motion into more external rotation and abduction, but not increase GH motion. METHODS: Motion analysis was performed in 15 children (ages 3-16) before and after transfer of teres major and/or latissimus dorsi. Scapulothoracic, GH, and HT joint angles were measured in a neutral, resting position and each of the modified Mallet positions. Joint angular displacements from the neutral position and the total arc of internal-external rotation for each joint were also calculated. Relevant joint angles, joint angular displacements, and internal-external rotation arcs were compared using multivariate analyses of variance with repeated measures and univariate post-hoc analyses. RESULTS: Glenohumeral and HT external rotation were significantly increased in all positions postoperatively. The arc of GH internal-external rotation was unchanged, but oriented in more external rotation after surgery. Only 6 patients gained active external rotation. Glenohumeral and HT internal rotation were significantly decreased after surgery, but ST internal rotation was significantly increased. Two patients had loss of midline function. In the abduction position, GH elevation joint angles were unchanged, but ST and HT elevation increased. DISCUSSION: Only four patients gained active GH external rotation and maintained their internal rotation. Each of those patients underwent isolated tendon transfer without concomitant joint release. Seven patients maintained their preoperative internal rotation, which was attributed to increased ST internal rotation. The other half of patients lost internal rotation and gained external rotation through reorientation of the arc of rotation. Nine patients gained HT elevation, with three attributed to increased ST upward rotation, five attributed to a combination of increased ST upward rotation and increased GH elevation, and one attributed to increased GH abduction contracture. These findings challenge the dogma that teres major/latissimus dorsi tendon transfers augment GH motion and highlight the importance of ST function for outcome determination.

Impact of Human Immunodeficiency Virus Drug Resistance Mutations Detected in Women Prior to Antiretroviral Therapy With Efavirenz + Tenofovir Disoproxil Fumarate + Lamivudine (or Emtricitabine).

Background: Two large studies suggest that resistance mutations to only nonnucleoside reverse transcriptase inhibitors (NNRTI) did not increase the risk of virologic failure during antiretroviral therapy (ART) with efavirenz/tenofovir disoproxil fumarate/lamivudine (or emtricitabine). We retrospectively evaluated a third cohort to determine the impact of NNRTI resistance on the efficacy of efavirenz-based ART. Methods: Postpartum women living with human immunodeficiency virus (HIV) were studied if they initiated efavirenz-based ART because of the World Health Organization's recommendation for universal ART. Resistance was detected by Sanger genotyping plasma prior to efavirenz-based ART and at virologic failure (HIV RNA >400 copies/mL). Logistic regression examined relationships between pre-efavirenz genotypes and virologic failure. Results: Pre-efavirenz resistance was detected in 169 of 1223 (13.8%) participants. By month 12 of efavirenz-based ART, 189 of 1233 (15.3%) participants had virologic failure. Rates of virologic failure did not differ by pre-efavirenz NNRTI resistance. However, while pre-efavirenz nucleos(t)ide reverse transcriptase inhibitors (NRTI) and NNRTI resistance was rare (8/1223 [0.7%]) this genotype increased the odds (adjusted odds ratio, 11.2 [95% confidence interval, 2.21-72.2]) of virologic failure during efavirenz-based ART. Age, time interval between last viremic visit and efavirenz initiation, clinical site, viremia at delivery, hepatitis B virus coinfection, and antepartum regimen were also associated with virologic failure. Conclusions: Resistance to NNRTI alone was prevalent and dual-class (NRTI and NNRTI) resistance was rare in this cohort, with only the latter associated with virologic failure. This confirms others' findings that, if needed, efavirenz-based ART offers most people an effective alternative to dolutegravir-based ART.

Shoulder Motion Overestimated by Mallet Scores.

BACKGROUND: Brachial plexus birth injuries (BPBI) occur in up 0.4 to 4.6 per 1000 live births. Weakness about the shoulder and development of glenohumeral joint contractures are common sequalae of BPBI. Shoulder function in children with BPBI is frequently assessed using the modified Mallet classification to evaluate upper extremity motion deficits. The purpose of this study was to assess the accuracy of the abduction, external rotation, and hand-to-mouth Mallet classification scores in children with BPBI using motion capture. METHODS: A retrospective study of 107 children with BPBI who underwent motion capture assessment and Mallet scores on the same date were reviewed. Motion capture measurements were used to calculate humerothoracic elevation and external rotation joint angles in the abduction/hand-to-mouth and external rotation positions, respectively. The humerothoracic joint angles were converted to the corresponding Mallet scores. Discrepancies between the Mallet scores determined by clinicians and those determined by motion capture were assessed. RESULTS: For abduction, 24.3% of Mallet scores were misclassified during clinical examination. Of the misclassified scores, 22 were overestimated by 1 point and 4 were underestimated by 1 point compared with motion capture. For external rotation, 72.9% of Mallet scores were misclassified during clinical examination. Only 5 patients had an HT elevation that was less than 40 degrees, with 4 of them (80%) having a Mallet hand-to-mouth score of 4. There were no differences in proportion of patients with HT elevation less than 40 degrees who had a Mallet score of 4 or a Mallet score less than 4. CONCLUSIONS: There was better agreement in global abduction Mallet scores compared with external rotation and hand-to-mouth Mallet scores. This difference was likely due to the complex compensatory strategies that patients employ while performing external rotation and hand-to-mouth positions. The inaccuracy of the clinically determined Mallet scores is alarming given that they are frequently utilized to assist with surgical indications and are commonly used as outcome measures. LEVEL OF EVIDENCE: Level IV Case series.

Changes in Shoulder Rotation Based on Elevation in Children With Brachial Plexus Birth Injury.

PURPOSE: Lack of shoulder external rotation is common in children with brachial plexus birth injuries. Development of glenohumeral (GH) dysplasia is associated with progressive loss of passive external rotation. Some authors recommend measuring external rotation with the arm adducted, whereas others recommend measurement with the arm in 90° of abduction. The purpose of this study was to compare active and passive external rotation and internal rotation measured in adduction versus abduction. METHODS: Fifteen children with brachial plexus birth injuries held their affected arms in maximal external and internal rotation with the arm adducted and the arm at approximately 90° of abduction. Active and passive rotations were measured with three-dimensional motion capture. Scapulothoracic (ST) internal/external rotation and GH internal/external rotation joint angles were calculated and compared using multivariable, one-way repeated measures analyses of variance. RESULTS: There were no significant differences for active or passive ST rotation in external rotation in adduction versus abduction. Glenohumeral external rotation was significantly increased with the arm in abduction compared with adduction both actively and passively. There were no differences in ST rotation in active versus passive conditions, but all GH rotations were significantly greater passively. CONCLUSIONS: Shoulder internal/external rotation in abduction and adduction is not interchangeable. Comprehensive assessment of shoulder external and internal rotation should include both adduction and abduction. CLINICAL RELEVANCE: For children with brachial plexus birth injuries, both active and passive GH external rotations were greater in abduction. Therefore, early GH joint dysplasia may be missed if GH external rotation is measured in abduction. Additionally, consistency in arm position is important for comparison over time. The entire ST rotation capacity was used to perform maximal internal and external rotation, but the entire passive GH range of motion was not actively used. This highlights an area for potential surgical intervention to improve motion.

Drug repurposing for glomerular diseases: an underutilized resource.

Drug repurposing in glomerular disease can deliver opportunities for steroid-free regimens, enable personalized multi-target options for resistant or relapsing disease and enhance treatment options for understudied populations (for example, children) and in resource-limited settings. Identification of drug-repurposing candidates can be data driven, which utilizes existing data on disease pathobiology, drug features and clinical outcomes, or experimental, which involves high-throughput drug screens. Information from databases of approved drugs, clinical trials and PubMed registries suggests that at least 96 drugs on the market cover 49 targets with immunosuppressive potential that could be candidates for drug repurposing in glomerular disease. Furthermore, evidence to support drug repurposing is available for 191 immune drug target-glomerular disease pairs. Non-immunological drug repurposing includes strategies to reduce haemodynamic overload, podocyte injury and kidney fibrosis. Recommended strategies to expand drug-repurposing capacity in glomerular disease include enriching drug databases with glomeruli-specific information, enhancing the accessibility of primary clinical trial data, biomarker discovery to improve participant selection into clinical trials and improve surrogate outcomes and initiatives to reduce patent, regulatory and organizational hurdles.

Corneal confocal microscopy detects early nerve regeneration after pharmacological and surgical interventions: Systematic review and meta-analysis.

Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that enables the identification of corneal nerve fibre degeneration and regeneration. To undertake a systematic review and meta-analysis of studies utilizing CCM to assess for corneal nerve regeneration after pharmacological and surgical interventions in patients with peripheral neuropathy. Databases (EMBASE [Ovid], PubMed, CENTRAL and Web of Science) were searched to summarize the evidence from randomized and non-randomized studies using CCM to detect corneal nerve regeneration after pharmacological and surgical interventions. Data synthesis was undertaken using RevMan web. Eighteen studies including 958 patients were included. CCM identified an early (1-8 months) and longer term (1-5 years) increase in corneal nerve measures in patients with peripheral neuropathy after pharmacological and surgical interventions. This meta-analysis confirms the utility of CCM to identify nerve regeneration following pharmacological and surgical interventions. It could be utilized to show a benefit in clinical trials of disease modifying therapies for peripheral neuropathy.

Symmetry in Frontal But Not Motor and Somatosensory Cortical Projections.

The neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision-making, where lateralization of function may be less important. This study contrasted the topographic precision of cell-type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to the ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. The motor cortex had somewhat stronger projections but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to the cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision-making.

Peritoneal dialysis versus haemodialysis for people commencing dialysis.

BACKGROUND: Peritoneal dialysis (PD) and haemodialysis (HD) are two possible modalities for people with kidney failure commencing dialysis. Only a few randomised controlled trials (RCTs) have evaluated PD versus HD. The benefits and harms of the two modalities remain uncertain. This review includes both RCTs and non-randomised studies of interventions (NRSIs). OBJECTIVES: To evaluate the benefits and harms of PD, compared to HD, in people with kidney failure initiating dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies from 2000 to June 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. MEDLINE and EMBASE were searched for NRSIs from 2000 until 28 March 2023. SELECTION CRITERIA: RCTs and NRSIs evaluating PD compared to HD in people initiating dialysis were eligible. DATA COLLECTION AND ANALYSIS: Two investigators independently assessed if the studies were eligible and then extracted data. Risk of bias was assessed using standard Cochrane methods, and relevant outcomes were extracted for each report. The primary outcome was residual kidney function (RKF). Secondary outcomes included all-cause, cardiovascular and infection-related death, infection, cardiovascular disease, hospitalisation, technique survival, life participation and fatigue. MAIN RESULTS: A total of 153 reports of 84 studies (2 RCTs, 82 NRSIs) were included. Studies varied widely in design (small single-centre studies to international registry analyses) and in the included populations (broad inclusion criteria versus restricted to more specific participants). Additionally, treatment delivery (e.g. automated versus continuous ambulatory PD, HD with catheter versus arteriovenous fistula or graft, in-centre versus home HD) and duration of follow-up varied widely. The two included RCTs were deemed to be at high risk of bias in terms of blinding participants and personnel and blinding outcome assessment for outcomes pertaining to quality of life. However, most other criteria were assessed as low risk of bias for both studies. Although the risk of bias (Newcastle-Ottawa Scale) was generally low for most NRSIs, studies were at risk of selection bias and residual confounding due to the constraints of the observational study design. In children, there may be little or no difference between HD and PD on all-cause death (6 studies, 5752 participants: RR 0.81, 95% CI 0.62 to 1.07; I2 = 28%; low certainty) and cardiovascular death (3 studies, 7073 participants: RR 1.23, 95% CI 0.58 to 2.59; I2 = 29%; low certainty), and was unclear for infection-related death (4 studies, 7451 participants: RR 0.98, 95% CI 0.39 to 2.46; I2 = 56%; very low certainty). In adults, compared with HD, PD had an uncertain effect on RKF (mL/min/1.73 m2) at six months (2 studies, 146 participants: MD 0.90, 95% CI 0.23 to 3.60; I2 = 82%; very low certainty), 12 months (3 studies, 606 participants: MD 1.21, 95% CI -0.01 to 2.43; I2 = 81%; very low certainty) and 24 months (3 studies, 334 participants: MD 0.71, 95% CI -0.02 to 1.48; I2 = 72%; very low certainty). PD had uncertain effects on residual urine volume at 12 months (3 studies, 253 participants: MD 344.10 mL/day, 95% CI 168.70 to 519.49; I2 = 69%; very low certainty). PD may reduce the risk of RKF loss (3 studies, 2834 participants: RR 0.55, 95% CI 0.44 to 0.68; I2 = 17%; low certainty). Compared with HD, PD had uncertain effects on all-cause death (42 studies, 700,093 participants: RR 0.87, 95% CI 0.77 to 0.98; I2 = 99%; very low certainty). In an analysis restricted to RCTs, PD may reduce the risk of all-cause death (2 studies, 1120 participants: RR 0.53, 95% CI 0.32 to 0.86; I2 = 0%; moderate certainty). PD had uncertain effects on both cardiovascular (21 studies, 68,492 participants: RR 0.96, 95% CI 0.78 to 1.19; I2 = 92%) and infection-related death (17 studies, 116,333 participants: RR 0.90, 95% CI 0.57 to 1.42; I2 = 98%) (both very low certainty). Compared with HD, PD had uncertain effects on the number of patients experiencing bacteraemia/bloodstream infection (2 studies, 2582 participants: RR 0.34, 95% CI 0.10 to 1.18; I2 = 68%) and the number of patients experiencing infection episodes (3 studies, 277 participants: RR 1.23, 95% CI 0.93 to 1.62; I2 = 20%) (both very low certainty). PD may reduce the number of bacteraemia/bloodstream infection episodes (2 studies, 2637 participants: RR 0.44, 95% CI 0.27 to 0.71; I2 = 24%; low certainty). Compared with HD; It is uncertain whether PD reduces the risk of acute myocardial infarction (4 studies, 110,850 participants: RR 0.90, 95% CI 0.74 to 1.10; I2 = 55%), coronary artery disease (3 studies, 5826 participants: RR 0.95, 95% CI 0.46 to 1.97; I2 = 62%); ischaemic heart disease (2 studies, 58,374 participants: RR 0.86, 95% CI 0.57 to 1.28; I2 = 95%), congestive heart failure (3 studies, 49,511 participants: RR 1.10, 95% CI 0.54 to 2.21; I2 = 89%) and stroke (4 studies, 102,542 participants: RR 0.94, 95% CI 0.90 to 0.99; I2 = 0%) because of low to very low certainty evidence. Compared with HD, PD had uncertain effects on the number of patients experiencing hospitalisation (4 studies, 3282 participants: RR 0.90, 95% CI 0.62 to 1.30; I2 = 97%) and all-cause hospitalisation events (4 studies, 42,582 participants: RR 1.02, 95% CI 0.81 to 1.29; I2 = 91%) (very low certainty). None of the included studies reported specifically on life participation or fatigue. However, two studies evaluated employment. Compared with HD, PD had uncertain effects on employment at one year (2 studies, 593 participants: RR 0.83, 95% CI 0.20 to 3.43; I2 = 97%; very low certainty). AUTHORS' CONCLUSIONS: The comparative effectiveness of PD and HD on the preservation of RKF, all-cause and cause-specific death risk, the incidence of bacteraemia, other vascular complications (e.g. stroke, cardiovascular events) and patient-reported outcomes (e.g. life participation and fatigue) are uncertain, based on data obtained mostly from NRSIs, as only two RCTs were included.