PIK3CA-related overgrowth spectrum (PROS) is an umbrella term to describe a diverse range of developmental disorders. Research to date has predominantly emerged from Europe and North America, resulting in a notable scarcity of studies focusing on East Asian populations. Currently, the prevalence and distribution of PIK3CA variants across various genetic loci and their correlation with distinct phenotypes in East Asian populations remain unclear. This study aims to elucidate the phenotype-genotype correlations of PROS in East Asian populations. We presented the phenotypes and genotypes of 82 Chinese patients. Among our cohort, 67 individuals carried PIK3CA variants, including missense, frameshift, and splice variants. Six patients presented with both PIK3CA and an additional variant. Seven PIK3CA-negative patients exhibited overlapping PROS manifestations with variants in GNAQ, AKT1, PTEN, MAP3K3, GNA11, or KRAS. An integrative review of the literature pertaining to East Asian populations revealed that specific variants are uniquely associated with certain PROS phenotypes. Some rare variants were exclusively identified in cases of megalencephaly and diffuse capillary malformation with overgrowth. Non-hotspot variants with undefined oncogenicity were more common in CNS phenotypes. Diseases with vascular malformation were more likely to have variants in the helical domain, whereas phenotypes involving adipose/muscle overgrowth without vascular abnormalities predominantly presented variants in the C2 domain. Our findings underscore the unique phenotype-genotype patterns within the East Asian PROS population, highlighting the necessity for an expanded cohort to further elucidate these correlations. Such endeavors would significantly facilitate the development of PI3Kα selective inhibitors tailored for the East Asian population in the future.

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OBJECTIVE: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. and STUDY DESIGN: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum (BWSp), PIK3CA-Related Overgrowth Spectrum (PROS), vascular overgrowth (VO) , or isolated (ILO), based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield.
RESULTS: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions and 11% reclassified. BWSp was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PROS had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. VO demonstrated significant clinical overlap with other syndromes. Molecular diagnosis of ILO proved challenging, with only 21% of cases classifiable into a specific condition.
CONCLUSIONS: Despite, LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which would be crucial for addressing potential cancer predisposition, enabling precision medicine treatments, or guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.

OBJECTIVE: This systematic review provides an overview of literature on the impact of MR-guided radiotherapy (MRgRT) on patient reported outcomes (PROs) in patients with prostate cancer (PC).
METHODS: A systematic search was performed in October 2023 in PubMed, EMBASE and Cochrane Library. The PICOS framework (i.e., patient, intervention, comparison, outcome, study design) was used to determine eligibility criteria. Included were studies assessing PROs following MRgRT for PC with sample size >10. Methodological quality was assessed using the ROBINS-I and RoB 2. Relevant mean differences (MD) compared to pre-RT were interpreted using minimal important differences (MID). Meta-analyses were performed using random-effects models. Between-study heterogeneity was assessed using the I2-statistic.
RESULTS: Eleven observational studies and one randomized controlled trial (n=897) were included. Nine studies included patients with primary PC with MRgRT as first-line treatment (n=813) and three with MRgRT as second-line treatment (n=84). Substantial risk of bias was found in five studies. EORTC QLQ-C30 and EORTC QLQ-PR25 scores were pooled from three studies, and EPIC-26 scores from four studies. Relevant MDs for the urinary domain were found with the EPIC-26 (MD-10.0 [95%CI -12.0 - -8.1]; I20%) and the EORTC QLQ-PR25 (MD8.6 [95%CI -4.7-22.0]; I297%), both at end-RT to one month follow-up. Relevant MDs for the bowel domain were found with the EPIC-26 (MD-4.7 [95%CI -9.2 - -0.2]; I282%), at end-RT or one month follow-up, but not with the EORTC QLQ-PR25. For both domains, no relevant MDs were found after three months of follow-up. No relevant MDs were found in the general QoL domains of the EORTC QLQ-C30.
CONCLUSIONS: MRgRT for PC results in a temporarily worsening of patient-reported urinary and bowel symptoms during the first month after treatment compared to pre-RT, resolving at 3 months. No clinically relevant changes were found for general QoL domains. These results provide important information for patient counseling and can serve as a benchmark for future studies.

Activating mutation of PIK3CA is linked with cases of overgrowth syndromes and belongs to the PIK3CA-related overgrowth spectrum (PROS). Mutations in this gene are associated with vascular malformations, brain abnormalities, and an increased risk for certain tumors. We report the case of a newborn girl, preterm at 34 weeks of gestation, referred to our center for atypical necrotizing enterocolitis (NEC). At laparotomy, the appearance of the intestinal tract was described as puffy, cauliflower-like with a dark purplish coloration. Subsequently, the colostomy was described as having a consistent proliferative appearance. Medical treatment with sirolimus resulted in minimal improvement. There are no reported cases in the literature of association between NEC and PIK3CA mutation. It is possible that PIK3CA mutation, including the related vascular anomalies, plays a role in the pathogenesis of NEC with this condition.

OBJECTIVE: This study aimed to investigate the impact of sarcopenia and lumbar paraspinal muscle composition (PMC) on patient-reported outcomes (PROs) after lumbar fusion surgery with 12-month follow-up (12 M-FU).
METHODS: A prospective investigation of patients undergoing elective lumbar fusion was conducted. Preoperative MRI-based evaluation of the cross-sectional area (CSA), the functional CSA (fCSA), and the fat infiltration(FI) of the posterior paraspinal muscles (PPM) and the psoas muscle at level L3 was performed. Sarcopenia was defined by the psoas muscle index (PMI) at L3 (CSAPsoas [cm2]/(patients\' height [m])2). PROs included Oswestry Disability Index (ODI), 12-item Short Form Healthy Survey with Physical (PCS-12) and Mental Component Scores (MCS-12) and Numerical Rating Scale back and leg (NRS-L) pain before surgery and 12 months postoperatively. Univariate and multivariable regression determined associations among sarcopenia, PMC and PROs.
RESULTS: 135 patients (52.6% female, 62.1 years, BMI 29.1 kg/m2) were analyzed. The univariate analysis demonstrated that a higher FI (PPM) was associated with worse ODI outcomes at 12 M-FU in males. Sarcopenia (PMI) and higher FI (PPM) were associated with worse ODI and MCS-12 at 12 M-FU in females. Sarcopenia and higher FI of the PPM are associated with worse PCS-12 and more leg pain in females. In the multivariable analysis, a higher preoperative FI of the PPM (β = 0.442; p = 0.012) and lower FI of the psoas (β = -0.439; p = 0.029) were associated with a worse ODI at 12 M-FU after adjusting for covariates.
CONCLUSIONS: Preoperative FI of the psoas and the PPM are associated with worse ODI outcomes one year after lumbar fusion. Sarcopenia is associated with worse ODI, PCS-12 and NRS-L in females, but not males. Considering sex differences, PMI and FI of the PPM might be used to counsel patients on their expectations for health-related quality of life after lumbar fusion.

BACKGROUND: The evaluation of electronic patient-reported outcomes (ePROs) is increasingly being used in clinical studies of patients with cancer and enables structured and standardized data collection in patients\' everyday lives. So far, few studies or analyses have focused on the medical benefit of ePROs for patients.
OBJECTIVE: The current exploratory analysis aimed to obtain an initial indication of whether the use of the Consilium Care app (recently renamed medidux; mobile Health AG) for structured and regular self-assessment of side effects by ePROs had a recognizable effect on incidences of unplanned consultations and hospitalizations of patients with cancer compared to a control group in a real-world care setting without app use. To analyze this, the incidences of unplanned consultations and hospitalizations of patients with cancer using the Consilium Care app that were recorded by the treating physicians as part of the patient reported outcome (PRO) study were compared retrospectively to corresponding data from a comparable population of patients with cancer collected at 2 Swiss oncology centers during standard-of-care treatment.
METHODS: Patients with cancer in the PRO study (178 included in this analysis) receiving systemic therapy in a neoadjuvant or noncurative setting performed a self-assessment of side effects via the Consilium Care app over an observational period of 90 days. In this period, unplanned (emergency) consultations and hospitalizations were documented by the participating physicians. The incidence of these events was compared with retrospective data obtained from 2 Swiss tumor centers for a matched cohort of patients with cancer.
RESULTS: Both patient groups were comparable in terms of age and gender ratio, as well as the distribution of cancer entities and Joint Committee on Cancer stages. In total, 139 patients from each group were treated with chemotherapy and 39 with other therapies. Looking at all patients, no significant difference in events per patient was found between the Consilium group and the control group (odds ratio 0.742, 90% CI 0.455-1.206). However, a multivariate regression model revealed that the interaction term between the Consilium group and the factor \"chemotherapy\" was significant at the 5% level (P=.048). This motivated a corresponding subgroup analysis that indicated a relevant reduction of the risk for the intervention group in the subgroup of patients who underwent chemotherapy. The corresponding odds ratio of 0.53, 90% CI 0.288-0.957 is equivalent to a halving of the risk for patients in the Consilium group and suggests a clinically relevant effect that is significant at a 2-sided 10% level (P=.08, Fisher exact test).
CONCLUSIONS: A comparison of unplanned consultations and hospitalizations from the PRO study with retrospective data from a comparable cohort of patients with cancer suggests a positive effect of regular app-based ePROs for patients receiving chemotherapy. These data are to be verified in the ongoing randomized PRO2 study (registered on ClinicalTrials.gov; NCT05425550).
BACKGROUND: ClinicalTrials.gov NCT03578731; https://www.clinicaltrials.gov/ct2/show/NCT03578731.
UNASSIGNED: RR2-10.2196/29271.

UNASSIGNED: Learning curves (LC) are typically defined by the number of different spinal procedures surgeons must perform before becoming \"proficient,\" as demonstrated by reductions in operative times, estimated blood loss (EBL), length of hospital stay (LOS), adverse events (AE), fewer conversions to open procedures, along with improved outcomes. Reviewing 12 studies revealed LC varied widely from 10-44 cases for open vs. minimally invasive (MI) lumbar diskectomy, laminectomy, transforaminal lumbar interbody fusion (TLIF), anterior lumbar interbody fusion (ALIF), and oblique/extreme lateral interbody fusions (OLIF/XLIF). We asked whether the risks of harm occurring during these LC could be limited if surgeons routinely utilized in-person/intraoperative mentoring (i.e., via industry, academia, or well-trained colleagues).
UNASSIGNED: We evaluated LC for multiple lumbar operations in 12 studies.
UNASSIGNED: These studies revealed no LC for open vs. MI lumbar diskectomy. LC required 29 cases for MI laminectomy, 10-44 cases for MI TLIF, 24-30 cases for MI OLIF, and 30 cases for XLIF. Additionally, the LC for MI ALIF was 30 cases; one study showed that 32% of major vascular injuries occurred in the first 25 vs. 0% for the next 25 cases. Shouldn\'t the risks of harm to patients occurring during these LC be limited if surgeons routinely utilized in-person/intraoperative mentoring?
UNASSIGNED: Twelve studies showed that the LC for at different MI lumbar spine operations varied markedly (i.e., 10-44 cases). Wouldn\'t and shouldn\'t spine surgeons avail themselves of routine in-person/intraoperative mentoring to limit patients\' risks of injury during their respective LC for these varied spine procedures ?

BACKGROUND: N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. Oxidative stress is a key pathogenic mechanism in chronic respiratory conditions such as COPD and chronic bronchitis (CB). In these meta-analyses we investigated the efficacy of NAC in subjects with COPD or CB, the latter being a potential pre-COPD condition (CB/pre-COPD).
METHODS: The meta-analyses were conducted according to PRISMA guidelines. Exacerbations were assessed using total number of exacerbations. Improvement in patients\' respiratory symptoms and/or patients quality of life (QoL) were measured by validated tools or assessed at the end of the study.
RESULTS: Twenty studies were included, of which seven evaluated NAC in patients with symptoms of CB/pre-COPD as entry criterion. NAC treated patients showed a significant reduction of the incidence of exacerbations as compared to placebo both in COPD (IRR=0.76; 95% confidence interval (CI) 0.59-0.99) and CB/pre-COPD (IRR=0.81; 95% CI 0.69-0.95). Sensitivity analyses in studies with duration higher than 5 months, confirmed the overall results. CB/pre-COPD patients treated with NAC were significantly more likely to experience an improvement in symptoms and/or QoL compared to placebo (odds ratio (OR)=3.47; 95% CI 1.92-6.26). A similar trend was observed in the few COPD studies evaluable. Sensitivity analyses showed a significant association of NAC with improvement in symptoms and/or QoL both in CB/pre-COPD and COPD patients.
CONCLUSIONS: These findings provide novel data of NAC on the improvement in symptoms and QoL in addition to prevention of exacerbations in COPD and CB/pre-COPD. PROSPERO registry no. CRD42023468154.

The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.