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Diminished ovarian reserve (DOR), generally defined as a decreased number or quality of oocytes, has a significant impact on quality of life and fertility in women. In recent years, the incidence of DOR has been increasing and the ages of patients are younger. The search for an effective DOR treatment has emerged as one of the preeminent research topics in reproductive health. An effective DOR therapy would improve ovarian function, fertility, and quality of life in patients. In this review we evaluated DOR treatment progress both in Western medicine and Chinese medicine, and elucidated the characteristics of each treatment. [ABSTRACT FROM AUTHOR]

Background: Currently available antiretroviral 2-drug regimen (2DR) fixed dose combinations may not be suitable for specific situations including the presence of resistance associated mutations (RAM) or drug − drug interactions (DDI). The data on the use of the non-nucleoside reverse transcriptase inhibitor doravirine (DOR) and the integrase inhibitor dolutegravir (DTG) as an alternative 2DR remain scarce. Methods: People living with HIV with DOR + DTG as a 2DR are being followed in a prospective observational study. Results: This analysis describes 85 participants with a median age of 57 years. Median CD4-nadir was 173/µl and a majority (66%) had a history of HIV-associated or AIDS-defining conditions. Antiretroviral history was mostly extensive, and documentation of RAM was frequent. The main reasons for choosing DOR + DTG were DDI (29%), tolerability (25%), and cardiovascular risk reduction (21%). Plasma viral load at switch was < 50 copies/ml in all but 3 instances, median CD4 count was 600/µl. DOR + DTG was later changed to another regimen in 10 participants after a median of 265 days, the other 75 participants have remained on DOR + DTG for a median of 947 days. Conclusion: DOR + DTG as a 2DR proved to be a durable treatment option even in extensively pretreated individuals. [ABSTRACT FROM AUTHOR]

orBec® is an oral enteric-coated tablet formulation of the corticosteroid beclometasone, which has been developed by Enteron Pharmaceuticals, a subsidiary of Corporate Technology Development (now DOR BioPharma). orBec® is being developed for the treatment of gastrointestinal graft-versus-host disease (GVHD) and an NDA has been filed in the US. DOR BioPharma has also filed an MAA in Europe for the same indication. orBec® is designed to reduce the need for systemic immunosuppressive drugs, thereby improving the outcome of bone marrow and stem cell transplantation. DOR BioPharma may seek a marketing partner in the US and elsewhere for orBec® in GVHD and will seek a partner for other potential indications of the drug. In December 2001, Corporate Technology Development was acquired by Endorex Corporation (now DOR BioPharma). In October 1998, Enteron Pharmaceuticals (DOR BioPharma) entered into an exclusive, worldwide, royalty bearing license agreement with George B. McDonald, MD, including the right to grant sublicenses, for the rights to the intellectual property and know-how relating to orBec®. In January 2007, DOR BioPharma received $U53 million under a non-binding letter of intent from Sigma-Tau Pharmaceuticals. The agreement grants Sigma-Tau an exclusive right to negotiate terms and conditions for a possible business transaction or strategic alliance regarding orBec® and potentially other DOR pipeline compounds until 1 March 2007. Under the terms of the agreement, Sigma-Tau purchased $US 1 million of DOR's common stock, with an additional $US2 million paid in cash. If no agreement is reached by 1 March 2007, DOR will return the $US2 million to Sigma-Tau within 60 days. DOR BioPharma received an unsolicited proposal from Cell Therapeutics, Inc. to acquire DOR BioPharma in January 2007. Because of the non-binding agreement already signed with Sigma-Tau, DOR BioPharma's board of directors cannot consider Cell Therapeutics' merger proposal at this time. orBec® has been filed for approval in the US for the treatment of gastrointestinal GVHD. The US FDA accepted the NDA filing and has established a target date of 21 July 2007 for completion of review of the NDA. In November 2006, the EMEA determined that the MAA for orBec® for the treatment of gastrointestinal GVHD is complete and that the review process has begun. The data provided in the MAA and NDA submissions demonstrate that orBec® safely provides a lower risk of mortality compared with the current standard of care. Both filings are supported by data from two rndomised, double-blinded, placebo-controlled clinical trials. The first was a 129-patient pivotal phase lU clinical trial for orBec® conducted at 16 bone marrow/stem cell transplant centres in the US and France. The second trial was a 60-patient phase II clinical trial conducted at the Fred Hutchinson Cancer Research Centre. In the primary endpoint of its pivotal trial, time to treatment failure through day 50, orBec® failed to achieve statistical significance (p-value 0.1177). However, orBec® did achieve statistical significance in the secondary endpoints of time to treatment failure through day 80, and a reduction in mortality compared with placebo. In this trial, patient survival at the prespecified endpoint of 200 days post-transplant showed a statistically significant 66% reduction in mortality among patients randomised to orBec®. DOR BioPharma believes the primary endpoint was not achieved due to a higher than expected rate of treatment failures during the initial 10 days in both treatment groups. The mortality benefit in favour of orBec® was confirmed in a retrospective analysis of the phase II study, in which there was a 55% reduction in mortality at 200 days post-transplant.… [ABSTRACT FROM AUTHOR]

Objective: To explore the therapeutic effect of Bushen Yiqi Huoxue Decoction BYHD) in patients with diminished ovarian reserve (DOR). Methods: A total of 180 patients with DOR diagnosed from December 2013 to December 2014 were equally assigned into progynova and duphaston (E+D) group, Zuogui Pill group and BYHD group with 60 cases in each by computerized randomization. Patients received E+D, Zuogui Pill or BYHD for 12 months, respectively. Follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), anti-Müllerian hormone (AMH), antral follicle count (AFC), ovarian volume, endometrial thickness, and the resistance indices (RIs) of ovarian arteries and uterine arteries were observed before and after treatment. Results: Nine women (4 from the E+D group, 3 from the Zuogui Pill group, and 2 from the BYHD group) withdrew from the study. After 6 months, Zuogui Pill and BYHD significantly decreased FSH and LH and increased endometrial thickness and AMH (all P<0.01). BYHD also resulted in E2 elevation (P<0.05), ovary enlargement (P<0.05), AFC increase (P<0.01), and RI of ovarian arteries decrease (P<0.05). After 12 months, further improvements were observed in the Zuogui Pill and BYHD groups (all P<0.01), but BYHD showed better outcomes, with lower FSH, larger ovaries and a thicker endometrium compared with the Zuogui Pill group (all P<0.01). However, E+D only significantly increased endometrial thickness (P<0.01) and no significant improvements were observed in the RI of uterine arteries in the three groups. Conclusions: BYHD had a favorable therapeutic effect in patients with DOR by rebalancing hormone levels, promoting ovulation, and repairing the thin endometrium. The combination of tonifying Shen (Kidney), benefiting qi and activating blood circulation may be a promising therapeutic strategy for DOR. [ABSTRACT FROM AUTHOR]

Hypoxic/ischemic injury remains the most dreaded cause of neurological disability and mortality. Despite the humbling experiences due to lack of promising therapy, our understanding of the complex cascades underlying the neuronal insult has led to advances in basic science research. One of the most noteworthy has been the effect of opioid receptors, especially the delta-opioid receptor (DOR), on hypoxic/ischemic neurons. Our recent studies, and those of others worldwide, present strong evidence that sheds light on DOR-mediated neuroprotection in the brain, especially in the cortex. The mechanisms of DOR neuroprotection are broadly categorized as: (1) stabilization of the ionic homeostasis, (2) inhibition of excitatory transmitter release, (3) attenuation of disrupted neuronal transmission, (4) increase in antioxidant capacity, (5) regulation of intracellular pathways-inhibition of apoptotic signals and activation of pro-survival signaling, (6) regulation of specific gene and protein expression, and (7) up-regulation of endogenous opioid release and/or DOR expression. Depending upon the severity and duration of hypoxic/ischemic insult, the release of endogenous opioids and DOR expression are regulated in response to the stress, and DOR signaling acts at multiple levels to confer neuronal tolerance to harmful insult. The phenomenon of DOR neuroprotection offers a potential clue for a promising target that may have significant clinical implications in our quest for neurotherapeutics. [ABSTRACT FROM AUTHOR]

Background: Dynamic arterial elastance (Eadyn) has been investigated for its ability to predict hypotension during the weaning of vasopressors. Our study focused on assessing Eadyn's performance in the context of critically ill adult patients admitted to the intensive care unit, regardless of diagnosis. Main body: Our study was conducted in accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. The protocol was registered in PROSPERO (CRD42023421462) on May 26, 2023. We included prospective observational studies from the MEDLINE and Embase databases through May 2023. Five studies involving 183 patients were included in the quantitative analysis. We extracted data related to patient clinical characteristics, and information about Eadyn measurement methods, results, and norepinephrine dose. Most patients (76%) were diagnosed with septic shock, while the remaining patients required norepinephrine for other reasons. The average pressure responsiveness rate was 36.20%. The synthesized results yielded an area under the curve of 0.85, with a sensitivity of 0.87 (95% CI 0.74–0.93), specificity of 0.76 (95% CI 0.68–0.83), and diagnostic odds ratio of 19.07 (95% CI 8.47–42.92). Subgroup analyses indicated no variations in the Eadyn based on norepinephrine dosage, the Eadyn measurement device, or the Eadyn diagnostic cutoff to predict cessation of vasopressor support. Conclusions: Eadyn, evaluated through subgroup analyses, demonstrated good predictive ability for the discontinuation of vasopressor support in critically ill patients. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor and non-motor symptoms. Although levodopa is the primary medication for PD, its long-term use is associated with complications such as dyskinesia and drug resistance, necessitating novel therapeutic approaches. Recent research has highlighted the potential of targeting opioid and cannabinoid receptors as innovative strategies for PD treatment. Modulating opioid transmission, particularly through activating µ (MOR) and δ (DOR) receptors while inhibiting κ (KOR) receptors, shows promise in preventing motor complications and reducing L-DOPA-induced dyskinesia. Opioids also possess neuroprotective properties and play a role in neuroprotection and seizure control. Similar to this, endocannabinoid signalling via CB1 and CB2 receptors influences the basal ganglia and may contribute to PD pathophysiology, making it a potential therapeutic target. In addition to opioid and cannabinoid receptor targeting, the NLRP3 pathway, implicated in neuroinflammation and neurodegeneration, emerges as another potential therapeutic avenue for PD. Recent studies suggest that targeting this pathway holds promise as a therapeutic strategy for PD management. This comprehensive review focuses on neuromodulation and novel therapeutic approaches for PD, specifically highlighting the targeting of opioid and cannabinoid receptors and the NLRP3 pathway. A better understanding of these mechanisms has the potential to enhance the quality of life for PD patients. [ABSTRACT FROM AUTHOR]

Rationale: Delta opioid receptors (DORs) have been considered as a potential target to relieve pain as well as treat depression and anxiety disorders and are known to modulate other physiological responses, including ethanol and food consumption. A small number of DOR-selective drugs are in clinical trials, but no DOR-selective drugs have been approved by the Federal Drug Administration and some candidates have failed in phase II clinical trials, highlighting current difficulties producing effective delta opioid-based therapies. Recent studies have provided new insights into the pharmacology of the DOR, which is often complex and at times paradoxical. Objective: This review will discuss the existing literature focusing on four aspects: (1) Two DOR subtypes have been postulated based on differences in pharmacological effects of existing DOR-selective ligands. (2) DORs are expressed ubiquitously throughout the body and central nervous system and are, thus, positioned to play a role in a multitude of diseases. (3) DOR expression is often dynamic, with many reports of increased expression during exposure to chronic stimuli, such as stress, inflammation, neuropathy, morphine, or changes in endogenous opioid tone. (4) A large structural variety in DOR ligands implies potential different mechanisms of activating the receptor. Conclusion: The reviewed features of DOR pharmacology illustrate the potential benefit of designing tailored or biased DOR ligands. [ABSTRACT FROM AUTHOR]

Purpose: Serum anti-Mullerian hormone (AMH) levels estimate ovarian reserve. The purpose of this study was to identify a minimum serum AMH level that correlates with acceptable clinical pregnancy rate (CPR) in women with severe diminished ovarian reserve (DOR) undergoing in vitro fertilization (IVF). Methods(s): A historical cohort of severe DOR participants (age ≥35) with day 3 FSH of >10 ng/mL were included ( n = 120). Participants were categorized into 3 groups: AMH <0.2 (Group 1, n = 38), AMH = 0.2-0.79 (Group 2, n = 57) and AMH ≥ 0.8 (Group 3, n = 25) ng/mL. The main outcome was CPR. The number of retrieved and mature oocytes, transferred embryos, spontaneous abortion (SAB) and live birth (LB) rates were also evaluated. Result(s): Among the three groups, there was no difference in day 3 FSH and estradiol, total gonadotropins dose used per cycle, or LB. Participants in Group 1 were two years older than those in Group 2 and had significantly higher BMI than those in Groups 2 and 3. The three groups significantly differed in AFC (Group 1< Group 2< Group 3; p = 0.001) and cycle cancellation rate (Group 1> Group 2> Group 3; p = 0.006), and had a trend toward significance in SAB rate (Group 1> Group 2> Group 3; p = 0.06). Group 3 had significantly more retrieved and mature oocytes than Groups 1 or 2. Group 2 and 3 had significantly higher CPR per cycle start compared to Group 1. Although Group 2 had significantly fewer oocytes retrieved and mature oocytes than Group 3, CPR per cycle start for both groups was not different. ROC curve indicated that the point of maximal inflection between lower and higher CPR represents an AMH value of 0.2 ng/mL. Conclusion(s): AMH of 0.2 ng/mL appears to be a meaningful threshold for predicting CPR in women with severe DOR at our practice. This information can be crucial during the pre-cycle counseling of these women. [ABSTRACT FROM AUTHOR]

Background: Esophageal achalasia can be classified on the grounds of three distinct manometric patterns that correlate well with final outcome after laparoscopic Heller-Dor myotomy (LHM). No analytical data are available, however, on the postoperative picture and its possible correlation with final outcome. The aims of this study were: (a) to investigate whether manometric patterns change after LHM for achalasia; (b) to ascertain whether postoperative patterns and/or changes can predict final outcome; and (c) to test the hypothesis that the three known patterns represent different stages in the evolution of the disease.Methods: During the study period, we prospectively enlisted 206 consecutive achalasia patients who were assessed using high-resolution manometry (HRM) before undergoing LHM. Symptoms were scored using a detailed questionnaire. Barium swallow, endoscopy and HRM were performed, before and again 6 months after surgery.Results: Preoperative HRM revealed the three known patterns with statistically different esophageal diameters (pattern I having the largest), and patients with pattern I had the highest symptom scores. The surgical treatment failed in 10 cases (4.9%). The only predictor of final outcome was the preoperative manometric pattern (p = 0.01). All patients with pattern I preoperatively had the same pattern afterward, whereas nearly 50% of patients with pattern III before LHM had patterns I or II after surgery. There were no cases showing the opposite trend.Conclusions: Neither a change of manometric pattern after surgery nor a patient's postoperative pattern was a predictor of final outcome, whereas preoperative pattern confirmed its prognostic significance. The three manometric patterns distinguishable in achalasia may represent different stages in the disease's evolution, pattern III and pattern I coinciding with the early and final stages of the disease, respectively. [ABSTRACT FROM AUTHOR]

Purpose: To test whether the localization of worsening of pain during coughing, sneezing and straining matters in the assessment of lumbosacral nerve root compression or disc herniation on MRI.Methods: Recently the diagnostic accuracy of history items to assess disc herniation or nerve root compression on magnetic resonance imaging (MRI) was investigated. A total of 395 adult patients with severe sciatica of 6-12 weeks duration were included in this study. The question regarding the influence of coughing, sneezing and straining on the intensity of pain could be answered on a 4 point scale: no worsening of pain, worsening of back pain, worsening of leg pain, worsening of back and leg pain. Diagnostic odds ratio's (DORs) were calculated for the various dichotomization options.Results: The DOR changed into significant values when the answer option was more narrowed to worsening of leg pain. The highest DOR was observed for the answer option 'worsening of leg pain' with a DOR of 2.28 (95 % CI 1.28-4.04) for the presence of nerve root compression and a DOR of 2.50 (95 % CI 1.27-4.90) for the presence of a herniated disc on MRI.Conclusions: Worsening of leg pain during coughing, sneezing or straining has a significant diagnostic value for the presence of nerve root compression and disc herniation on MRI in patients with sciatica. This study also highlights the importance of the formulation of answer options in history taking. [ABSTRACT FROM AUTHOR]

Diagnosis of esophageal disorders is well ahead of available treatment options. With HRM, for example, one can identify numerous conditions and their variants, which may lose meaning if the clinical and therapeutic implications of these subclassifications are limited. We report an exemplary case of a patient with hiatal hernia complaining of reflux, dysphagia, and chest pain refractory to medical treatment. Jackhammer esophagus was diagnosed and a hybrid approach consisting of POEM and concomitant crural repair and Dor fundoplication is proposed. [ABSTRACT FROM AUTHOR]

Purpose: The aims were to assess (1) the diagnostic value of serum procalcitonin (PCT) for acute pyelonephritis (APN) in infants and children with urinary tract infections (UTIs) and (2) to compare the performance of two commonly used cutoff values. Methods: A meta-analysis of serum PCT in the diagnosis of APN among pediatrics with lower UTIs was conducted. The process of search strategy, publications selection and data analysis was in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. Results: Eighteen high-quality studies with a total of 831 APN patients and 651 individuals with lower UTIs were analyzed. The overall performance of serum PCT ≥ 0.5 ng/mL was as follows: pooled sensitivity of 0.86 (95 % CI 0.73-0.93), pooled specificity of 0.76 (95 % CI 0.66-0.83), DOR of 18.90 (95 % CI 6.78-52.71) and AUROC of 0.86 (95 % CI 0.83-0.89), with significant heterogeneity. However, use of 1.0 ng/mL as a cutoff value produced an improved specificity of 0.91 (95 % CI 0.86-0.94), a DOR of 55.06 (95 % CI 22.57-115.48) and an AUROC of 0.94 (95 % CI 0.92-0.96), without obvious heterogeneity. Conclusion: In pediatrics with UTIs, the cutoff value of serum PCT, 1.0 ng/mL, has a preferable diagnostic performance compared with 0.5 ng/mL for APN. Additional prospective studies that propose an appropriate cutoff value and validate the performance of PCT for young with APN are needed in the future. [ABSTRACT FROM AUTHOR]

We carried out a retrospective cohort study on patients with metastatic non-small cell lung cancer (mNSCLC) to identify the peripheral blood count parameters associated with response to immune checkpoint inhibitors (ICIs). There were 17 males and 15 females. Their median age was 64.5 years (range 20-84). History of smoking was present in 25/32 (78%) patients. Twelve patients received pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial responses. There was no difference in the distribution of sex, age, and smoking status between responders and non-responders. The median time to response (TTR) was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm3 had a significantly shorter median TTR than those with AMCs ≤ 700/mm3 (8 weeks vs 12 weeks; p = 0.048). Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs ≤ 4200/mm3 after first dose were more likely to respond than those with ANCs > 4200/mm3 (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy. [ABSTRACT FROM AUTHOR]

Background: Alterations in neurosteroid secretion have been implicated in the efficacy of antidepressants. In a previous study, the adrenal androgen DHEA, a precursor of the neurosteroid androsterone, produced antidepressant and libido-enhancing effects in patients with midlife depression. To investigate the mechanisms underlying DHEA's behavioral effects in this same patient group, we examined plasma levels of four additional neurosteroids implicated in the regulation of affective behavior. Methods: Blood samples were assayed for neurosteroids in men ( n = 13) and women ( n = 10) with midlife depression who previously participated in a crossover study in which DHEA and placebo were administered for 6 weeks each. Depression severity was measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma levels of androsterone (ADT), allopregnanolone, pregnanolone, and pregnenolone were measured by GC-MS at baseline and week 6 of each treatment phase. Data were analyzed with repeated measures analysis of variance (ANOVA-R) and Bonferroni t tests. Results: ADT levels (but not allopregnanolone, pregnanolone, and pregnenolone) increased after DHEA but not after placebo ( F = 3.3, p < 0.05). Post-DHEA ADT levels were higher in women than men [ t = 2.9, p < 0.05]. However, in both men and women who met criteria for clinical response on the CES-D, baseline ADT levels significantly increased post-DHEA, and the magnitude of the ADT increase post-DHEA treatment was similar in men and women. Consequently, it was the non-responders who accounted for the sex difference in post-DHEA plasma ADT levels, a difference that was driven by values in two women (the only female non-responders). Conclusions: The small sample size notwithstanding, these data emphasize the potential behavioral relevance of ADT in humans, which may include contribution to the antidepressant effects of DHEA. [ABSTRACT FROM AUTHOR]

Treatment-resistant major depressive disorder remains inadequately treated with currently available antidepressants. Opioid receptors (ORs) are involved in the pathophysiology of depression yet remain an untapped therapeutic intervention. The μ-δ OR heteromer represents a unique signaling complex with distinct properties compared with μ- and δ-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the μ-δ heteromer, we devised a strategy to selectively antagonize the function of the μ-δOR complex using a specific interfering peptide derived from the δOR distal carboxyl tail, a sequence implicated in μ-δOR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of δ-agonists at the μ-δ heteromer, with no effect on μ- or δ-OR homomers, and a dissociation of the μ-δOR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the δ-agonist UFP-512 (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid) measured in the forced swim test, novelty-induced hypophagia and elevated plus maze paradigms in rats. UFP-512's antidepressant-like and anxiolytic-like actions were abolished by pretreatment with either μOR or δOR antagonists. Overall, these findings demonstrate that the μ-δ heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders. [ABSTRACT FROM AUTHOR]

Purpose: Surgical outcomes data for patent ductus arteriosus (PDA) ligation come primarily from single institution case series. The purpose of this study was to evaluate national PDA ligation trends, and to compare outcomes between pediatric general (GEN) and pediatric cardiothoracic (CT) surgeons. Methods: The Pediatric Health Information System database was queried to identify neonates who underwent PDA ligation from 2006 through 2009. Outcomes evaluated included surgical morbidity, in-hospital mortality, length of stay, and total charges. Outcomes were compared between pediatric general and pediatric cardiothoracic surgeons. Results: The records of 1,482 neonates who underwent PDA ligation were identified and analyzed. Overall mean gestational age was 26 ± 3 weeks and birth weight was 888 ± 428 g. The majority of patients among both surgeons had birth weights of ≤1,000 g (77.2 %) and were born at ≤27-week gestation (81.5 %). Most of the PDA ligations were performed by pediatric CT surgeons ( n = 1,196, 80.7 %). The mortality rate did not differ by surgeon subspecialty training (GEN = 5.2 %, CT 7.9 %, p = 0.16). Neonates in the cardiothoracic surgeon cohort showed lower length of stay ( p < 0.001-0.05) and total hospital charges ( p < 0.05) among patients with birth weight ≤1,200 g. Proxy measures of surgical morbidity-gastrostomy, fundoplication, and tracheostomy-showed no significant differences between the two surgical subspecialists overall or across birth weight subgroups ( p > 0.05). Conclusion: These data provide a contemporary snapshot of PDA ligation outcomes at American children's hospitals. Pediatric general surgeons achieve comparable outcomes performing PDA ligation compared to pediatric cardiothoracic surgeons. [ABSTRACT FROM AUTHOR]

Purpose: Vinorelbine-trastuzumab combination proved to be an effective first-line treatment for patients with locally advanced or metastatic breast cancer (MBC). Oral chemotherapy represents a step forward in MBC management. To improve patients' comfort using the oral form of vinorelbine, we conducted a multicenter phase II study to investigate the efficacy and safety of the oral vinorelbine-trastuzumab combination in women with MBC with human epidermal growth factor receptor 2 (HER2) overexpression.Methods: Main eligibility criteria: HER2-positive disease, no adjuvant chemotherapy within the last 6 months and no prior chemotherapy for MBC. Patients were treated with oral vinorelbine 80 mg/m(2) D1, D8, D15 (following first 3 administrations at 60 mg/m(2) during the first cycle) for a total of 8 cycles (1 cycle = 3 weeks), in combination with trastuzumab 6 mg/kg on D1 (loading dose: 8 mg/kg) every 3 weeks or 4 mg/kg (loading dose: 6 mg/kg) weekly. Response was evaluated every 2 cycles using RECIST 1.0.Primary Endpoint: objective response rate (ORR); secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Results: In the full population (n = 26), median age was 50.7 years and median WHO PS 0. Median disease-free interval was 50.7 months [95 % CI (43.6-57.9)]. In the evaluable patients population, ORR was 56 % [95 % CI (34.9-75.6)], including 3 complete responses (12 %) and 11 partial (44 %); 8 (32 %) patients had stable disease resulting in a clinical benefit (or disease control) rate of 88 % [95 % CI (68.8-97.5)]. Median DOR was 7.1 months [95 % CI (3.9-10.2)], median PFS 6.7 months (95 % CI 3.5-10), and median OS 27.9 months (95 % CI 17.4-38.3). Treatment was generally well tolerated with main observed grade 3/4 hematological toxicities being neutropenia (46 %) and anemia (4 %). Grade 3-4 nausea-vomiting were observed in 11.5 % of patients.Conclusions: Our results confirm the efficacy of oral vinorelbine-trastuzumab combination as a first-line treatment in HER2-positive locally advanced or MBC patients with an acceptable safety profile. Oral vinorelbine-trastuzumab optimizes the convenience of this chemotherapy regimen, especially for patients receiving trastuzumab every 3 weeks. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the feasibility and utility of reduced port surgery (RPS) for achalasia. Methods: Between September 2005 and June 2013, 359 patients with esophageal achalasia, excluding cases of reoperation, underwent laparoscopic Heller myotomy and Dor fundoplication (LHD) according to our clinical pathway. Three-hundred and twenty-seven patients underwent LHD with five incisions (conventional approach), while the other 32 patients underwent RPS, including eight via SILS. The clinical data were collected in a prospective fashion and retrospectively reviewed. We selected 24 patients matched for gender, age and morphologic type with patients in the RPS group from among the 327 patients (C group). The surgical outcomes were compared between the C and RPS groups. Results: There were no significant differences between the two groups in the duration of symptoms, dysphagia score, chest pain score, shape of the distal esophagus and esophageal clearance. The operative time was significantly longer in the RPS group than in the C group ( p < 0.001). There were no significant differences between the two groups in the length of postoperative hospital stay or rates of bleeding, mucosal injury of the esophagus and/or stomach and postoperative complications. The symptom scores significantly improved after surgery in both groups ( p < 0.001). Furthermore, there were no significant differences between the C group and RPS group in terms of the postoperative symptom scores or satisfaction scores after surgery. Conclusions: The surgical outcomes of RPS for achalasia are comparable to those obtained with the conventional method. [ABSTRACT FROM AUTHOR]

Objective: Pepsin in saliva has been proposed as a biomarker for the diagnosis of laryngopharyngeal reflux (LPR), but the results remain controversial. We assessed the diagnostic value of pepsin in saliva for LPR.Methods: PubMed, Embase, and Web of Science were searched for studies in English that evaluated the utility of pepsin in saliva in the diagnosis of LPR, published up to 15 March 2017. We used Stata 12.0 to summarize the diagnostic indexes for the meta-analysis.Results: Eleven eligible studies met the inclusion criteria. After the meta-analysis of included studies, the pooled sensitivity and specificity were 64% [95% confidence interval (CI) 43–80%] and 68% (95% CI 55–78%), respectively; the positive (PLR) and negative (NLR) likelihood ratios were 2.0 (95% CI 1.4–2.9) and 0.54 (95% CI 0.33–0.87), respectively; the diagnostic odds ratio (DOR) was 4 (95% CI 2–8); and the area under the curve (AUC) was 0.71 (95% CI 0.67–0.75).Conclusion: Pepsin in saliva has moderate value in the diagnosis of LPR. The cutoff value used could affect the diagnostic value. Therefore, further investigations are required to find the optimal method to detect salivary pepsin in diagnosing LPR. [ABSTRACT FROM AUTHOR]

Background: Controversy remains whether preoperative pneumatic balloon dilation (PBD) influences the surgical outcome of laparoscopic esophagocardiomyotomy in patients with esophageal achalasia. The aim of this study was to evaluate whether preoperative PBD represents a risk factor for surgical complications and affects the symptomatic and/or functional outcomes of laparoscopic Heller myotomy with Dor fundoplication (LHD).Methods: A retrospective chart review was conducted on a prospectively compiled surgical database of 103 consecutive patients with esophageal achalasia who underwent LHD from November 1994 to September 2014. The following data were compared between the patients with preoperative PBD (PBD group; n = 26) and without PBD (non-PBD group; n = 77): (1) patients' demographics: age, gender, body mass index, duration of symptoms, maximum transverse diameter of esophagus; (2) operative findings: operating time, blood loss, intraoperative complications; (3) postoperative course: complications, clinical symptoms, postoperative treatment; and (4) esophageal functional tests: preoperative and postoperative manometric data and postoperative profile of 24-h esophageal pH monitoring.Results: (1) No significant differences were observed in the patients' demographics. (2) Operative findings were similar between the two groups; however, the incidence of mucosal perforation was significantly higher in the PBD group (n = 8; 30.7 %) compared to the non-PBD group (n = 6; 7.7 %) (p = 0.005). (3) Postoperative complications were not encountered in either group. The differences were not significant for postoperative clinical symptoms, the incidence of gastroesophageal reflux disease, or necessity of postoperative treatments. (4) Lower esophageal sphincter pressure was effectively reduced in both groups, and no differences were observed in manometric data or 24-h pH monitoring profiles between the two groups. Multivariate logistic regression analysis showed that preoperative PBD and the maximum transverse diameter of esophagus were significantly associated with intraoperative mucosal perforation.Conclusions: Although postoperative outcomes were not affected, additional caution is recommended in identifying intraoperative mucosal perforation in patients with preoperative PBD when performing LHD. [ABSTRACT FROM AUTHOR]

We herein report our technique for laparoscopic esophageal myotomy combined with Collis gastroplasty and Nissen fundoplication for severe esophageal stenosis. Our patient had experienced vomiting since childhood, and his dysphagia had gradually worsened. He was referred to our department for surgery because of resistance to pneumatic dilation. He was diagnosed with a short esophagus based on the findings of a preoperative upper gastrointestinal series and GI endoscopy. After exposing the abdominal esophagus, esophageal myotomy around the esophago-gastric junction (EGJ) was undertaken to introduce an esophageal bougie into the stomach. Then, stapled wedge gastroplasty was performed, and a short and loose Nissen fundoplication was performed. In addition, the bulging mucosa after myotomy was patched using the Dor method. The patient's postoperative course was uneventful. Most patients with esophageal stricture require subtotal esophagectomy. Laparoscopic surgery for patients with benign esophageal stricture refractory to repeated pneumatic dilation is challenging. However, our current procedure might abrogate the need for invasive esophagectomy for the surgical management of severe esophageal stenosis. [ABSTRACT FROM AUTHOR]

Purpose: Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC.Materials and Methods: We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL).Results: A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1-53.2%). The CBR was 54.3% (95% CI 37.8-70.8%). The median PFS was 6.2 months (95% CI 2.7-9.4 months) and median OS was 21.4 months (95% CI 11.5-32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients.Conclusions: Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC. [ABSTRACT FROM AUTHOR]

Purpose: Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC).Methods: Patients were randomized to EP 145 mg/m2 or irinotecan 350 mg/m2 Q21d until disease progression/unacceptable toxicity. The primary endpoint was progression-free survival (PFS) with response determined by central radiologic review (RECIST version 1.1).Results: The study was terminated before completing accrual due to evolving standards of care. Eighty-three patients were randomized. Median PFS was longer with EP versus irinotecan (4.0 versus 2.8 months, respectively; HR 0.65; 95% CI 0.40-1.04; P = 0.07). Six-month PFS rates were 32.8 and 15.4%, respectively. Median OS was 9.6 and 8.4 months in EP and irinotecan arms, respectively (HR 0.91; 95% CI 0.56-1.49). ORRs were 10 and 5%, respectively (P = 0.676); median DOR was significantly longer in EP arm (7.9 versus 1.4 months; P = 0.018). The most common grade-3/4 adverse events for EP and irinotecan were diarrhea (21 vs 20%), neutropenia (10 vs 22%), abdominal pain (14 vs 5%), nausea (14 vs 2%), and vomiting (12 vs 7%), respectively.Conclusion: EP is active and safe for second-line treatment of KRAS-mutant, irinotecan-naïve mCRC. [ABSTRACT FROM AUTHOR]

In this review, we cover the current understanding of BRAF mutations and associated clinical characteristics in patients with metastatic NSCLC, approved and emerging treatment options, BRAF sequencing approaches, and unmet needs. The BRAFV600E mutation confers constitutive activity of the MAPK pathway, leading to enhanced growth, proliferation, and survival of tumor cells. Testing for BRAF mutations enables patients to be treated with therapies that directly target BRAFV600E and the MAPK pathway, but BRAF testing lags behind other oncogene testing in metastatic NSCLC. Additional therapies targeting BRAFV600E mutations provide options for patients with metastatic NSCLC. Emerging therapies and combinations under investigation could potentially overcome issues of resistance and target non-V600E mutations. Therefore, because targeted therapies with enhanced efficacy are on the horizon, being able to identify BRAF mutations in metastatic NSCLC may become even more important. [ABSTRACT FROM AUTHOR]

Until recently, pneumatic dilatation and intrasphincteric injection of botulinum toxin (Botox) have been used as initial treatments for achalasia, with myotomy reserved for patients with residual dysphagia. It is unknown, however, whether these nonsurgical treatments affect the performance of a subsequent myotomy. We compared the results of laparoscopic Heller myotomy and Dor fundoplication in 44 patients with achalasia who had been treated with medications (group A, 16 patients), pneumatic dilatation (group B, 18 patients), or botulinum toxin (group C, 10 patients). The last group was further subdivided according to whether there was (C2, 4 patients) or was not (C1, 6 patients) a response to the treatment. Results for groups A, B, C1, and C2, respectively, were: anatomic planes identified at surgery (% of patients)--100%, 89%, 100%, and 25%; esophageal perforation (% of patients)--0%, 5%, 0%, and 50%; hospital stay (hrs)--26+/-8, 38+/-25, 26+/-11, and 72+/-65; and excellent/good results (% of patients)--87%, 95%, 100%, and 50%. These results show that: (1) previous pneumatic dilatation did not affect the results of myotomy; (2) in patients who did not respond to botulinum toxin, the myotomy was technically straightforward and the outcome was excellent; (3) in patients who responded to botulinum toxin, the LES muscle had become fibrotic (perforation occurred more often in this setting, and dysphagia was less predictably improved); and (4) myotomy relieved dysphagia in 91% of patients who had not been treated with botulinum toxin. These data support a strategy of reserving botulinum toxin for patients who are not candidates for pneumatic dilatation or laparoscopic Heller myotomy. [ABSTRACT FROM AUTHOR]

Introduction: Traditional treatment for the esophageal motility disorder, achalasia, ranges from endoscopic botulinum toxin (Botox) injections or balloon dilatation, to laparoscopic or open surgical myotomy. Recent advances in endoscopic therapy have led to peroral endoscopic myotomy (POEM) as a viable alternative to traditional techniques for myotomy. Uncertainty exists as to whether the procedure is feasible for patients who have already received prior endoscopic or surgical procedures for therapy, as these groups experience higher failure rates as well as intraoperative mucosal perforations and technical difficulty during Heller myotomy. We describe our first 40 patients who have undergone POEM and compare outcomes between patients who have or have not received previous treatment for achalasia. Methods and procedures: We evaluated our prospectively collected database of POEM procedures performed by two surgeons (JLP and JMM) at a single institution. Perioperative data was collected for operative and hospital outcomes. Patients completed pre- and postoperative GERD-Health-Related Quality of Life Questionnaires (GERD-HRQL) and SF-12 surveys for symptom scoring. Results: Forty patients received a POEM procedure between 2011 and 2013. Of these, 40 % ( n = 16) had had at least one prior endoscopic or surgical procedure. Nine had prior Botox injections, 7 had balloon dilations, 3 had both Botox and dilations, and 3 received prior laparoscopic Heller myotomy (two with Dor fundoplication). Mean operative time was 102 min for patients with prior procedures (Prior Tx) and 118 min for patients without any prior procedure (No Tx) ( p = 0.07). Intraoperative complication rates for the Prior Tx group were 12.5 versus 16.7 % for the No Tx group. Mean follow-up was 10 months. Both groups independently demonstrated clinical improvement in both the GERD-HRQL and SF-12 scores following POEM. There were no statistical differences between the two groups for GERD-HRQL reflux and dysphagia subset scores, or SF-12 mental component summary. Conclusion: We found favorable outcomes following POEM in patients who have had prior endoscopic or surgical treatments for achalasia, as well as for patients without prior intervention. There were no significant differences between these two groups with regards to operative times, GERD-HRQL scores, and mental component SF-12 scores. One complication requiring intervention occurred in a patient that had received multiple prior Botox injections and balloon dilatations. POEM appears to be a viable alternative for treatment of achalasia compared to traditional techniques, however, long-term data are needed to establish the durability of this technique and to determine whether symptoms will recur necessitating re-intervention. [ABSTRACT FROM AUTHOR]

The maturation and meiotic competence of human oocyte requires both healthy cytoplasmic and nuclear compartments. Germinal vesicle (GV) transfer techniques have represented useful tools for studying the interaction between the nucleus and the cytoplasm in oocyte maturation process in mammals. This report summarizes an update on the recent findings on GV transfer pertaining to improving meiotic resumption and ability of immature oocytes to mature. It also addresses mitochondrial DNA heteroplasmy as a challenge in GV transfer technology. Altogether, data to date indicate that GV transfer could improve the quality of human oocytes especially in women with advanced maternal age who usually have high rates of spindle abnormality and chromosomal misalignment. Although experimental, this technique represents a viable therapeutic option for women with diminished ovarian reserve who do not produce mature oocytes or good embryos during IVF treatment. [ABSTRACT FROM AUTHOR]

Research on COVID-19 vaccine hesitancy has been sparse among Latino/a immigrants, a population at high risk for infection. This exploratory study examines rates of vaccine acceptance and its association with psychological antecedents of vaccination among Latino/a immigrants. A cross-sectional telephone survey on perceptions of COVID-19 was administered between October 2020 to February 2021 in South Florida to 200 adult Latino/a immigrants. Descriptive statistics, bivariate analysis, and logistic regression were employed to determine the influence of independent variables on vaccine acceptance. Most participants indicated a willingness to get vaccinated. Participants with higher confidence (aOR = 10.2, 95% CI: 4.8–21.8) and collective responsibility scores were (aOR = 3.1, 95%CI:1.3–6.9) more likely to report vaccine acceptance than those with lower scores. No other psychological antecedents or demographic variables were significantly associated with vaccine acceptance. Study results provide insights into motivating factors for vaccination that can inform culturally tailored education campaigns to increase vaccine acceptability in this population. [ABSTRACT FROM AUTHOR]

Entrectinib (Rozlytrek®) is an oral selective inhibitor of the tyrosine kinases tropomyosin receptor kinases (Trk)A/B/C [encoded by the genes neurotrophic tyrosine receptor kinase (NTRK) 1, 2 and 3, respectively], c-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) with central nervous system (CNS) activity developed by Roche for the treatment of various solid tumours harbouring NTRK1/2/3 or ROS1 gene fusions. In June 2019, entrectinib received its first global approval in Japan, for the treatment of adult and paediatric patients with NTRK fusion-positive, advanced or recurrent solid tumours and is under regulatory review for the treatment of adult patients with ROS1-positive non-small cell lung cancer (NSCLC). Entrectinib is also under regulatory review in the USA (PDUFA date 18 August 2019) and EU [Priority Medicines (PRIME) designation] for NTRK-positive solid tumours and ROS1-positive NSCLC. This article summarizes the milestones in the development of entrectinib leading to this first global approval for solid tumours in Japan. [ABSTRACT FROM AUTHOR]

Background Imatinib mesylate is a potent inhibitor of the Abl, KIT and platelet derived growth factor (PDGF) receptor tyrosine kinases. Preclinical data suggest that combining imatinib mesylate with anti-estrogen therapy may be synergistic in hormone receptor-positive breast cancer. We report results of the first phase II trial evaluating the efficacy of the novel combination of imatinib mesylate and letrozole in the treatment of postmenopausal women with metastatic breast cancer. Patients and Methods 45 postmenopausal women with hormone receptor-positive metastatic breast cancer whose tumors demonstrated c-kit and/or PDGFR-β positivity were treated with imatinib mesylate 400 mg PO twice daily and letrozole 2.5 mg PO once daily until disease progression or unacceptable toxicity. Results There were no complete responses and five partial responses for an objective response rate of 11%. An additional 16 patients had stable disease lasting at least 24 weeks for a clinical benefit rate of 46.7%. The median progression-free and overall survival was 8.7 months (95% confidence interval: 3.8-11.4 months) and 44.3 months (95% confidence interval: 34.0-55.3 months), respectively. The most common grade 3 or higher treatment related adverse events were fatigue and diarrhea, occurring in 9 (20%) and 7 patients (16%), respectively. Conclusion The combination of imatinib mesylate and letrozole is well tolerated but appears to have limited efficacy in the treatment of hormone receptor-positive metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Known as a selective δ1 opioid receptor (DOR1) antagonist, the 7-benzylidenenaltrexone (BNTX) is also a DOR1-independent immunosuppressant with unknown mechanisms. Here we investigated if BNTX could be beneficial for diseased MRL/lpr lupus mice. We treated mice with 0.5, 2, 5 or 10 mg/kg/day of BNTX for 2 weeks. At as low as 2 mg/kg/day, BNTX significantly improved splenomegaly and lymphadenopathy. Notably, B cell numbers, particularly autoreactive plasma cells, were preferentially reduced; moreover, BNTX enhanced surface expression of FcγRIIB, an immune complex (IC)-dependent apoptotic trigger of B cells. Consequently, serum autoantibody concentrations were significantly decreased, leading to diminished glomerular IC deposition and renal fibrosis, thereby improving proteinuria. Microarray and pathway analyses revealed heme oxygenase-1 (HO-1) and p38 MAPK as key mediators of BNTX-induced upregulation of FcγRIIB. Moreover, HO-1 expression was also induced by BNTX via p38 MAPK at renal proximal tubules to further cytoprotection. Taken together, we demonstrate that BNTX can alleviate lupus nephritis by reducing autoreactive B cells via FcγRIIB and by augmenting renal protection via HO-1. Accordingly, we propose a new strategy to treat lupus nephritis via such a dual immuno-renal targeting using either a single agent or combined agents to simultaneously deplete B cells and enhance renal protection.Key messages: 7-Benzylidenenaltrexone (BNTX) alleviates lupus nephritis in diseased MRL/lpr mice.BNTX reduces autoreactive plasma cell numbers and serum autoantibody titers.BNTX upregulates FcγRIIB levels via p38 MAPK and HO-1 to reduce B cell numbers.Reduction of immune complex deposition and fibrosis by BNTX improves proteinuria.BNTX induces HO-1 via p38 MAPK to enhance protection of renal proximal tubules. [ABSTRACT FROM AUTHOR]

Purpose: Supplementation of growth hormone (GH) during controlled ovarian stimulation (COS) has been suggested to improve ovarian response. Despite potential benefits in poor responders, multiple injections of GH during COS are inconvenient. We conducted a randomized controlled study to evaluate the efficacy and safety of sustained-release human GH in poor responders undergoing in vitro fertilization (IVF).Methods: This was a single-center, randomized, open-label, parallel study. Infertile women who satisfied the Bologna criteria for poor responders were randomized into GH treatment and control groups. The treatment group received a sustained-release GH (Eutropin Plus® 20 mg) three times before and during COS (mid-luteal, late luteal, and menstrual cycle day 2). The baseline characteristics and IVF outcomes were compared between the two groups.Results: A total of 127 patients were included in the analysis. The mean age was 39.6 years and mean anti-Müllerian hormone level was 0.6 ng/ml. There was no significant difference in the baseline characteristics between GH treatment and control groups. The number of follicles on the human chorionic gonadotropin triggering day (3.1 ± 2.3 vs. 2.4 ± 1.6, P = 0.043) and the proportion of metaphase II oocytes (67.5 vs. 52.3%, P = 0.030) were higher in the GH group than in controls. The percentage of clinical and ongoing pregnancy and miscarriage was not different between the two groups.Conclusion: Supplementation of sustained-release GH before and during COS improved ovarian response, with an increase in mature oocytes in poor responders. Further studies are needed to ensure this benefit in general infertility patients. [ABSTRACT FROM AUTHOR]

Objective: To report our experience in POEM vs. LHM, with particular focus on myotomy extension.Background: POEM has been adopted worldwide as a treatment for achalasia. While resolution of dysphagia is above 90%, postoperative reflux ranges from 10 to 57%. Myotomy length has been a controversial topic.Methods: Thirty-five cases of POEM were prospectively analyzed and compared retrospectively to the last 35 patients that underwent LHM, from December 2010 to August 2016. Mean follow-up was 10 months (6/32) for POEM and 20 months (6/68) for LHM. All patients with LHM had a myotomy extension ≥3 cm on the gastric side. In POEM cases, extension was defined by direct vision (Hill type II) and never exceeded 2 cm.Results: Follow-up was completed in 100% of patients. Efficacy (ES ≤ 3) was 33/35 (94.2%) for POEM and 32/35 (91.4%) for LHM in a short-term follow-up (p = 1.000) and 31/35 (88.6%) and 27/35 (77.1%), respectively, in a long-term follow-up (p = 1.000), with average ES drop from 9 to 1.2 (p = 0.0001) in POEM vs. 9.2 to 1.3 (p = 0.0001) in LHM. Major Postoperative complications occurred in 1 patient (leak) for LHM and 1 patient (massive capnothorax) in POEM. Hospital stay was shorter for POEM than for LHM (1.3 vs. 2.1, respectively) (p = 0.0001). Symptomatic reflux cases included 7/35 POEM (20%) vs. 6/35 LHM (17.1%) (p = 0.4620). Esophagitis signs in endoscopy appeared in 1/21 POEM (4.7%) vs. 1/22 LHM (4.5%) (p = 1.000). Patients requiring PPI included 8/35 POEM (22.8%) vs. 7/35 LHM (20%) (p = 0.6642). Further treatment (endoscopic dilation) was performed in 10/35 POEM (28.5%) vs. 8/35 LHM (22.8%).Conclusions: A shorter myotomy on the gastric side in POEM may contribute to an acceptable reflux rate with comparable relief of dysphagia. Although our follow-up for POEM is shorter than for LHM, the trends are promising and warrant future prospective studies to address this topic. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody–drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal. [ABSTRACT FROM AUTHOR]

Purpose: Circularly permuted TRAIL (CPT) has exhibited promising efficacy as a mono-therapy or in combination with thalidomide for patients with multiple myeloma (MM). In this phase 2 study, the safety and efficacy of CPT in combination with thalidomide and dexamethasone (CPT + TD) was evaluated in patients with pretreated relapsed/refractory MM (RRMM).Methods: Patients who received at least two previous therapies for MM were randomly assigned at a 2:1 ratio to receive treatment with CPT + TD or thalidomide and dexamethasone (TD). The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), duration of response (DOR) and safety.Results: Overall, 47 patients were assigned to the CPT + TD group, and 24 patients were recruited to the TD group. The ORR in the CPT + TD group was 38.3 vs. 25.0% in the TD group. The median PFS time was 6.7 months for the CPT + TD group and 3.1 months for the TD group. The median DORs for the CPT + TD and TD groups were 7.1 and 3.2 months, respectively. Most of the adverse effects (AEs) were grade 1 or 2. Serious AEs were reported in 19.7% of the patients. No treatment-related deaths were reported.Conclusion: CPT plus TD could serve as a new therapeutic strategy for patients with RRMM. A randomized, double-blind, placebo-controlled confirmatory study is currently under way. [ABSTRACT FROM AUTHOR]

Background: POEM is a recently developed achalasia treatment method, which combines the efficacy of surgical myotomy with the benefits of endoscopic procedures. Very few studies have focussed on the efficacy and usefulness of POEM in over 100 cases.Methods: The first 100 adult patients treated according to standard POEM technique in a single center and followed up for 3 months were identified and included in this study (men 42; women 58; mean age 48.2 ± 18.8; range 9-91 years) The pre- and postoperative assessments included Eckardt scores, manometry, endoscopy, and monitoring pH.Results: Mean operative time was 150.8 ± 49.3 min (75-370 min). Adverse events over Grade IIIb by the Clavien-Dindo classification were not encountered. The mean preoperative and postoperative lower esophageal sphincter pressures were 43.6 ± 26.2 and 20.9 ± 12.7 mmHg, respectively, indicating a statistically significant decrease after POEM (P < 0.05). The mean preoperative and postoperative integrated relaxation pressure values were 33.5 ± 15.2 and 15.3 ± 6.5 mmHg (P < 0.05). Furthermore, the Eckardt score significantly decreased from 5.9 ± 2.5 preoperatively to 0.8 ± 0.9 postoperatively (P < 0.05). Clinical success was documented in 99 % of the patients. Short-term outcomes after POEM were extremely good and independent of the age, type of achalasia, and previous treatment method. The percent of monitoring time with a pH < 4 was 25.6 % (22/86) in patients not on proton-pump inhibitors. Nine patients were diagnosed with symptomatic gastroesophageal reflux disease (GERD); patients with reflux esophagitis and symptomatic GERD improved with PPI treatment.Conclusions: Our results confirm the efficacy of POEM in a large patient series and support POEM as one of the first-line achalasia therapies in the near future. [ABSTRACT FROM AUTHOR]

Background: Gastroesophageal reflux disease (GERD) is one of the most common diseases in North America and globally. The aim of this guideline is to provide evidence-based recommendations regarding the most utilized and available endoscopic and surgical treatments for GERD. Methods: Systematic literature reviews were conducted for 4 key questions regarding the surgical and endoscopic treatments for GERD in adults: preoperative evaluation, endoscopic vs surgical or medical treatment, complete vs partial fundoplication, and treatment for obesity (body mass index [BMI] ≥ 35 kg/m2) and concomitant GERD. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Recommendations for future research were also proposed. Results: The consensus provided 13 recommendations. Through the development of these evidence-based recommendations, an algorithm was proposed for aid in the treatment of GERD. Patients with typical symptoms should undergo upper endoscopy, manometry, and pH-testing; additional testing may be required for patients with atypical or extra-esophageal symptoms. Patients with normal or abnormal findings on manometry should consider undergoing partial fundoplication. Magnetic sphincter augmentation or fundoplication are appropriate surgical procedures for adults with GERD. For patients who wish to avoid surgery, the Stretta procedure and transoral incisionless fundoplication (TIF 2.0) were found to have better outcomes than proton pump inhibitors alone. Patients with concomitant obesity were recommended to undergo either gastric bypass or fundoplication, although patients with severe comorbid disease or BMI > 50 should undergo Roux-en-Y gastric bypass for the additional benefits that follow weight loss. Conclusion: Using the recommendations an algorithm was developed by this panel, so that physicians may better counsel their patients with GERD. There are certain patient factors that have been excluded from included studies/trials, and so these recommendations should not replace surgeon–patient decision making. Engaging in the identified research areas may improve future care for GERD patients. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is one of the most common vasculitides of early childhood. There are no previous studies on KD in Cyprus. The aim of this study was to evaluate the epidemiology of KD in Cyprus, risk factors for resistance to treatment and the development of cardiac complications. This is a retrospective multicenter study of pediatric patients with KD hospitalized between January 2000 and-December 2019. The data were collected from medical records. A total of 136 patients with KD were included in the study. 83% of patients were < 5 years of age and 10% were < 6 months. Thirty patients (22%) developed coronary artery lesions. Serum sodium ≤ 133 mmol/L, albumin ≤ 3.2 g/dl, ALT ≥ 80 U/L and neutrophils percentage ≥ 80% at diagnosis, were identified as risk factors for resistance to IVIG. Clinical and epidemiological characteristics of KD in Cyprus population were similar to those reported in the literature. Although the majority of cases received appropriate treatment in time, cardiac complications still occurred. [ABSTRACT FROM AUTHOR]

Background: Treatment failure with recurrent dysphagia after Heller myotomy occurs in fewer than 10 % of patients, most of whom will seek repeat surgical intervention. These reoperations are technically challenging, and as such, there exist only limited reports of reoperation with esophageal preservation.Methods: We retrospectively reviewed the records of patients who sought operative intervention from March 1998 to December 2014 for obstructed swallowing after esophagogastric myotomy. All patients underwent a systematic approach, including complete hiatal dissection, takedown of prior fundoplication, and endoscopic assessment of myotomy. Patterns of failure were categorized as: fundoplication failure, inadequate myotomy, fibrosis, and mucosal stricture.Results: A total of 58 patients underwent 65 elective reoperations. Four patients underwent esophagectomy as their initial reoperation, while three patients ultimately required esophagectomy. The remainder underwent reoperations with the goal of esophageal preservation. Of these 58, 46 were first-time reoperations; ten were second time; and two were third-time reoperations. Forty-one had prior operations via a trans-abdominal approach, 11 via thoracic approach, and 6 via combined approaches. All reoperations at our institution were performed laparoscopically (with two conversions to open). Inadequate myotomy was identified in 53 % of patients, fundoplication failure in 26 %, extensive fibrosis in 19 %, and mucosal stricture in 2 %. Intraoperative esophagogastric perforation occurred in 19 % of patients and was repaired. Our postoperative leak rate was 5 %. Esophageal preservation was possible in 55 of the 58 operations in which it was attempted. At median follow-up of 34 months, recurrent dysphagia after reoperation was seen in 63 % of those with a significant fibrosis versus 28 % with inadequate myotomy, 25 % with failed wrap, and 100 % with mucosal stricture (p = 0.10).Conclusions: Laparoscopic reoperation with esophageal preservation is successful in the majority of patients with recurrent dysphagia after Heller myotomy. The pattern of failure has implications for relief of dysphagia with reoperative intervention. [ABSTRACT FROM AUTHOR]

Purpose: A nationwide survey was conducted to investigate the current status of pediatric gastroesophageal reflux disease (GERD) in Japan, with special reference to the characteristics of intractable GERD. Methods: Data were collected using a questionnaire from facilities specializing in the treatment of pediatric GERD in Japan. Intractable GERD was defined as follows: I, no symptomatic improvement after 8 weeks of optimal medical treatment (OMT) plus fundoplication; II, no symptomatic improvement after 8 weeks of OMT and with no indications for fundoplication; and III, no symptomatic improvement after surgery without OMT. Results: We collected data from 3,463 pediatric patients with GERD from 91 institutions, and 81 satisfied the definition of intractable GERD. Additional clinical information was obtained from 56 patients, and 41 represented cases of definite intractable GERD. The main underlying disorders included neurological impairment (NI), esophageal atresia (EA), and congenital heart disease (CHD), which altogether accounted for 85% of patients. Of the 41 patients, 33 received fundoplication, and the remaining 8 received medical treatment alone because surgery was considered unsuitable. Conclusions: The nationwide survey revealed that pediatric intractable GERD is rare in Japan. Three main underlying disorders—NI, EA, and CHD—were implicated in the majority of cases of intractable GERD. [ABSTRACT FROM AUTHOR]

Purpose: Copanlisib, a pan-PI3K inhibitor, has previously shown clinical efficacy and a tolerable safety profile in patients with indolent non-Hodgkin lymphoma. However, the pharmacokinetics, safety, tolerability, and efficacy of copanlisib in Chinese patients have not been reported. Methods: This was a single-arm, open-label, phase I study of copanlisib in Chinese patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). Patients received a single intravenous 60 mg infusion of copanlisib over 1 h on days 1, 8, and 15 of a 28-day cycle, with 1 week of rest. Safety was monitored throughout the study, and plasma copanlisib levels were measured for pharmacokinetic analysis. Tumor response was determined by independent central radiologic review. Results: Sixteen patients were enrolled and 13 were treated with 60 mg of copanlisib for a median of 15.0 weeks. With a Cmax of 566 μg/L and a AUC (0–24) of 1880 μg·h/L following single intravenous infusion, the pharmacokinetic parameters of copanlisib were consistent with that in previous studies, and no accumulation in plasma was observed. Treatment-emergent adverse events were reported for all 13 patients, the most common of which were hyperglycemia (100.0%), hypertension (76.9%), decreased neutrophil count (76.9%), and decreased white blood cell count (69.2%). Seven out of 12 evaluated patients achieved partial response, resulting in an overall response rate of 58.3% Conclusions: Copanlisib was well tolerated in Chinese patients with relapsed or refractory iNHL at the dose of 60 mg and demonstrated encouraging disease control, thus warranting further clinical investigation. Clinical trial registration number: NCT03498430 (April 13, 2018). [ABSTRACT FROM AUTHOR]

Early recognition of patients at risk for severe acute kidney injury (AKI) by renal angina index (RAI) may help in the early institution of preventive measures. Objective was to evaluate performance of RAI alone or in combination with biomarkers in predicting severe AKI (KDIGO stage 2 and 3 or equivalent) and receipt of kidney replacement therapy (KRT) in critically ill children. We searched PubMed, EMBASE, Web of Sciences, and CENTRAL for studies published till May 2021. Search terms included acute kidney injury, pediatrics, adolescent, renal angina index, and biomarker. Proceedings of relevant conferences and references of included studies were also scrutinized. Two reviewers independently assessed the study eligibility. Cohort and cross-sectional studies evaluating the diagnostic performance of RAI in predicting AKI or receipt of KRT in children were included. Eligible participants were the children less than 18 years with RAI assessment on day 0 ofadmission. We followed PRISMA-DTA guidelines and used the QUADAS-2 tool for quality assessment. A bivariate model for meta-analysis was used to calculate the summary estimates of diagnostic parameters. Major outcomes were the diagnostic accuracy of RAI (≥ 8) alone or with biomarkers in predicting severe AKI and KRT receipt. Diagnostic accuracy was reported using summary sensitivity, specificity, and area under the curve (AUC). Overall, 22 studies (24 reports, 14,001 participants) were included. RAI ≥ 8 on day 0 has summary sensitivity, specificity, and AUC of 0.86 (95% CI, 0.77–0.92), 0.77 (0.68–0.83), and 0.88 (0.85–0.91) respectively for prediction of severe AKI on day 3. In comparison, a combination of RAI and urinary neutrophil gelatinase-associated lipocalin (NGAL) showed summary sensitivity, specificity, and AUC of 0.76 (0.62–0.85), 0.89 (0.74–0.96), and 0.87 (0.84–0.90) respectively for predicting severe AKI. The sensitivity, specificity, and AUC of RAI for predicting receipt of KRT were 0.82 (0.71–0.90), 0.74 (0.66–0.81), and 0.85 (0.81–0.88) respectively. In meta-regression, only the study setting (sepsis vs. heterogenous) was associated with heterogeneity. We observed substantial heterogeneity among eligible studies. Five studies had concerns in patient selection, and seven studies also had applicability concerns in patient selection for this review. Moderate certainty evidence showed that RAI ≥ 8 has good predicting ability in recognizing children at risk of severe AKI and receipt of KRT. The combination of urinary NGAL and RAI further improves the predicting ability (low-certainty evidence). Further studies are required on the context-driven assessment of novel biomarkers in the early prediction of AKI in RAI-positive children. Systematic review registration number: CRD4202122268. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Lenalidomide and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the 'real world' (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (≥PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders ( p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. [ABSTRACT FROM AUTHOR]

The most important factor associated with oocytes' developmental competence has been widely identified as the presence of chromosomal abnormalities. However, growing application of genome-wide sequencing (GS) in population diagnostics has enabled the identification of multifactorial genetic predispositions to sub-lethal pathologies, including those affecting IVF outcomes and reproductive fitness. Indeed, GS analysis in families with history of isolated infertility has recently led to the discovery of new genes and variants involved in specific human infertility endophenotypes that impact the availability and the functionality of female gametes by altering unique mechanisms necessary for oocyte maturation and early embryo development. Ongoing advancements in analytical and bioinformatic pipelines for the study of the genetic determinants of oocyte competence may provide the biological evidence required not only for improving the diagnosis of isolated female infertility but also for the development of novel preventive and therapeutic approaches for reproductive failure. Here, we provide an updated discussion and review of the progresses made in preconception genomic medicine in the identification of genetic factors associated with oocyte availability, function, and competence. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Pneumatic dilation (PD) and laparoscopic Heller myotomy (LHM) can be definitive therapies for achalasia; recent data suggest comparable efficacy. However, risk must also be considered. We reviewed the major complication rate of PD and LHM in a high-volume center and reviewed the corresponding literature.METHODS:We reviewed 12 years of our institution's achalasia treatment experience. During this interval, a consistent technique of PD was used utilizing Rigiflex dilators. Medical records were reviewed for post-procedure complications. We administered a telephone survey and examined medical records to assess efficacy of treatment. We also performed a systematic review of the literature for comparable clinical data and examined 80 reports encompassing 12,494 LHM and PD procedures.RESULTS:At our center, 463 achalasia patients underwent 567 PD or LHM procedures. In all, 78% of the PDs used a 30-mm Rigiflex dilator. In all, 157/184 (85%) patients underwent 1 or 2 PD without any subsequent treatment. There were seven clinically significant perforations; one from PD and six from LHM. There were no resultant deaths from these perforations; two deaths occurred within 30 days of LHM from unrelated causes. Complications and deaths post-PD were significantly fewer than those post-LHM (P=0.02).CONCLUSIONS:Esophageal perforation from PD at our high-volume center was less common than often reported and lower than that associated with LHM. We conclude that, in the hands of experienced operators using conservative technique, PD has fewer major complications and deaths than LHM. [ABSTRACT FROM AUTHOR]

Pharmacological therapy, botulinum toxin injection, pneumatic dilatation, and surgical myotomy are the primary therapeutic modalities for achalasia, for which laparoscopic myotomy is recommended as state-of-the-art therapy. However, its efficacy and safety remain unclear compared with other approaches in the treatment of achalasia. We searched electronic databases (MEDLINE, EMBASE, Cochrane Central Registry of Controlled Trials, LILACS-Latin American, Caribbean health science literature, and Science Citation Index Expanded) for randomized controlled trials to evaluate which therapeutic measures are temporary and reversible and which measures are definitive and effective by pooling data including remission rate, relapse rate, complications, and adverse effects. Seventeen studies with 761 patients met our inclusion criteria. There was better remission rate in pneumatic dilation than in botulinum toxin injection for initial intervention [relative risk (RR) 2.20, 95% confidence interval (CI) 1.51–3.20], Pneumatic dilation had lower relapse rate than did botulinum toxin injection (RR 0.12, 95% CI 0.04–0.32). Compared with pneumatic dilation, laparoscopic myotomy further increased remission rate (RR 1.48, 95% CI 1.48–1.87), and reduced clinical relapse rate (RR 0.14, 95% CI 0.04–0.58), and there was no difference in complication rate (RR 1.48, 95% CI 0.37–5.99). Based on limited randomized and controlled trials, laparoscopic myotomy is the preferred method for patients with achalasia. Future trials should investigate whether laparoscopic myotomy combined with different modalities of fundoplication is superior to isolated laparoscopic myotomy. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have shown important but variable efficacy in mesothelioma despite a lack of strong biological rationale. Initial trials assessed ICI monotherapy in patients with relapsed mesothelioma, with objective response rates (ORR) between 4.5 and 29%, median progression-free survival (PFS) between 2.5–6.2 months, and median overall survival (OS) between 7.7 and 18.0 months. In randomised trials of chemotherapy pre-treated patients, nivolumab was recently shown to improve PFS compared to placebo, but tremelimumab was not superior to placebo, and there was no difference in OS between pembrolizumab and chemotherapy. However, response to combination ICI appear more promising in both pre-treated and treatment-naïve mesothelioma. The randomised Phase 3 trial of upfront ipilimumab-nivolumab versus platinum-pemetrexed chemotherapy demonstrated improved OS favouring ipilimumab-nivolumab (HR 0.74, 96.6% CI 0.60–0.91; p = 0.0020), establishing this regimen as a new standard of care, especially in non-epithelioid histological subtypes. However, initially PFS was poorer in the ipilimumab-nivolumab than chemotherapy treatment arms. A single-arm Phase 2 trial of upfront platinum chemotherapy and durvalumab met its primary endpoint, with a 6-month PFS of 57% (95% CI 44–70) with chemo-immunotherapy under evaluation as an alternative upfront regimen. Several questions remain unanswered. Comparative studies of chemo-immunotherapy versus chemotherapy are underway, but these do not compare chemo-immunotherapy to combination ICI. There is a critical need to establish predictive biomarkers to improve patient selection. As ICI use moves into the front-line setting, patient selection, role for operable patients, and understanding ICI resistance mechanisms alongside role of ICI rechallenge in previous responders need further evaluation. [ABSTRACT FROM AUTHOR]

Sixty-seven patients with symptoms of gastroesophageal reflux not responsive to medical therapy were treated by 180° anterior fundoplication. The operative mortality was 1.5% (one patient). The follow-up period ranged from 6 to 132 months and averaged 3 1/2 yr. The overall clinical results were satisfactory in 94% of the cases; one patient had mild retroesternal heartburn after operation, and three patients had recurrence of symptoms with persistent reflux in two of them. Among the improved patients, one experienced a transient gas-bloat syndrome. In 41 patients manometric evaluation of the gastroesophageal high pressure zone showed a significant increase in both the pressure and the length below the respiratory inversion point (p < 0.001) but not in the total length. The standard acid reflux test carried out on 47 patients after surgery was found to be negative in all of them. We conclude that in patients with severe gastroesophageal reflux, 180° anterior fundoplication achieved good clinical results confirmed by objective methods. [ABSTRACT FROM AUTHOR]

The emergence of various novel therapies over the last decade has changed the therapeutic landscape for multiple myeloma. While the clinical outcomes have improved significantly, the disease remains incurable, typically in patients with relapsed and refractory disease. Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable clinical success in B-cell malignancies. This scope of research has more recently been extended to the field of myeloma. While B-cell maturation antigen (BCMA) is currently the most well-studied CAR T antigen target in this disease, many other antigens are also undergoing intensive investigations. Some studies have shown encouraging results, whereas some others have demonstrated unfavorable results due to reasons such as toxicity and lack of clinical efficacy. Herein, we provide an overview of CAR T-cell therapies in myeloma, highlighted what has been achieved over the past decade, including the latest updates from ASH 2020 and discussed some of the challenges faced. Considering the current hits and misses of CAR T therapies, we provide a comprehensive analysis on the current manufacturing technologies, and deliberate on the future of CAR T-cell domain in MM. [ABSTRACT FROM AUTHOR]