Purpose/Objective(s) The Partner and localizer of BRCA2 (PALB2) gene has crucial role in DNA double-strand break repair, upkeep of genome integrity, and suppression of cancer development. PALB2-deficient cells are known to be hypersensitive to ionizing radiation. Multigene panel testing has increasingly identified patients with PALB2 variants raising the question if those patients with heterozygous PALB2 variants have compromised outcomes or are at increased risk of radiation toxicity. We hypothesize that outcomes with radiation are acceptable with moderately hypofractionated (Hypo-RT) or conventionally fractionated (CRT) radiation after breast conserving surgery (BCS) or mastectomy in patients with heterozygous germline PALB2 pathogenic variants or variants of uncertain significance (VUS). Materials/Methods Between 2005 and 2023, breast cancer patients treated with radiation were consented for peripheral blood sequencing (PBS) on an institutionally approved IRB protocol. PALB2 variants detected by high-throughput PBS were designated benign, pathogenic, VUS, or with conflicting interpretations of pathogenicity using the ClinVar database. Variants designated benign or likely benign were excluded and those with conflicting interpretations of pathogenicity or variants of uncertain significance were classified as VUS. Toxicities were abstracted from medical records and were graded per Common Terminology Criteria for Adverse Events v5. Additional clinicopathologic information was abstracted from the medical records. Results A total of 583 patients were sequenced. After excluding benign PALB2 variants, 14 were included in this analysis: 5(36%) were pathogenic and 9(64%) were VUS. Median tumor size was 2 cm and median age at diagnosis was 51.5 years (range = 42–69). Among these patients 12(86%) had invasive disease, 10(71%) were ER+, and 9(64%) received chemotherapy; 11(79%) had BCS with 7(50%) undergoing sentinel lymph node dissection. All patients received photon based external beam radiation, 3 (21%) were treated with Hypo-RT, 11 (79%) with CRT, and 7(50%) received nodal irradiation. Median follow up was 69 months. Grade 2 acute radiation dermatitis (ARD) was noted in 8(57%) patients, and grade 3 in 2(14%) patients. For patients with grade 3 ARD, one had a pathogenic variant of PALB2, the other had a VUS. Late grade 2 fibrosis was recorded in 1(7%) patient. There were no grade 4 or 5 toxicities. Contralateral breast cancer did not occur in any patients. One patient (7%) had chest wall recurrence 4 months after finishing radiation. Conclusion This represents the first report on clinical outcomes in breast cancer patients with PALB2 undergoing radiation. We concluded that radiation therapy in individuals with heterozygous PALB2 germline pathogenic variants or variants of uncertain significance (VUS) appears to be well-tolerated with acceptable clinical outcomes.

Purpose/Objective(s) Acute radiation dermatitis (RD) is a notable side effect in breast cancer patients undergoing radiation therapy. This study aims to predict such adverse effect through an integrated machine learning model that synthesizes clinical data, mammographic radiomic features, and genetic mutations identified by single nucleotide polymorphism (SNP) testing. Materials/Methods In this retrospective study, data from 174 breast cancer patients treated with radiation following breast-conserving surgery or mastectomy between 2004 and 2016 were evaluated. Genetic profiling included 30 genes, sequenced from peripheral blood samples. Extracted genomic DNA was annotated using Illumina Variant Studio Software and verified with ClinVar database. Patients were stratified based on germline genetic status into four groups: non-carriers, carriers of benign or likely benign variants, variants of uncertain significance (VUS), and pathogenetic variants. Pre-surgery contralateral mammograms were processed to extract 94 radiomics texture features using open-source software. Clinical parameters clinical parameters such as race, age, BMI, TNM staging, total radiation dose, and hypofractionation were also recorded. RD of grade 2 or above were identified as positive cases in this work. A linear support vector machine (LSVM) model was trained with 5-fold cross-validation, to identify significant predictive features from the compiled clinical, radiomics and genomics data. Results The LSVM model with genetic data integration pinpointed 3 genetic markers (CDH1, PTEN, TGFBRAP1), 4 radiomic features, and 2 clinical features (hypofractionation and race) as significant predictors of radiation side effects, achieving an area under the ROC curve (AUC) of 0.75 (± 0.04). The inclusion of mammographic patterns offers additional insight into correlation between germline genetic status and the associated toxicities. Conclusion This study demonstrates the potential of a radiogenomic approach to predict acute radiation therapy side effects in breast cancer patients. The preliminary findings underscore the need for further investigation into the underlying mechanisms linking mammographic appearance and genomic features to side effects, facilitating personalized treatment strategies to mitigate these adverse outcomes.

Purpose/Objective(s) The ataxia telangiectasia mutated (ATM) gene has significant roles in DNA double-strand break repair, and homozygous deficiency in ATM is known to cause significant sensitivity to ionizing radiation. Multigene panel testing has increasingly identified patients with ATM variants raising the question if those patients with heterozygous ATM variants are at increased risk of radiation toxicity. We hypothesize that there will be no significant difference in toxicity between hypofractionated (Hypo-RT) or conventionally fractionated (CRT) radiation treatments after breast conserving surgery (BCS) or mastectomy in patients with heterozygous germline ATM pathogenic variants or variants of uncertain significance (VUS). Materials/Methods Between 2004 and 2016, breast cancer patients treated with radiation were consented for peripheral blood sequencing (PBS). ATM variants detected by high-throughput PBS were designated benign, pathogenic, VUS, or with conflicting interpretations of pathogenicity using the ClinVar database. Variants designated benign or likely benign were excluded and those with conflicting interpretations of pathogenicity or variants of uncertain significance were classified as VUS. Toxicities were abstracted from medical records and were graded per Common Terminology Criteria for Adverse Events v5. Additional clinicopathologic information was abstracted from the medical records. Fisher's exact test was used to compare Grade 2 or 3 acute skin toxicity among patients with pathogenic variants or VUS treated with Hypo-RT versus CRT. Results A total of 400 patients were sequenced. After excluding benign ATM variants, 23 were included in this analysis, 2 (8%) were pathogenic and 21 (91%) were VUS. Median tumor size was 1.5cm and median age at diagnosis was 54 years (range: 33–74). Among these patients 91% had invasive disease, 72% were ER+, and 39% received chemotherapy; 86% elected for BCS with 78% undergoing sentinel lymph node dissection. All patients received photon based external beam radiation, 10 (43%) were treated with Hypo-RT, 12 (52%) with CRT, one (4%) with accelerated partial breast irradiation, and 4 (17%) with nodal irradiation. Median follow up was 5.04 years. Grade 2 acute radiation dermatitis (ARD) was noted in 8 patients (34%) and grade 3 in 2 patients (8%). There was no difference in Grade 2 or 3 ARD between patients receiving Hypo-RT or CRT (P= 0.4). Late grade 2 fibrosis was recorded in 1 patient (4%) and there were no events of any late grade 3 toxicity. Contralateral breast cancer occurred in 2 patients (8%) at 6 months and 9 years after the initial diagnosis. Conclusion Radiation treatment in patients with heterozygous ATM germline pathogenic or VUS appears well tolerated. In our study, there was no statistical difference in toxicity between Hypo-RT or CRT.

The emotional and psychosocial stress experienced by cancer patients can significantly impact treatment outcomes and overall quality of life. Standard methods of screening for psychosocial distress have been established, including the National Comprehensive Cancer Network (NCCN) distress screening thermometer and problem list. Limited data is available elucidating the distress that Veterans with cancer face. This report provides an overview of the results of a distress screening program at a single VA institution We reviewed 413 consecutive patients undergoing cancer treatment during the period 1/26/17 to 3/19/2019. The goal of this review was to understand the physical, emotional, practical, family, and spiritual difficulties veterans with cancer experience, as reflected by their responses to a standard evidence-based screening tool. Screenings were completed utilizing the NCCN distress thermometer at first consultation in Radiation Oncology and Hematology/Medical Oncology clinics Mean age of the patient population was 68.5 and 96.1% were male. The treatment population was 55.2% Caucasian, 40.6% African American, 3.6% Hispanic, 0.6% other. The most prevalent cancer diagnoses were prostate 48.4%, lung 11.8%, head and neck 8.9%, hematologic 7.5%, GI 4.8%, breast 2.4%, and CNS 1.1%. Skin and other malignancies comprised 15%. Screenings were completed on > 90% of patients at first visit. 54% of patients screened scored at or above the numerical distress value of 4, indicating moderate to severe distress. Significant mental health comorbidities were identified: 43.3% addictive disorder, 20.8% PTSD, 15% depressive disorder, 10.10% adjustment disorder. 53.5% of patients experienced at least 1 practical problem, 16.2% at least 1 family problem, 62.2% at least 1 emotional or spiritual problem. 40.4% of the population experienced fatigue and 39.2% experienced pain. Referrals to the Oncology Psychology team were placed in 42.4% of the treatment population. These results support the utility of the distress screening process in identifying psychosocial and physical conditions experienced by Veterans undergoing cancer treatment. The screening process, implemented by the interdisciplinary treatment team, consistently facilitated referrals to both embedded mental health specialty care within Oncology (Oncology Psychology) and to the medical center's general mental health service. Further data is being collected to investigate the effect of interventions by mental health professionals on veteran reported distress

Background: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid’s metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. Methods: We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT ≥5 times the upper limit of normal (ULN), or ALT ≥3 times the ULN with total bilirubin ≥2 times the ULN. Results: In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I’s NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. Conclusions: Variants in complex I’s subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor.

Background:Fusarium species are isolated from about 3% of onychomycoses in the Swiss native population. On the basis of macroscopic characters and microscopic examination of the cultures, identification of Fusarium often remains difficult or uncertain because of variations from one isolate to another and overlapping characteristics between species. Objective: To obtain information about the prevailing species of Fusarium collected from onychomycoses. Methods: An analysis of the Fusarium specimens isolated in the Department of Dermatology at the University Hospital of Lausanne was conducted during a 2-year period (71 isolates). A 311-bp fragment of the gene encoding 28S rRNA was amplified by PCR and sequenced. DNA sequences were compared to those available for reference strains. Results:Fusarium oxysporum was the most frequently isolated species, accounting for 54% of the isolates. F. proliferatum and 4 taxons belonging to the F. solani species complex were identified with an appreciable frequency ranging from 4 to 14%. Conclusion: The Fusarium species identified were the same as those known to cause disseminated fusariosis in immunocompromised patients. The presence of these Fusarium species in onychomycoses warrants that careful attention should be paid to abnormal nails before beginning immunosuppressive treatments in patients.

Background: Dermatophytes are usually identified on the basis of macroscopic characteristics and microscopic examination of the cultures. Identification of dermatophytes often remains difficult or uncertain because there are variations from one isolate to another and overlapping characteristics between species. Objective: To identify dermatophyte species producing numerous microconidia and resembling Trichophyton mentagrophytes by DNA sequence analysis. Methods: The complete ITS1 + 5.6s + ITS2 rDNA region of various dermatophytes isolated in culture was amplified by PCR and sequenced. Results: Nine isolates of a fast-growing dermatophyte species were identified as Arthroderma benhamiae by DNA sequencing. Retrospective investigations revealed that the isolates were from 8 children and 1 adult suffering from inflammatory dermatophytosis. Eight of the 9 patients had had previous contact with rodents, mostly guinea pigs. Conclusion: It is the first time that A. benhamiae is reported in Switzerland. In cases of dermatophytosis attributed to A. benhamiae, a rodent is the most likely cause of infection.

ABSTRACT We have shown that dermatophyte species can be easily identified on the basis of a DNA sequence encoding a part of the large-subunit (LSU) rRNA (28S rRNA) by using the MicroSeq D2 LSU rRNA Fungal Sequencing Kit. Two taxa causing distinct dermatophytoses were clearly distinguished among isolates of the Trichophyton mentagrophytes species complex.

Between August 1994 and September 1996, 28 glycopeptide-resistant enterococci (GRE) were isolated from 8 infected patients and 11 intestinal carriers hospitalized at the University Hospital of Geneva. Identification to the species was made by both phenotypic (API 20 STREP and Rapid ID 32 STREP systems, and Vitek Gram Positive Identification Card) and genotypic methods using a multiplex PCR assay developed also for the determination of the genotype of glycopeptide resistance (vanA, vanB, vanC1, and vanC2-C3 genes). Fifteen isolates were identified as Enterococcus faecium, 8 as E. gallinarum, 4 as E. faecalis, and 1 as E. hirae. All of the phenotypic identification methods failed to differentiate some isolates of E. gallinarum from E. faecium, or vice versa. Both vanA (n = 18) and vanB (n = 4) glycopeptide resistance genotypes were found. For the first time, the vanB determinant was found in two isolates of E. gallinarum. Two patients were colonized by two different species containing the vanA gene and one by two different species containing the vanB gene. All vanA isolates were highly resistant to both vancomycin and teicoplanin except for three isolates which were susceptible to teicoplanin. Molecular typing by pulsed-field gel electrophoresis showed identical or similar patterns among E. faecium isolates with the vanA gene in five patients for whom the epidemiological link could not be always elucidated. This study emphasizes the necessity of utilizing both phenotypic and genotypic methods to characterize GRE.