To evaluate the contrast enhancement of the breast parenchyma in MRI using gadopiclenol (GP) at half the standard dose of gadolinium compared with gadobutrol (GB) at the standard dose of gadolinium. This retrospective, single-center study considered 319 consecutive female patients who underwent breast MRI with a half-standard dose of gadopiclenol (0.05mmol/kg) between January and March of 2025. Complete data sets of patients who had received a prior cycle-appropriate MRI using a standard dose of gadobutrol (0.1mmol/kg) within 2 years, without interim therapy, were evaluated. Absolute signal enhancement of the aorta, axillary lymph nodes, and breast parenchyma was measured to provide an objective assessment. Two independent radiologists evaluated subjective image quality and diagnostic confidence using a 5-point Likert Scale in a side-by-side comparison. Statistical analyses were performed using Wilcoxon signed-rank tests and weighted Cohen kappa. A total of 145 patients (mostly with hereditary breast and ovarian cancer syndrome) met the inclusion criteria. GP revealed significantly higher absolute enhancement values for all regions (eg, breast parenchyma: GP: 41.8, IQR: 27.1 to 65.4 vs GB: 33.4, IQR: 21.6 to 56.3; P < 0.001). Both contrast agents achieved excellent overall diagnostic confidence ratings (5; IQR: 4 to 5) and demonstrated moderate agreement (GP: κ = 0.59/ GB: κ = 0.48). GP received more excellent ratings (71.9% vs 56.8%; P = 0.002). Most pairs were considered equal on terms of image quality (R1: 90/145; R2: 92/145; P = 0.845) with fair agreement (κ = 0.366). Agreement was achieved in 97 of the 145 cases (67 "equal," 21 "pro GP", and 9 "pro GB"). The combination "equal & pro GP" accounted for most of the remaining comparisons (37/48). Breast MRI using gadopiclenol with half standard gadolinium dose offers equivalent to superior objective contrast enhancement and subjective diagnostic confidence compared with a gadobutrol-enhanced MRI with full standard gadolinium dose.

Recent advances in phosphatases as new biomarker in personalized medicine.

Morbid obesity is a complex, multifactorial disorder characterized by metabolic and inflammatory dysregulation. The aim of this study was to observe changes in obese patients adhering to a personalized nutrition plan based on multi-omic data. This study included 14 adult patients with a body mass index (BMI) &gt; 40 kg/m2 who were consecutively recruited from those presenting to our outpatient clinic and who met the inclusion criteria. Clinical, biochemical, hormonal, and glycomic parameters were assessed, along with whole-genome sequencing (WGS) that included a focused analysis of obesity-associated genes and an extended analysis encompassing genes related to cardiometabolic disorders, hereditary cancer risk, and nutrigenetic profiles. Patients were stratified into nutrigenetic clusters using a patented unsupervised machine learning platform (German Patent Office, No. DE 20 2025 101 197 U1), which was employed to generate personalized nutrigenetic dietary recommendations for patients with morbid obesity to follow over a six-month period. At baseline, participants exhibited elevated glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides, and C-reactive protein (CRP) levels, consistent with insulin resistance and chronic low-grade inflammation. The majority of participants harbored risk alleles within the fat mass and obesity-associated gene (FTO) and the interleukin-6 gene (IL-6), together with multiple additional significant variants identified across more than 40 genes implicated in metabolic regulation and nutritional status. Using an AI-driven clustering model, these genetic polymorphisms delineated a uniform cluster of patients with morbid obesity. The mean GlycanAge index (56 ± 12.45 years) substantially exceeded chronological age (32 ± 9.62 years), indicating accelerated biological aging. Following a six-month personalized nutrigenetic dietary intervention, significant reductions were observed in both BMI (from 52.09 ± 7.41 to 34.6 ± 9.06 kg/m2, p &lt; 0.01) and GlycanAge index (from 56 ± 12.45 to 48 ± 14.83 years, p &lt; 0.01). Morbid obesity is characterized by a pro-inflammatory and metabolically adverse molecular signature reflected in accelerated glycomic aging. Personalized nutrigenetic dietary interventions, derived from AI-driven analysis of whole-genome sequencing (WGS) data, effectively reduced both BMI and biological age markers, supporting integrative multi-omics and machine learning approaches as promising tools in precision-based obesity management.

Background/Objectives: Lynch syndrome (LS), is traditionally managed uniformly despite being caused by pathogenic variants in four distinct mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). This approach fails to leverage gene-specific characteristics for precision healthcare delivery. This review redefines LS as four distinct genetic syndromes and establishes a genotype-guided precision management framework to optimize risk stratification, surveillance, and therapeutic interventions. Methods: We synthesized molecular, clinical, and outcomes data from the Prospective Lynch Syndrome Database (8500+ carriers; 70,000 person-years), genomic studies characterizing gene-specific mutational patterns, and immunotherapy trials while referencing international guidelines [National Comprehensive Cancer Network (NCCN), European Hereditary Tumour Group (EHTG)/European Society of Coloproctology (ESCP), and European Society for Medical Oncology (ESMO)] to formulate genotype-stratified recommendations. Results: Fundamental molecular differences necessitate differentiated management strategies. MLH1 deficiency exhibits unique “two-in-one hit” mechanisms driving aggressive tumorigenesis with high interval cancer rates. MSH2 deficiency presents the highest tumor mutational burden (≈47 mutations per megabase; Mut/Mb) and broadest cancer spectrum. MSH6 deficiency displays distinctive high-single-nucleotide variant (SNV)/low-insertion–deletion (Indel) patterns often presenting as microsatellite instability-low (MSI-low) or microsatellite stable (MSS), complicating conventional detection. PMS2 deficiency demonstrates substantial attenuation due to redundancy. These translate into precision interventions: MLH1/MSH2 carriers require colonoscopy from age 25 at 1–2-year intervals with extended colectomy preferred, while MSH6/PMS2 carriers can defer surveillance to age 35–40 with longer intervals and undergo segmental resection. Immune checkpoint inhibitors (ICIs) are effective in deficient MMR (dMMR)/microsatellite instability-high (MSI-H) tumors across all four MMR genotypes. Conclusions: Genotype-specific precision management optimizes the benefit–burden balance, enhances early cancer detection, reduces overtreatment, and enables personalized genetic counseling, advancing precision healthcare for LS families and addressing critical gaps in hereditary cancer care.

The BRCA2 c.156_157insAlu variant is a Portuguese founder mutation implicated in hereditary breast and ovarian cancer (HBOC). This study aims to determine its occurrence and clinical implications in the northern interior region of Portugal. A retrospective study of 571 individuals referred for HBOC genetic counseling and testing between 2021 and 2024 was conducted. Genetic screening was performed using next-generation sequencing of 27 hereditary cancer genes, with confirmatory PCR for BRCA2 c.156_157insAlu. Pathogenic or likely pathogenic variants were detected in 19.8% of participants, with BRCA1/2 variants accounting for 5.4%. The BRCA2 c.156_157insAlu variant was identified in 6 individuals (25% of all BRCA2 pathogenic variants identified), including breast cancer patients and asymptomatic carriers. Clinically, it was associated with early onset and contralateral breast cancer. Cascade testing and genetic counseling were offered to at-risk relatives. The BRCA2 c.156_157insAlu variant remains a significant contributor to HBOC in northern Portugal. Its high local proportion among BRCA2 variants supports the implementation of targeted genetic testing strategies, enhancing early detection and personalized cancer risk management.

Indications for germline genetic testing (GT) for hereditary cancer predispositions have increased; however, a critical shortage of genetic counselors (GCs) necessitates the implementation of alternative delivery models. Here, we present the design and implementation of a coordinator-based alternative GT delivery model, called Fast-Track, embedded in a comprehensive cancer genetics program with oversight by GCs. The Fast-Track Program includes visits with clinical genetics coordinators (GCCs) who are trained by GCs in cancer genetic pre-test education and testing. Referrals received to the Smilow Cancer Genetics and Prevention Program (SCGP) are reviewed and triaged by GCs; patients that meet National Comprehensive Cancer Network (NCCN) guidelines for GT are then assigned to the Fast-Track Program. Patients are shown an educational video, which was created by the SCGP and have GT coordinated by the GCC. All cases are reviewed by a GC after the initial visit, regardless of whether GT is completed, for appropriate medical management recommendations. All patients with pathogenic/likely pathogenic variants (PGVs) identified or with complicated results are scheduled with a GC for result disclosure, while remaining patients have disclosure by GCCs. The Fast-Track Program was implemented in June 2023, and this report includes data from 6/12/2023 to 3/29/2024. During this 9-month period, 415 patients were seen in the Fast-Track Program and 12.3% of patients tested had PGVs identified. Mean days from the referral date to the appointment date were significantly shorter for the FT program compared with the standard GC pipeline (21.92 and 90.14 days, respectively) (p < 0.001). A coordinator-based genetics delivery model has been successful in expediting GT visits and is expanding at our institution. Oversight by GCs is essential to ensure standard-of-care delivery for cancer GT in the precision medicine era. Future work evaluating additional quality-of-care outcomes, such as patient satisfaction, will be essential to fully contextualize this model's impact.

There is an increasing demand for fertility-sparing treatment (FST) among young women with gynecological cancer. This study aimed to clarify the current status of FST implementation across Japan by focusing on institutional practice patterns and clinical protocols for cervical, endometrial, and ovarian cancers. A nationwide cross-sectional survey was conducted between August and September 2024. An online questionnaire was distributed to 481 gynecologic tumor registry institutions through the Japan Society of Obstetrics and Gynecology mailing list. Data on institutional characteristics, specific FST eligibility criteria, treatment methods, and post-treatment management were collected. Responses were received from 226 institutions (response rate: 47.0%), and all respondent institutions (100%) performed FST for at least one gynecological cancer. Although FST is widely available, significant heterogeneity in clinical protocols was observed across all three cancers. Key variations among respondent institutions included a low implementation rate of radical trachelectomy for cervical cancer (20.8%), a high rate of post-FST hysterectomy for endometrial cancer (63.6%) compared to cervical cancer and ovarian cancer, and exclusion criteria for patients with hereditary cancer syndromes. FST is an established practice in Japan; however, there is a lack of consensus regarding its clinical application. These findings provide a critical benchmark for future efforts to standardize care and develop collaborative networks to optimize this essential treatment modality for young patients with gynecological cancer.

A germline CHEK2 nonsense variant was identified in a patient presenting with both diffuse large B-cell lymphoma, a subtype of non-Hodgkins lymphoma, and endometrioid adenocarcinoma, through next-generation sequencing of a 113-gene hereditary cancer panel.

Understanding patient priorities: Sexual health and hereditary ovarian cancer syndromes.

Cancer family syndromes can predispose to malignancies of different sites, including brain and spinal tumours. Germline mutations associated with a high risk of cancer can also be found in patients with metastatic tumours of the brain. We present a few such cases, underscoring the importance of DNA germline testing in all primary and metastatic brain tumours. We report four cases illustrating the role of DNA testing in intervention decisions in families of patients with both primary and secondary brain tumours. In this article, we included a case of Li-Fraumeni, Lynch, and von Hippel-Lindau syndromes, as well as a metastatic widespread example of BRCA1-related ovarian cancer. In all primary and metastatic brain tumours, genetic testing for germline mutations of high-risk cancers should be considered.

Informed consent in medical care is supposed to guarantee patient autonomy. However, in practice, written consent is often inadequate for this purpose: In an effort to meet legal requirements, consent forms are often comprehensive and complex. They cover all information that could potentially be relevant, possibly overwhelming patients rather than addressing their concerns. Thus, there is an urgent need for more patient-centered consent forms. As a first step toward this goal, this study assessed the importance of various aspects of consent to genetic testing from the patients' perspective. A cross-sectional online study was conducted with 224 participants at elevated risk for hereditary breast and/or ovarian cancer. Participants rated the importance of 14 aspects typically covered on the consent form. Each aspect was compared with all other aspects using multiple contrast tests for repeated measures. Participants also provided hypothetical consent to each aspect. Voluntary comments to the consent aspects were analyzed using qualitative content analysis. Although the majority of consent aspects were rated important in absolute terms, we observed relative differences. Specifically, consent aspects reflecting a clinical benefit for the patient and her family were rated as more important relative to all other aspects. This included, for example, consent to receiving additional test results which could imply further clinical consequences. Our results may inform the communication between patients and their counseling physicians prior to genetic testing. They also provide an empirical basis for revising consent forms to better align with patients' needs while remaining legally sound.

Multiple cancers occur in the same individual, such as hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome. Here, we report a patient with HBOC syndrome who developed four different cancer types (pancreatic cancer, right lung adenocarcinoma, prostate cancer, and left lung adenocarcinoma) within a relatively short period of 6.5years. In HBOC syndrome, the lung adenocarcinoma is rare, and the tumors were initially suspected to be lung metastases from pancreatic cancer, respectively. The pathological analysis results in each of the three lesions were inconsistent. A whole-exome analysis was performed on all three tumors using next-generation sequencing (NGS). The results showed that many of the deletion mutations found in pancreatic cancer were not present in other lung tumors. Homologous recombination is required for the repair of deletion mutations, but this function is impaired in HBOC syndrome. Deletions occurring in the primary tumor are irreversible and should be inherited in metastatic lesions. Therefore, we hypothesized that these three cancers arose independently, that each lung tumor was a primary tumor rather than a metastasis of pancreatic cancer, and that their resection would be curative. This assumption was reasonable, as no new lesions were observed in a 10-year follow-up study since the onset of pancreatic cancer. Tracking genetic traits using NGS helps understand the origins and progression of malignant tumors.

Germline pathogenic variants are increasingly recognized as critical determinants of pancreatic ductal adenocarcinoma (PDAC) susceptibility, prognosis, and response to targeted therapies such as PARP inhibitors. Recent guidelines recommend germline testing for all PDAC patients, regardless of family history, to identify hereditary cancer syndromes and guide treatment decisions. However, data from populations underrepresented in genomic studies, such as the Turkish population, remain limited. We retrospectively analyzed 151 unselected PDAC patients who underwent germline testing using a next-generation sequencing (NGS) panel between January 2023 and April 2025. The panel covered established cancer susceptibility genes. Clinical parameters-including age, sex, tumor location and stage, diabetes status, and cancer family history-were reviewed. Variants were classified as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or benign. Among the 151 patients, 17 (11.3%) harbored P/LP variants, most frequently in ATM (n=3), BRCA1 (n=2), BRCA2 (n=2), and CDKN2A (n=2). An additional 33 patients (21.9%) carried VUS, again most commonly affecting ATM. No benign variants were reported. Notably, 70.6% of P/LP carriers had a first- or second-degree family history of cancer. Most tumors originated in the pancreatic head (72.8%), and 41.1% of patients had metastatic disease at diagnosis. Our findings confirm the relevance of multigene panel testing in PDAC and reveal a germline mutation spectrum consistent with global data. These results support universal germline screening and emphasize the need for continued VUS interpretation, particularly in genomically understudied populations.

IntroductionBreast cancer is the most prevalent cancer among women in Brazil, with up to 10% of cases linked to hereditary factors. Genetic testing and counseling are critical for identifying hereditary breast cancer risk, guiding treatment decisions, and preventing cancer in high-risk populations.ObjectivesThis study aimed to analyze the experience, perspectives, and access barriers to breast cancer genetic testing in the Brazilian respondents of the Multinational Survey Study Assessing GENetic Testing and Counseling Among Patients with Breast Cancer (MAGENTA) study.MethodsA 38-multiple-choice question, branched survey was distributed by patient advocacy agencies to collect sociodemographic and patient-perspective data about their experience with breast cancer genetic testing. A multivariate analysis was conducted to explore the association between sociodemographic variables and the genetic testing status.Results207 breast cancer patients completed the survey. In this cohort, the rates of genetic testing and counseling were 81.6% and 60.4%, respectively. 66.7% of respondents reported a high or advanced educational level. Notably, 71.7% of patients reported that genetic testing changed their treatment plans, and 77.1% of those who took the test were willing to test their familiars. In addition, 98.7% stated they did not regret undergoing genetic testing. Higher income was independently associated with higher odds of undergoing genetic testing (OR: 4.43 [95% CI: 1.64;13.11]; p = 0.0011), while having more than 50 years-old was associated with a lower odds of undergoing testing (OR: 0.21 [95% CI: 0.08;0.56]; p=0.0018). Barriers such as costs and limited awareness were prominent, with 89% of patients in Brazil reporting low awareness of genetic testing prior to their diagnosis.ConclusionsThe survey respondents in Brazil comprised a highly educated and financially secure group of patients. Although not generalizable to the entire Brazilian population, our results revealed that even in a highly educated and well-informed cohort there is a strong association between age and income level with genetic testing. These findings expose the real-world challenges for increasing genetic testing coverage in Brazil, where testing is only warranted in the private health system, highlighting the need for health policies to increase test availability for lower income brackets.

Recently, the Tohoku Medical Megabank Organization released whole-genome allele frequencies of single-nucleotide variants and indels from approximately 60,000 individuals from the general Japanese population in the Tohoku region (60KJPN). Here we analyzed the 60KJPN dataset for BRCA1/BRCA2 variants and compared them with the previous version, 54KJPN, to ascertain the frequency of hereditary breast and ovarian cancers in the general Japanese population. We hope that these results will contribute to strategies for cancer prevention.

Individuals with the breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) associated hereditary breast and ovarian cancer (HBOC) have an elevated risk of developing breast cancer in both men and women. The aim of the study was to assess the risk of HBOC using clinical history in patients diagnosed with breast or ovarian cancer (OC) receiving treatment. A cross-sectional study was conducted among 180 patients diagnosed with breast or OC, selected using a nonprobability convenience sampling technique. Data was collected using a self-structured tool for the sociodemographic and clinical variables, and the CanRisk tool was used to assess the estimated risk percentage value of BRCA1 or BRCA2 pathogenic or likely pathogenic variants based on the clinical variables. Data was analyzed using IBM SPSS version 20, Mann-Whitney U-test, and Kruskal-Wallis test, with P < 0.05 as the significance level. The results indicate an increased hereditary risk associated with early breast or OC diagnosis, married, late menarche, early menopause, young maternal age at first childbirth, and family history in patients diagnosed with breast or OC. A statistically significant association (P < 0.05) was found between estimated risk percentages for pathogenic or likely pathogenic variants BRCA1 or BRCA2 (including BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51D, RAD51C, or BRIP) with the selected sociodemographic and clinical variables. Genetic counseling and testing for patients diagnosed with breast or OC can identify HBOC risk, reducing complications and mitigating lifetime cancer risk through timely assessment and awareness.

Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift and molecularly assayed for biological impact. Using in silico tools, population-based genetic databases and other resources, three of the five reported BRIP1 variants were likely to be damaging: c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61. The carrier frequencies ranged from 0 to 0.7% in ancestry-defined cancer groups comprising 47 OC families, 49 hereditary breast and ovarian cancer syndrome families, 142 hereditary breast cancer syndrome families, 435 sporadic OC cases and 563 sporadic BC cases and 0–0.2% in 1025 population-matched controls. Multiple carriers of the these variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61, which were predicted to be damaging, conferred cellular sensitivity to mitomycin C and cisplatin unlike p.Ser139Ala and p.Ala406Ser. Collectively, our investigation implicates BRIP1 c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61 as deleterious variants in OC and BC.

ObjectivesThis study evaluates artificial intelligence (AI) reasoning capabilities in gynecologic cancer genetic counseling, comparing the performance of ChatGPT and DeepSeek models to guide patient-centered AI implementation in clinical genetics.MethodsUsing 40 National Comprehensive Cancer Network-aligned counseling scenarios, we conducted blinded dual-oncologist evaluations of two large language models. Methodological rigor included model anonymization, a pre-calibrated scoring framework, and validated metrics (Global Quality Scale and Patient Education Materials Assessment Tool) assessing informational coherence, understandability, and actionability.ResultsDeepSeek demonstrated superior informational breadth (mean character difference: −609.0, p < .0001) and visual communication (diagram integration, p < .01), with 49-fold greater probability in recommending clear and actionable actions (p < .01, OR = 49.0). ChatGPT excelled in concise summarization (22% faster response generation, p = .013).ConclusionStrategic AI model selection—leveraging DeepSeek's visually-rich, structured educational approach for complex information, and ChatGPT's concise, rapid summarization for efficient communication—enhances patient-centered genetic education when combined with clinician oversight. This framework supports healthcare's digital transformation by optimizing human-AI collaboration in hereditary cancer care.

Postoperative Management After Risk-Reducing Salpingo-Oophorectomy for Hereditary Breast and Ovarian Cancer Syndrome: A Narrative Review on Balancing Oncologic Benefit and Quality of Life

Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R–MCU activity. This calcium imbalance strengthens VDAC1–IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.