Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer: Interim analyses of the prospective, observational RAPIT study.

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

Increased Apolipoprotein A1 Expression Correlates with Tumor-Associated Neutrophils and T Lymphocytes in Upper Tract Urothelial Carcinoma.

An increased neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic biomarker in various types of cancer, because it reflects the inhibition of lymphocytes in the circulation and tumors. In urologic cancers, upper tract urothelial carcinoma (UTUC) is known for its aggressive features and lack of T cell infiltration; however, the association between neutrophils and suppressed T lymphocytes in UTUC is largely unknown. In this study, we examined the relationship between UTUC-derived factors and tumor-associated neutrophils or T lymphocytes. The culture supernatant from UTUC tumor tissue modulated neutrophils to inhibit T cell proliferation. Among the dominant factors secreted by UTUC tumor tissue, apolipoprotein A1 (Apo-A1) exhibited a positive correlation with NLR. Moreover, tumor-infiltrating neutrophils were inversely correlated with tumor-infiltrating T cells. Elevated Apo-A1 levels in UTUC were also inversely associated with the population of tumor-infiltrating T cells. Our findings indicate that elevated Apo-A1 expression in UTUC correlates with tumor-associated neutrophils and T cells. This suggests a potential immunomodulatory effect on neutrophils and T cells within the tumor microenvironment, which may represent therapeutic targets for UTUC treatment.

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder.

BACKGROUND: Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated. OBJECTIVES: To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder. METHODS: Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients' stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients' SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically. RESULTS: We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients' SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients' SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype. CONCLUSIONS: We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.

The decisional balance, attitudes, and practice behaviors, its predicting factors, and related experiences of advance care planning in Taiwanese patients with advanced cancer.

BACKGROUND: Patients with advanced cancer are prone to experience burdensome physical, psychological, and financial consequences. Healthcare providers may not fully appreciate advanced cancer patients' medical care autonomy, such as at that emboded by Advance Care Planning (ACP), and by doing so may compromise their quality of end-of-life (EOL). Hence, it is essential for healthcare providers to effectively assess and communicate with patients' regarding their medical decisions before their patients are incapacitated by their disease progression. The purpose of this investigation was to describe the decisional balance, attitudes, and practice behaviors of ACP and its predictors of ACP-related experiences in Taiwanese patients with advanced cancer. METHODS: This cross-sectional, descriptive study employed a mixed-methodsquantitative and qualitative design with a sample of 166 patients that were purposely recruited from in-patient oncology units at a regional teaching hospital in southern Taiwan. Study data consisted of patient replies to a 34-item self-report tool, Decisional Balance, Attitudes, Practice Behaviors of ACP (DAP-ACP) and 4 semi-structured questions. RESULT: Findings indicated that, in general, study participants exhibited favorable ACP-decisional balance and positive ACP-attitudes & practice behaviors. The results also indicated that gender, educational level, and cancer diagnosis were associated with significant differences on the "ACP-decisional balance" and "ACP-attitudes" scales. In addition, our findings documented that the participants' gender and educational level were significant predictors of both ACP-decisional balance and ACP-attitudes. Furthermore the participants' ACP-practice behaviors were predicted by ACP-decisional balance, but not with their ACP-attitudes. The qualitative analysis of the semi-structured questions identified six themes in responses to current medical decision making (e.g., compliance with physician instructions, family engagement in treatment decision-making); and eight themes pertaining to future ACP-related concerns were identified (e.g., family conflict, effectiveness of time-limited trials). CONCLUSION: To promote patients' engagement in ACP, the healthcare professional need to assess and advocate patients' concerns or attitudes regarding ACP in a timely manner. In addition, factors or concerns that might influence patients' responses to ACP derived from both the quantitative and qualitative findings of this current study need to be considered especially in initiating the dialogue regarding ACP with patients with advanced cancer. TRIAL REGISTRATION: No. CYCH 2,019,072, Date of registration 5 Dec 2019.

Parathyroidectomy Improves the Consumption of Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Secondary hyperparathyroidism (SHPT) is common in end-stage renal disease (ESRD) patients, and it can suppress erythropoiesis. We aimed to investigate the relationship between the consumption of erythropoiesis-stimulating agents (ESAs) and parathyroidectomy (PTX) in ESRD patients with SHPT and to determine the predictors for anemia improvement. The current standard of chronic kidney disease anemia therapy relies on the prescription of iron supplementation, and ESA. We retrospectively analyzed 81 ESRD patients with PTX at Ditmanson Medical Foundation Chiayi Christian Hospital from July 2004 to Dec 2018. The requirement of ESA therapy markedly declined from a dose of 41.6 (interquartile range [IQR], 0−91.2) to 10.3 (IQR, 0−59.5, p = 0.001) unit/kg/week. In addition, 63.7% of patients required iron replacement therapy preoperatively and the proportion reduced to 52.5% after PTX (p < 0.001). The hemoglobin (Hb) level showed an insignificant change from a median value of 10.7 g/dL (9.5−11.6 g/dL) before PTX to 10.5 g/dL (9.6−11.2 g/dL) at 6 months after PTX. A preoperative Hb level ≤ 10 mg/dL (odds ratio [OR], 20.1; 95% confidence interval [CI], 4.71−125, p < 0.001) and transferrin saturation (TSAT) < 25% (OR, 12.8; 95% CI, 2.51−129, p < 0.001) were predictors for anemia improvement. Our study demonstrated that PTX markedly decreased the requirement of ESA. Patients with a low preoperative Hb level or low TSAT showed an increase in the Hb level after PTX. PTX may be considered not only for SHPT with refractory anemia but also for high ESA-dependent patients.

Rapid Administration of Antibiotics for Reducing Fever Days in Patients Receiving Hematopoietic Stem Cell Transplantation.

Background and Objectives: Neutropenic fever (NF) is a major cause of mortality and morbidity in patients undergoing hematopoietic stem cell transplantation (HSCT). To date, no study has discussed the relationship of fever days in HSCT with the time between recording the fever and administering antibiotics. This study aimed to examine the association between fever days in HSCT and the time interval between recording the fever and intravenous (IV) antibiotics to the febrile neutropenia patient. Materials and Methods: A total of 22 patients who developed NF after HSCT in one hospital were analyzed. Patients who received IV antibiotics injection within 30 min were categorized in group A and those who received the injection after 30 min were categorized in group B. Fever was defined by an attack with an oral temperature of 38.3 °C. Patients' characteristics and possible risk factors were recorded and analyzed. Results: Groups A and B had 14 and 8 patients, respectively. Patient characteristics, including age, diagnosis, sex, and antibiotics level, were similar between the two groups. The median duration of fever days was 1.5 (range, 1−5) in group A and 6.5 (range, 1−14) in group B (p = 0.003). Multivariant analysis of possible independent impact factors of "fever days in HSCT" was performed. The odds ratio of "antibiotics given time" was 4.00 (95% confidence interval [CI] = 2.26 to 7.22, p = 0.001). The "antibiotics level" did not affect the NF period (odds ratio = −0.80, 95% CI = −2.40 to 1.07, p = 0.453). Conclusions: Rapid IV administration of antibiotics (<30 min after fever attack) can reduce the fever days in patients undergoing HSCT.

Validation of a Post-Transplant Lymphoproliferative Disorder Risk Prediction Score and Derivation of a New Prediction Score Using a National Bone Marrow Transplant Registry Database.

BACKGROUND: We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD) and aimed to create a superior scoring system using machine learning methods. MATERIALS AND METHODS: Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, least absolute shrinkage and selection operator (LASSO), was used to construct a new score system, which was validated using the fivefold cross-validation method. RESULTS: We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probabilities for PTLD development by Fujimoto score at 5 years for patients in the low-, intermediate-, high-, and very-high-risk groups were 1.15%, 3.06%, 4.09%, and 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test p = .81). Using LASSO regression analysis, a four-risk group model was constructed, and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65). CONCLUSION: Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD. IMPLICATIONS FOR PRACTICE: This study validated the Fujimoto score for the prediction of post-transplant lymphoproliferative disorder (PTLD) development following hematopoietic cell transplant (HCT) in an external, independent, and nationally representative population. This study also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HCT were identified using the machine learning algorithm, least absolute shrinkage and selection operator, including pre-HCT medical history of mechanical ventilation and the chemotherapy agents used in conditioning regimen.

Accuracy of long-form data in the Taiwan cancer registry.

The Taiwan Cancer Registry (TCR) is a nationwide population-based registry that collects the data of patients with newly diagnosed cancer from hospitals with ≥50 beds. TCR data are high quality in terms of completeness and timeliness. However, accuracy is also a crucial quality indicator. This study evaluated the accuracy rates of selected 55 major items in the long-form TCR data between 2014 and 2016 with 700 reported cases randomly selected from 25 long-form-reporting hospitals. We calculated the accuracy rates of the reported data by employing a reabstracted chart review. Among the 55 items, the accuracy rates of 38 (69%) were at least 95%, those of 10 (18%) were between 90% and 95%, those of 5 (9%) were between 85% and 90%, and the remaining 2 (4%) were between 80% and 85%. This demonstrates a high degree of accuracy in the TCR long-form data.

A nationwide survey of fatigue in cancer patients in Taiwan: an unmet need.

BACKGROUND: Cancer-related fatigue (CRF) is an emerging clinical issue, although its prevalence and impact on quality of life (QOL) in cancer patients in Taiwan remain unclear. The present nationwide cross-sectional study was conducted to provide a thorough overview of the prevalence, related factors and impact of CRF in Taiwan. METHODS: In this multi-center survey, data were collected using the International Classification of Diseases 10th Revision (ICD-10) Fatigue evaluation, Brief Fatigue Inventory-Taiwan (BFI-T), the Chinese version of the Symptom Distressed Scale and a fatigue experience survey. Logistic regression was used to determine the correlations between fatigue characteristics and the factors studied. RESULTS: A total of 1207 cancer patients were recruited from 23 hospitals in Taiwan. Fatigue was the most distressing symptom in Taiwanese cancer patients. The distress score was higher if CRF was diagnosed using ICD-10 compared with BFI-T. Rest and nutritional supplementation were the most common non-pharmacological treatments; blood transfusion was the most common pharmacological treatment. There were 45% of patients reported not receiving a timely intervention for fatigue. CONCLUSIONS: Fatigue is the most bothersome symptom reported by Taiwanese cancer patients. Caregivers should be aware of the impact of CRF on QOL in cancer patients, constantly measure the severity of fatigue and provide appropriate interventions.

The incidence and risk factors of hepatic veno-occlusive disease after hematopoietic stem cell transplantation in Taiwan.

Hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). We conducted this study to investigate the incidence and risk factors of hepatic VOD for patients receiving HSCT in Taiwan. We retrospectively analyzed the data from a nationwide registry for patients receiving HSCT, which was collected by the Taiwan Society of Blood and Marrow Transplantation. The data collection period was from 2009 to 2014. A total 2345 patients were reviewed and 39 patients among them were diagnosed as having hepatic VOD. The cumulative incidence of hepatic VOD in the whole cohort of 2345 patients was 1.66%. In multivariate analysis, disease diagnosis of myelodysplastic syndrome, chronic HCV infection, condition regimens of bulsulfan intravenously administered, and antithymocyte immunoglobulin were independent factors to predict higher risk of hepatic VOD. The overall mortality rate for patients with hepatic VOD was 79%. Patients with hepatic VOD had significant worse survival outcomes when compared with those without hepatic VOD (P = 0.00063). In conclusion, although the incidence is low, hepatic VOD remains a serious complication after HSCT in Taiwan. The findings of this study could be the basis for developing prophylactic or early treatment strategies for hepatic VOD.

Patients with head and neck cancer may need more intensive pain management to maintain daily functioning: a multi-center study.

PURPOSE: The purpose of this study is to investigate the prevalence of pain, pain management, and impact of recent pain on daily functioning in patients with head and neck cancer (HNC) and patients with other cancers. METHODS: This multi-center survey was conducted by using Brief Pain Inventory questionnaire to evaluate pain status and its impact on daily functioning. RESULTS: A total of 3289 patients were analyzed including 708 HNC patients and 2581 patients with other cancers. The overall pain prevalence was 69.17%. A higher percentage of HNC patients had recent pain (60.59 vs. 44.01%, P < 0.001), required pain management (86.29 vs. 72.03%, P < 0.001), and used any analgesics (53.81 vs. 34.52%, P < 0.001). HNC patients with pain management had a higher prevalence of recent pain (85.83 vs. 81.14%, P = 0.044) and a slightly lower satisfaction rate (74.00 vs. 79.70%, P = 0.070). Regarding the impact of pain on daily functioning, HNC patients had a lower mean interference score for general activity such as walking, normal work, sleep, and life enjoyment. CONCLUSIONS: The HNC patients may need more intensive pain management to achieve optimal pain control and maintain daily functioning.

A nationwide survey of adherence to analgesic drugs among cancer patients in Taiwan: prevalence, determinants, and impact on quality of life.

PURPOSE: Poor adherence to analgesic drugs is one of the most common barriers to adequate pain management. This prospective, cross-sectional, patient-oriented observational study aimed to explore the adherence rate, clinical factors, and impact of adherence to analgesic drugs on the quality of life (QoL) among cancer outpatients in Taiwan. METHODS: Eight hundred ninety-seven consecutive adult outpatients with cancer who had reported tumor pain and received regular analgesic drug treatment were enrolled from 16 medical centers across Taiwan. The Brief Pain Inventory was used to assess pain intensity and QoL. Morisky's four-item medication adherence scale was used to assess adherence to analgesic drugs. Clinical factors possibly associated with good adherence to analgesic drugs were analyzed using multivariate logistic regression analyses. RESULTS: Of the 897 patients, 26.9% met criteria for the good, 35.5% for the moderate, and 37.6% for the poor adherence groups. The good adherence group had significantly better QoL outcomes than the moderate and poor adherence groups (all p < 0.05). Age ≥ 50 years, head and neck or hematological malignancies, cancer-related pain, patients who agreed or strongly agreed that the side effects of analgesic drugs were tolerable, and patients who disagreed or strongly disagreed that the dosing schedule could be flexibly self-adjusted to deal with the actual pain were predictors of good adherence to analgesic drugs. CONCLUSIONS: Awareness of the clinical factors associated with adherence to analgesic drugs may help clinicians to identify cancer patients at a greater risk of non-adherence, reinforce optimal pain management, and improve the QoL by enhancing adherence to pain medications.

The development and validation of the Emotional Cultivation Scale: An East Asian cultural perspective.

Research on emotion regulation in East Asian children and adolescents is limited. One obstacle hindering the development of emotion regulation for East Asian children and adolescents is the lack of a culturally sensitive measure. To fill this gap, we have developed and validated the Emotional Cultivation Scale using samples of Taiwanese children and adolescents. In Study 1, an exploratory factor analysis (n = 341) identified two factors: Cultivating Emotion Strategies and Understanding Emotion Connotations. A confirmatory factor analysis (n = 358) confirmed this two-factor structure. Coefficient αs were .69 to .88 for Emotional Cultivation. Convergent validity was evidenced by positive associations with cognitive reappraisal and cognitive flexibility. Discriminant validity was supported by a nonsignificant association with suppression. Concurrent validity was revealed by positive associations with positive affect, basic psychological need satisfaction, gratitude, responsiveness from teachers, responsiveness from parents, and academic self-efficacy. Incremental validity was evidenced by the finding that emotional cultivation significantly accounted for an additional 2 to 20% of the variance in predicting cognitive flexibility, positive affect, basic psychological need satisfaction, gratitude, responsiveness from teachers, responsiveness from parents, and academic self-efficacy above and beyond cognitive reappraisal and suppression. Results from the multigroup analysis further indicated factor loading invariance and validity invariance between boys and girls and between elementary and middle schools. The factor structure was cross-validated by a clinical sample of Taiwanese children and adolescents (N = 161) and their parents in Study 2 (N = 159). The counseling implications were discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.

Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare, autosomal-dominant disorder characterized by severe skin hyperkeratosis, congenital alopecia and leukonychia totalis. The genetic defect underlying KHLS remained undetermined. By performing whole-exome sequencing in a family with KHLS, we identified a heterozygous mutation (c.23G>T [p.Gly8Val]) in GJA1, which cosegregated with the phenotype in the family. In an additional affected individual, we also found the identical de novo mutation which was absent in his unaffected family members. GJA1 encodes a gap junction protein connexin 43 (Cx43) which is ubiquitously expressed in various organs, including the epidermis and hair follicles. In vitro studies on HEK293 cells expressing Cx43(Gly8Val) found that the protein formed gap junction plaques between adjacent transfected cells, as observed in the wild-type. Dye-transfer experiments by microinjection of Lucifer yellow displayed functional gap junction of the Cx43(Gly8Val) mutant. Using patch clamp and Ca(2+) imaging methods, we observed that the Cx43(Gly8Val) hemichannel had significantly more openings than Cx43(WT), facilitating Ca(2+) influx at resting potential. Such gain-of-function effect might result in cytoplasmic Ca(2+) overload, accelerated apoptosis of keratinocytes and subsequent skin hyperkeratosis. Taken together, our results demonstrated that, with probably enhanced hemichannel activities, a mutation in GJA1 is linked to KHLS without extracutaneous involvement.

Loss-of-function mutations in HOXC13 cause pure hair and nail ectodermal dysplasia.

Pure hair and nail ectodermal dysplasia (PHNED) is a congenital condition characterized by hypotrichosis and nail dystrophy. Autosomal-recessive PHNED has previously been mapped to chromosomal region 12q12-q14.1, which contains the type II hair keratin and HOXC clusters. Hoxc13-null mice are known to develop hair and nail defects very similar to those seen in human PHNED. We performed whole-exome sequencing in a consanguineous Chinese family affected by PHNED and identified a homozygous nonsense mutation (c.390C>A [p.Tyr130(∗)]) in HOXC13 in all affected individuals. In an additional affected female from a consanguineous Afghan family, we found a 27.6 kb homozygous microdeletion involving the first exon of HOXC13. We examined HOXC13 expression in scalp specimen obtained from the index individual of the Chinese family and detected dramatically reduced mRNA levels in skin tissue and nearly absent protein staining in hair follicles, suggesting a mechanism of nonsense-mediated mRNA decay. We also observed markedly decreased expression of four HOXC13 target genes in the specimen. Taken together, our results demonstrate that loss-of-function mutations in HOXC13 cause autosomal-recessive PHNED and further highlight the importance of HOXC13 in hair and nail development.

Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.

Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching. The genetic basis for OS remained unidentified. Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS. Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each). Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord. In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants. These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals. Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders.

Cyproheptadine significantly improves the overall and progression-free survival of sorafenib-treated advanced HCC patients.

OBJECTIVE: Sorafenib is a recommended treatment for advanced hepatocellular carcinoma. The study is to evaluate the efficacy of sorafenib plus cyproheptadine compared with sorafenib alone in patients with advanced hepatocellular carcinoma. METHODS: A retrospective cohort study reviewed all consecutive advanced hepatocellular carcinoma cases with Child-Pugh Class A disease starting sorafenib treatment at our hospital from August 2012 to March 2013. They were followed up until 31 December 2013. A total of 52 patients were enrolled: 32 patients in the combination (sorafenib-cyproheptadine) group and 20 patients in the control (sorafenib alone) group. The response to treatment, overall survival and progression-free survival were compared. RESULTS: The median overall survival was 11.0 months (95% confidence interval: 6.8-15.1 months) in the combination group compared with 4.8 months (95% confidence interval: 3.1-6.6 months) in the control group (crude hazard ratio = 0.45, 95% confidence interval: 0.22-0.82). The median progression-free survival time was 7.5 months (95% confidence interval: 5.1-10.0 months) in the combination group compared with 1.7 months (95% confidence interval: 1.4-2.1 months) in the control group (crude hazard ratio = 0.43, 95% confidence interval: 0.22-0.86). Kaplan-Meier survival analysis revealed that both overall survival and progression-free survival in the combination group were significantly longer than that in the control group. The multivariate model found patients in the combination group were 76% less likely to die (adjusted hazard ratio = 0.24, 95% confidence interval: 0.10-0.58) and 82% less likely to have progression (adjusted hazard ratio = 0.18, 95% confidence interval: 0.08-0.44) during the 17 months of follow-up. CONCLUSION: Cyproheptadine may significantly improve survival outcomes of sorafenib-treated advanced hepatocellular carcinoma patients.