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Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations. Methods: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. Results: We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice ( P = 3.4 × 10 −8 ). This enrichment is only partially explained by mutations found in known disease-causing genes. Conclusion: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications. Genet Med 17 10, 774–781.

Purpose Temple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical findings in 32 Japanese patients with TS14. Methods We performed molecular studies for TS14 in 356 patients with variable phenotypes, and clinical studies in all TS14 patients, including 13 previously reported. Results We identified 19 new patients with TS14, and the total of 32 patients was made up of 23 patients with maternal uniparental disomy (UPD(14)mat), six patients with epimutations, and three patients with microdeletions. Clinical studies revealed both Prader-Willi syndrome (PWS)-like marked hypotonia and Silver-Russell syndrome (SRS)-like phenotype in 50% of patients, PWS-like hypotonia alone in 20% of patients, SRS-like phenotype alone in 20% of patients, and nonsyndromic growth failure in the remaining 10% of patients in infancy, and gonadotropin-dependent precocious puberty in 76% of patients who were pubescent or older. Conclusion These results suggest that TS14 is not only a genetically diagnosed entity but also a clinically recognizable disorder. Genetic testing for TS14 should be considered in patients with growth failure plus both PWS-like hypotonia and SRS-like phenotypes in infancy, and/or precocious puberty, as well as a familial history of Kagami-Ogata syndrome due to maternal microdeletion at 14q32.2.

Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established. One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians. We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.

Background and ObjectiveWith the rising importance of precision oncology in biliary tract cancer (BTC), the aim of this retrospective single-center analysis was to describe the clinical and molecular characteristics of patients with BTC who underwent comprehensive genomic profiling (CGP) and were discussed in the CCCMunichLMU molecular tumor board (MTB).Patients and MethodsIn this single-center observational study, we included BTC patients with intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA (eCCA), and gallbladder cancer (GB), who had been discussed in the institutional MTB from May 29, 2017, to July 25, 2022. Patients were followed up until 31 January 2023. Data were retrospectively collected by review of medical charts, and MTB recommendation.ResultsIn total, 153 cases were registered to the MTB with a median follow-up of 15 months. Testing was successful in 81.7% of the patients. CGP detected targetable alterations in 35.3% of our BTC patients (most commonly ARID1A/ERBB2/IDH1/PIK3CA/BRAF-mutations and FGFR2-fusions). Recommendations for molecularly guided therapy were given in 46.4%. Of those, treatment implementation of targeted therapy followed in 19.4%. In patients receiving the recommended treatment, response rate was 57% and median overall survival was 19 months (vs 8 months in the untreated cohort). The progression-free survival ratio of 1.45 suggest a clinical benefit of molecularly guided treatment.ConclusionsIn line with previous work, our series demonstrates feasibility and clinical utility of comprehensive genomic profiling in BTC patients. With the growing number of targeted agents with clinical activity in BTC, CGP should become standard of care in the management of this group of patients.

BackgroundIn pancreatic cancer, systemic treatment options in addition to chemotherapy remain scarce, and so far only a small proportion of patients benefit from targeted therapies.ObjectiveThe patients with pancreatic cancer discussed in the CCCMunichLMU Molecular Tumor Board were reviewed to gain a better real-world understanding of the challenges and chances of precision oncology in this hard-to-treat cancer.MethodsPatients with pancreatic cancer who received comprehensive genomic profiling and were discussed in the interdisciplinary Molecular Tumor Board between May 2017 and July 2022 were included. These patients’ medical charts, comprehensive genomic profiling results, and Molecular Tumor Board recommendations were analyzed in this retrospective cohort study.ResultsMolecular profiles of 165 patients with pancreatic cancer were discussed in the Molecular Tumor Board. In the 149 cases where comprehensive genomic profiling was successful, KRAS mutations were detected in 87.9%, TP53 in 53.0%, and CDKN2A in 14.1%. 33.3% of KRAS wild-type patients harbored targetable mutations, while these were only found in 19.1% of patients with the KRAS mutation; however, this difference was not statistically significant. 63.8% of patients with successful testing received a targeted treatment recommendation by the Molecular Tumor Board; however, only 3.2% of these were put into practice. Compared to a historic cohort of patients with pancreatic cancer with synchronous metastatic disease diagnosed between 2010 and 2017, the patients from the pancreatic cancer cohort with synchronous metastatic disease had a longer survival.ConclusionsThis single-center experience emphasizes the challenges of targeted treatment in pancreatic cancer. Very few patients ultimately received the recommended therapies, highlighting the need for more and better targeted treatment options in pancreatic cancer, early comprehensive genomic profiling to allow sufficient time to put Molecular Tumor Board recommendations into practice, and close cooperation with clinical trial units to give patients access to otherwise not available targeted treatments.

Background Research on regenerative medicine using basic fibroblast growth factor (bFGF) has recently advanced in the field of laryngology. We previously reported that local administration of bFGF 1 month after recurrent laryngeal nerve (RLN) paralysis compensated for atrophy of the thyroarytenoid muscle. The objective of this study was to elucidate the effects of early bFGF administration on the thyroarytenoid muscle after RLN transection and to investigate the underlying mechanisms. Methods A rat model of RLN paralysis was established in this study. One day after RLN transection, low- (200 ng) or high-dose (2000 ng) bFGF or saline (control) was administered to the thyroarytenoid muscle. The larynges were excised for histological and immunohistochemical examinations at 1, 7, 14, 28, and 56 days after administration. Results The cross-sectional thyroarytenoid muscle area was significantly larger in the high-dose group than in the saline and low-dose groups on days 28 and 56. Immunohistochemistry indicated that bFGF significantly increased the number of satellite cells in the thyroarytenoid muscle up to day 14 and that of neuromuscular junctions on days 28 and 56. Conclusions A single, early local administration of high-dose bFGF prevented atrophic changes in the thyroarytenoid muscles by activating satellite cell proliferation and reforming neuromuscular junctions. As increased neuromuscular junctions are expected to maintain myofiber volume, bFGF administration may prevent thyroarytenoid muscle atrophy in the mid to long term. Graphical abstract

Background Acute suppurative thyroiditis through the congenital pyriform sinus fistula (PSF) often recurs if the fistula is not resected. Although endoscopic chemo-cauterization (ECC) to obliterate the orifice of the fistula is less invasive than open fistulectomy, it may require repeated treatments. We recently adopted an endoscopic diode laser-cauterization (ELC) system with the intention of improving treatment outcomes in PSF. Here, we describe ELC and compare the outcomes of these three modalities. Methods We evaluated 83 patients with PSF who underwent treatment between 2007 and 2018 at Kuma Hospital, a tertiary thyroid treatment hospital. ECC and ELC were implemented in 2007 and 2015, respectively. Patients who were ineligible for the endoscopic procedures underwent open fistulectomy. Barium swallow studies and computed tomography scan under a trumpet maneuver were performed after treatment to evaluate obliteration or removal of the fistula. Results In total, 70 of the 81 (86%) patients who underwent barium swallow studies after the first treatment achieved obliteration or removal of the fistula. The success rates for open fistulectomy, ECC, and ELC were 100% (9/9), 83% (49/59), and 100% (13/13), respectively. ECC and ELC had significantly shorter operative times and lower blood loss than open fistulectomy. Insufficient opening of the mouth was the major reason for converting endoscopic procedures to open fistulectomy. Conclusions ELC may yield superior outcomes and is therefore the optimal treatment modality for PSF. However, it is still associated with certain limitations. Thus, treatment selection remains dependent on the shape and size of the PSF and the mouth opening of the individual patient. Graphical Abstract

Background Malignancies occur in approximately 1:1000 pregnancies; the most common being breast (46%) and hematological (18%) malignancies. Oral cancers account for only 2% of all cancers in pregnant women, and there are no standard guidelines for the treatment of oral cancer during pregnancy. Methods Between 2007 and 2014, our department managed 1109 patients with oral cancers; four (0.4%) had tongue carcinomas during pregnancy. These cases were retrospectively reviewed. Results The four women were aged 29–39 (median 32.5) years. Two underwent partial glossectomy at 39 and 40 weeks’ gestation, respectively, one received radiotherapy at 17 weeks’ gestation, and one underwent supraomohyoid neck dissection and hemi-glossectomy with a forearm flap reconstruction. Conclusion In addition to tumor factors, the wishes of the patient and her family, gestational age, and fetal and maternal conditions are important factors in deciding on a treatment protocol. Moreover, treatment decisions require multidisciplinary approach.

Age-associated differences in the effect of repetitive vaccination, particularly on memory T-cell and B-cell responses, remain unclear. While older adults (aged ≥65 years) exhibited enhanced IgG responses following COVID-19 mRNA booster vaccination, they produced fewer spike-specific circulating follicular helper T cells-1 than younger adults. Similarly, the cytotoxic CD8 + T-cell response remained diminished with reduced PD-1 expression even after booster vaccination compared with that in younger adults, suggesting impaired memory T-cell activation in older adults. In contrast, although B-cell responses in older adults were weaker than those in younger adults in the primary response, the responses were significantly enhanced upon booster vaccination, reaching levels comparable with that observed in younger adults. Therefore, while booster vaccination ameliorates impaired humoral immunity in older adults by efficiently stimulating memory B-cell responses, it may less effectively enhance T-cell-mediated cellular immunity. Our study provides insights for the development of effective therapeutic and vaccine strategies for the most vulnerable older population.

Purpose Caudal septoplasty is a difficult procedure. The cutting and suture technique is suitable for caudal septoplasty, but a batten graft is always necessary and bears the risk of nasal tip projection loss. We established a modified cutting and suture technique (MCAST), without using a batten graft, and investigated its effectiveness in correcting nasal obstruction and preventing nasal tip projection loss. Methods We retrospectively reviewed the medical records of 22 patients who underwent caudal septoplasty using MCAST. Subjective assessment by Nasal Obstruction Symptom Evaluation (NOSE) score and objective assessment by computed tomography (CT) were performed before and after the surgery. For evaluating nasal tip projection, we asked patients about their awareness of external nasal deformity. Additionally, the nasal tip projection was measured by CT and compared before and after surgery. Results The median preoperative NOSE score reduced significantly after MCAST ( P  < 0.001). On CT, the ratio of the area of the convex side to that of the concave side in the anterior portion of the nasal cavity increased significantly after MCAST ( P  < 0.001). All patients were unaware of external nasal deformity. There were no significant differences in the mean preoperative and postoperative nasal tip height and nasolabial angle. The mean supra tip height was significantly greater postoperatively than preoperatively ( P  = 0.02). Conclusions The MCAST was useful for correcting nasal obstruction with caudal septal deviation. There was no postoperative loss of nasal tip projection. The MCAST can be suitable for correcting C-shaped caudal deviations without dislocating the caudal septum from the anterior nasal septum.