Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with poor quality of life. Debilitating symptoms and the reality of shortened survival impact patients’ physical and emotional ...well-being and constrain the lives of patients’ caregivers. This study assessed the informational needs of medical providers who care for patients with IPF, IPF patients themselves, and their caregivers. Tailored surveys were sent electronically to providers, patients with IPF, and caregivers of patients with IPF collected on a rolling basis in March of 2017. Providers answered questions regarding their own informational needs and what information they believed patients needed. Patients and caregivers identified their own informational needs and the perceived needs for each other. About 2636 surveys were sent to providers, including 2041 to physicians, of whom 156 completed it. One hundred sixty patients and 29 caregivers responded to the survey via a link on a website. Eighty-six percent of providers described themselves as physicians who diagnose and treat IPF patients themselves. Providers ranked information on “making the diagnosis of IPF” as their top informational need. Patients and caregivers chose “disease progression/what to expect” as the most important informational need for themselves and for each other. Providers want to make a correct diagnosis when IPF is in the differential diagnosis. Patients and caregivers desire clarity around how IPF will behave over time and what their futures with IPF will look like. Resources for patients and their caregivers should include information on disease natural history in empathically worded, clear, and easily accessible formats.
To reverse the dramatic decline in the U.S. physician-scientist workforce, interventions are necessary to retain physicians in research careers.
To evaluate the impact of an annual 3-day symposium, ...the Respiratory Disease Young Investigators' Forum (RDYIF), designed to guide fellows and junior faculty into successful physician-scientist careers.
In this retrospective, observational study, a questionnaire was e-mailed to 308 physicians who participated in the RDYIF between 2005 and 2018. The questionnaire was administered by National Jewish Health study personnel in the spring of 2019. Responses were primarily analyzed using descriptive and qualitative approaches.
The response rate was 39.3% (
= 121), with 107 of responders (88.4%) completing the full survey. The majority of survey completers currently worked as physician-scientists (76.6%;
= 82), held faculty positions (88.8%;
= 95) in an academic center (90.6%;
= 97), and were currently involved in research (93.4%;
= 100). The majority had been an author on ≥10 peer-reviewed publications (61.3%,
= 65) and had been awarded research grants (71.7%;
= 76). Thirty completers (28.3%) had served as a principal investigator on one or more clinical trials. Completers indicated that participation in the RDYIF had a "strong impact" or "very strong impact" on their career development as physician-scientists.
Participation in the RDYIF strengthened participants' interest in physician-scientist careers and appeared to track with successful career development. Young Investigator Forums such as the RDYIF may be an effective intervention to support the declining supply of physician-scientists in North America.
BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, incurable lung disease whose intrusive symptoms rob patients of their quality of life. Patients with IPF rely on their caregivers for ...support and assistance in amounts that vary according to patients’ individual circumstances and disease severity. Knowledgeable and well-informed patients and caregivers are best suited to deal with life-altering conditions like IPF.MethodsWe conducted two hour-long focus groups with 13 patients with IPF and 4 caregivers of patients with IPF to better understand their informational needs and in what format such information should be delivered.ResultsPatients discussed the challenges IPF creates in their daily lives. They wanted information on how to live well despite having IPF, practical information on how they could remain active and travel and how they could preserve their quality of life despite living with a life-threatening disease like IPF. Caregivers wanted information on the general aspects of IPF, because it would help them understand what patients were going through. They also wanted specific information on how to give care to a patient with IPF, even when physical care may not be needed (as in earlier phases of the disease). Patients and caregivers both needed efficient information delivery from trustworthy sources, including the healthcare team involved in their care. They considered both spoken and written information valuable, and ease of access was critical.ConclusionThis study provides valuable insight regarding the informational needs of IPF patients and their caregivers. It is hoped that identifying or creating sources of this information, and insuring that patients and caregivers have access to it, will improve well-being for patients with IPF and their caregivers.
We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and ...skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.
Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ...ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.
Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, ...and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.
Background
Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle‐invasive bladder cancer (MIBC) has been associated with improved overall survival ...(OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre‐NAC cT stage) on the OS of patients with MIBC treated with NAC.
Methods
The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2‐4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability–weighted regression adjustment.
Results
Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P < .001 for NCDB), and it yielded better discrimination (incremental C index, 4.2 for RISC and 1.6 for NCDB). The treatment effect of NAC in achieving pDS was 2.07‐fold (P < .001) in comparison with cystectomy alone.
Conclusions
A decrease of at least 1 stage from the cT stage to the pT stage is associated with improved OS in patients with MIBC treated with NAC.
Using 2 different cohorts, this study demonstrates that a decrease in tumor size, even without complete disappearance, is associated with better survival than no response in patients with muscle‐invasive bladder cancer treated with neoadjuvant chemotherapy.
Structural variation and single-nucleotide variation of the complement factor H (CFH) gene family underlie several complex genetic diseases, including age-related macular degeneration (AMD) and ...atypical hemolytic uremic syndrome (AHUS). To understand its diversity and evolution, we performed high-quality sequencing of this ∼360-kbp locus in six primate lineages, including multiple human haplotypes. Comparative sequence analyses reveal two distinct periods of gene duplication leading to the emergence of four CFH-related (CFHR) gene paralogs (CFHR2 and CFHR4 ∼25–35 Mya and CFHR1 and CFHR3 ∼7–13 Mya). Remarkably, all evolutionary breakpoints share a common ∼4.8-kbp segment corresponding to an ancestral CFHR gene promoter that has expanded independently throughout primate evolution. This segment is recurrently reused and juxtaposed with a donor duplication containing exons 8 and 9 from ancestral CFH, creating four CFHR fusion genes that include lineage-specific members of the gene family. Combined analysis of >5,000 AMD cases and controls identifies a significant burden of a rare missense mutation that clusters at the N terminus of CFH P = 5.81 × 10−8, odds ratio (OR) = 9.8 (3.67-Infinity). A bipolar clustering pattern of rare nonsynonymous mutations in patients with AMD (P < 10−3) and AHUS (P = 0.0079) maps to functional domains that show evidence of positive selection during primate evolution. Our structural variation analysis in >2,400 individuals reveals five recurrent rearrangement breakpoints that show variable frequency among AMD cases and controls. These data suggest a dynamic and recurrent pattern of mutation critical to the emergence of new CFHR genes but also in the predisposition to complex human genetic disease phenotypes.
The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with ...muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2–4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p=0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3–4 or pN1 disease who received AC (75% vs 54%; p<0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p=0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%.
Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.
Adjuvant chemotherapy after neoadjuvant treatment and radical cystectomy for muscle-invasive bladder cancer should be offered only to patients with a high risk of 1-yr recurrence. Time-based endpoints may be more useful to help data interpretation for the next adjuvant and neoadjuvant immunotherapy studies.
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