Can chatbots enhance the management of pediatric sialadenitis in clinical practice?

OBJECTIVE: The purpose of this study was to assess how well ChatGPT, an AI-powered chatbot, performed in helping to manage pediatric sialadenitis and identify when sialendoscopy was necessary. METHODS: 49 clinical cases of pediatric sialadenitis were retrospectively reviewed. ChatGPT was given patient data, and it offered differential diagnoses, proposed further tests, and suggested treatments. The decisions made by the treating otolaryngologists were contrasted with the answers provided by ChatGPT. Analysis was done on ChatGPT response consistency and interrater reliability. RESULTS: ChatGPT showed 78.57% accuracy in primary diagnosis, and 17.35% of cases were considered likely. On the other hand, otolaryngologists recommended fewer further examinations than ChatGPT (111 vs. 60, p < 0.001). For additional exams, poor agreement was found between ChatGPT and otolaryngologists. Only 28.57% of cases received a pertinent and essential treatment plan via ChatGPT, indicating that the platform's treatment recommendations were frequently lacking. For treatment ratings, judges' interrater reliability was greatest (Kendall's tau = 0.824, p < 0.001). For the most part, ChatGPT's response constancy was high. CONCLUSIONS: Although ChatGPT has the potential to correctly diagnose pediatric sialadenitis, there are a number of noteworthy limitations with regard to its ability to suggest further testing and treatment regimens. Before widespread clinical use, more research and confirmation are required. To guarantee that chatbots are utilized properly and effectively to supplement human expertise rather than to replace it, a critical viewpoint is required.

MR sialographic assessment of the masseter muscle and the ductal kinking in patients with recurrent parotitis.

Dysfunction of the masseter muscle may cause pathological kinking of the parotid duct leading to parotitis; MR sialography is a non-invasive radiological examination that allows to evaluate dynamically the ductal system of the parotid glands. In the present study we aimed to assess the relationships between Stensen's duct and masseter muscle and their implications in the aetiopathogenesis of recurrent parotitis secondary to masseter muscle dysfunction. Forty-one patients with recurrent unilateral parotitis and nine with bilateral recurrent parotitis, all with a clinical suspicious of masseter muscle hypertrophy due to bruxism were enrolled. They underwent ultrasonography as a first line examination and then MR sialography and sialendoscopy. Different anatomical features were studied. Involved parotid glands had a wider duct compared to contralateral unaffected parotid glands of patients with recurrent parotitis (p = 0.00134); male subjects with parotitis had a longer duct compared to the salivary glands of healthy patients (p = 0.00943 for affected glands and p = 0.00629 for the contralateral). A concordance between the evidence of an acute duct angle during sialendoscopy and a wider duct in patients with parotitis was observed although not statistically significant. These initial findings suggest that the masticatory muscle dysfunction related to bruxism seems to condition alteration of parotid duct course and anatomy thus favouring the occurrence of recurrent parotitis. A specific diagnostic iter based on clinical evaluation, dynamic ultrasonography and MR sialography, is therefore, mandatory to confirm the relationship between masseter muscle anatomy and parotid duct anomalies; this is the premise for an adequate therapeutic approach to underlying masticatory muscle disorder.

Diagnostic performance of image-guided vacuum-assisted breast biopsy after neoadjuvant therapy for breast cancer: prospective pilot study.

BACKGROUND: Image-guided vacuum-assisted breast biopsy (VABB) of the tumour bed, performed after neoadjuvant therapy, is increasingly being used to assess residual cancer and to potentially identify to identify pathological complete response (pCR). In this study, the accuracy of preoperative VABB specimens was assessed and compared with surgical specimens in patients with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive invasive ductal breast cancer after neoadjuvant therapy. As a secondary endpoint, the performance of contrast-enhanced MRI of the breast and PET-CT for response prediction was assessed. METHODS: This single-institution prospective pilot study enrolled patients from April 2018 to April 2021 with a complete response on imaging (iCR) who subsequently underwent VABB before surgery. Those with a pCR at VABB were included in the primary analysis of the accuracy of VABB. The performance of imaging (MRI and PET-CT) was analysed for prediction of a pCR considering both patients with an iCR and those with residual disease at postneoadjuvant therapy imaging. RESULTS: Twenty patients were included in the primary analysis. The median age was 44 (range 35-51) years. At surgery, 18 of 20 patients showed a complete response (accuracy 90 (95 per cent exact c.i. 68 to 99) per cent). Only two patients showed residual ductal intraepithelial neoplasia of grade 2 and 3 respectively. In the secondary analysis, accuracy was similar for MRI and PET-CT (77 versus 78 per cent; P = 0.76). CONCLUSION: VABB in patients with an iCR might be a promising method to select patients for de-escalation of surgical treatment in triple-negative or HER2-positive breast cancer. The present results support such an approach and should inform the design of future trials on de-escalation of surgery.

Advances in breast cancer risk modeling: integrating clinics, imaging, pathology and artificial intelligence for personalized risk assessment.

Breast cancer risk models represent the likelihood of developing breast cancer based on risk factors. They enable personalized interventions to improve screening programs. Radiologists identify mammographic density as a significant risk factor and test new imaging techniques. Pathologists provide data for risk assessment. Clinicians conduct individual risk assessments and adopt prevention strategies for high-risk subjects. Tumor genetic testing guides personalized screening and treatment decisions. Artificial intelligence in mammography integrates imaging, clinical, genetic and pathological data to develop risk models. Emerging imaging technologies, genetic testing and molecular profiling improve risk model accuracy. The complexity of the disease, limited data availability and model inputs are discussed. A multidisciplinary approach is essential for earlier detection and improved outcomes.

Morphological and Metrical Relationships Between Sphenoid Sinus and Sella Turcica: Possible Applications in Transnasal Transsphenoidal Surgery.

INTRODUCTION: Transsphenoidal surgeries imply the risk of intraoperative lesions to the neurovascular structures surrounding the sphenoid sinus (SS). Aim of the present study is to assess the metrical and morphologic relationships existing between SS and sella turcica (ST). MATERIALS AND METHODS: Two hundred computed tomography-scans of patients were selected. For each patient volumes of SS were calculated from their 3-dimensional models segmented through ITK-SNAP program. Variants of SS in pneumatisation and sellar diameters [antero-posterior (AP) diameter, depth, and length] were evaluated on each computed tomography-scan. Correlations among different measurements were assessed through Spearman test ( P <0.01), whereas associations between sellar parameters and presence of pneumatisation variants were assessed through Mann-Whitney test ( P <0.01). RESULTS: In males, pneumatization of the greater wings was related to smaller AP diameter ( P <0.01) and depth of ST ( P <0.01), whereas in females lower values of depth were found in patients with pneumatization of the pterygoid processes ( P <0.01). In both sexes, a positive correlation was found between AP diameter and, respectively, length and depth of ST ( P <0.01), together with a negative correlation between volume of SS and depth of ST ( P <0.01). Lastly, in females a positive correlation was found between age and, respectively, length and depth of ST ( P <0.01). CONCLUSIONS: The present study highlighted new metrical and morphologic relationships between volume and pneumatisation of SS and diameters of ST. Knowledge of these correlations allows to understand more clearly, in the preoperative setting, the surgical working space. Further studies are needed, especially for what concerns the relationship between sellar measurements and age in females.

A Randomized Trial of Robotic Mastectomy Versus Open Surgery in Women With Breast Cancer or BrCA Mutation.

OBJECTIVE: The aim of this study was to compare robotic mastectomy with open classical technique outcomes in breast cancer patients. SUMMARY BACKGROUND DATA: As the use of robotic nipple sparing mastectomy continues to rise, improved understanding of the surgical, oncologic, and quality of life outcomes is imperative for appropriate patient selection as well as to better understand indications, limits, advantages, and dangers. METHODS: In a phase III, open label, single-center, randomized controlled trial involving 80 women with breast cancer (69) or with BRCA mutation (11), we compared the outcome of robotic and open nipple sparing mastectomy. Primary outcomes were surgical complications and quality of life using specific validated questionnaires. Secondary objective included oncologic outcomes. RESULTS: Robotic procedure was 1 hour and 18 minutes longer than open (P < 0.001). No differences in the number or type of complications (P = 0.11) were observed. Breast-Q scores in satisfaction with breasts, psychosocial, physical and sexual well-being were significantly higher after robotic mastectomy versus open procedure. Respect to baseline, physical and sexual well-being domains remained stable after robotic mastectomy, whereas they significantly decreased after open procedure (P < 0.02). The overall Body Image Scale questionnaire score was 20.7 ±â€Š13.8 versus 9.9 ±â€Š5.1 in the robotic versus open groups respectively, P < 0.0001. At median follow-up 28.6months (range 3.7-43.3), no local events were observed. CONCLUSIONS: Complications were similar among groups upholding the robotic technique to be safe. Quality of life was maintained after robotic mastectomy while significantly decrease after open surgery. Early follow-up confirm no premature local failure.ClinicalTrials.gov NCT03440398.

Ductal carcinoma in situ of the male breast: clinical radiological features and management in a cancer referral center.

PURPOSE: To present an overview of the management of male patients with Ductal Carcinoma In Situ of the breast (male DCIS). METHODS: We retrospectively studied all male patients with a diagnosis of pure DCIS from January 1999 to December 2018: 20 patients were identified in our cancer referral center. We collected data regarding clinical presentation, age of onset, radiological features, receptor status of the neoplasm, histological type, and the follow-up of those patients. RESULTS: The median age was 62 years (range 21-80). All patients underwent surgery, in 15/20 (75%) cases a mastectomy was carried out. Two patients (10%) underwent endocrine treatment and 1/20 (5%) underwent radiotherapy. The receptor status for 15/20 patients was documented: 13/15 patients were ER+/Pr+. In 3 cases the Ki 67% was positive (i.e., > 20%). All cases were negative for Her2. The median follow-up time was 9.0 years (IQR 4.0-13.7). Only one patient had an ipsilateral recurrence with the finding of an infiltrating carcinoma in the same breast after 14 years. The 5-year disease-free survival was 92.9%. CONCLUSION: Pure DCIS in men is an extremely rare disease: proper diagnosis and management allow an excellent prognosis.

Patient- versus physician-reported outcomes in a low-dose tamoxifen trial in noninvasive breast cancer.

BACKGROUND: We recently conducted a de-escalation trial of low-dose tamoxifen 5 mg/day ("babytam", BT) or placebo given for 3 years in 500 women with noninvasive breast cancer. Women on babytam had a 52% reduction of recurrence (invasive breast cancer or DCIS) after 5 years. Since menopausal symptoms are major reasons for treatment withdrawal during tamoxifen preventive therapy, we compared and analyzed the patient-reported outcomes (PROs) with the physician-reported adverse events and studied their association with recurrence. METHODS: Menopausal symptoms recorded by physicians using the Common Terminology Criteria (CTCAEs) were compared with a patient self-reported validated questionnaire reviewed by a research nurse at baseline and every 6 months up to 36 months. Hot flashes (HF), the main outcome measure, were detected through a self-report 7-day diary for frequency and intensity. Treatment adherence and efficacy were assessed by the Kaplan-Meier curves and the Cox model. RESULTS: The number of HF events at 12, 24, and 36 months for PROs versus CTCAEs was 246 versus 12, 238 versus 8, and 210 versus 4, respectively. The majority of events were grade 1. There was no difference in PROs between babytam and placebo except for HF daily frequency, which increased by 1.5 events (95% CI, 1.1-1.8) on placebo to 2.1 on babytam (95% CI, 1.7-2.5, p = 0.05). The presence of HF at baseline was a favorable prognostic factor for recurrence and a predictive factor for response to babytam. Adherence was similar between babytam and placebo. CONCLUSIONS: The use of PROs is effective for identifying frequent mild grade menopausal symptoms which are underestimated by physicians but important prognostic and predictive factors. Research nurse can use these results as a tool to reassure patients about symptoms, improve adherence to treatment, and limit dropouts.

A Presurgical Study of Curcumin Combined with Anthocyanin Supplements in Patients with Colorectal Adenomatous Polyps.

Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4-6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of ß-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72; 95% confidence interval (CI): 0.51-1.00; p-value: 0.05) and a trend to a reduction of Ki-67 (GMR: 0.73; 95% CI: 0.50-1.08; p-value: 0.11). No significant modulation of biomarkers in normal adjacent mucosa was observed. We concluded that the combined supplementation of anthocyanins and curcumin seems to lead to a potentially favorable modulation of tissue biomarkers of inflammation and proliferation in colon adenomas.

Prognostic and predictive value of cell cycle progression (CCP) score in ductal carcinoma in situ of the breast.

The natural history of ductal carcinoma in situ (DCIS) is highly variable and difficult to predict. Biomarkers are needed to stratify patients with DCIS for adjuvant therapy. We investigated the prognostic and predictive relevance of cell cycle progression (CCP) score in women with DCIS. We measured the expression of 23 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumor samples, and assessed the correlation of a predefined score with histopathologic features and recurrence. The signature was analyzed in a cohort of 909 consecutive DCIS with full histopathological features treated in a single institution. The main outcome measure was ipsilateral breast event (IBE) as first event observed, be it in situ or invasive. Median follow-up time was 8.7 years (IQR 6.5-10.5 years). There were 150 ipsilateral IBEs, 84 (56%) of which were invasive. In the first 5 years of follow-up, the score provided statistically different findings (p = 0.009), with IBE rates of 14.7% (95% CI, 10.4-19.7) for the highest quartile of CCP score (Q4) and 8.7% (95% CI, 6.7-11.0) for the lowest quartiles (Q1-3). The prognostic value for IBEs approached significance also in women treated with mastectomy (adjusted hazard ratio [HR] Q4 vs. Q1-3 = 2.60; 95% CI: 0.96-7.08; P = 0.06). Radiotherapy provided a greater benefit in women with higher CCP score. In addition, Q4 predicted a different risk after tamoxifen depending on menopausal status, with a beneficial trend on IBEs in postmenopausal women (HR 0.30; 95% CI, 0.07-1.39), and an opposite trend in premenopausal women (HR 1.68; 95% CI, 0.38-7.44) (P-interaction = 0.03). The results of this study provide for the first time the evidence that CCP score is a prognostic marker, which, after additional validation, could have an important role in personalizing the management of DCIS.

Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.

Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with "any event" was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20-1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P < 0.004). After a median follow-up of 7 years, women carrying the "low estrogen" alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17-0.93; P = 0.03). Our analysis points to an impact of UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592.

Development of an HPLC-MS/MS Method for the Determination of Silybin in Human Plasma, Urine and Breast Tissue.

Silybin is a flavonolignan extracted from Silybum marianum with chemopreventive activity against various cancers, including breast. This study was designed to develop an HPLC-MS/MS method for the determination of silybin in human plasma, urine and breast tissue in early breast cancer patients undergoing Siliphos® supplementation, an oral silybin-phosphatidylcholine complex. The determination of silybin was carried out by liquid-liquid extraction with methyl-tert-butyl ether (MTBE); total silybin concentration was determined by treating the samples with ß-glucuronidase, while for the determination of free silybin, the hydrolytic step was omitted. Naringenin and naproxen were selected as internal standards. The detection of the analyte was carried out by mass spectrometry and by chromatography. The HPLC-MS/MS method was evaluated in terms of selectivity, linearity, limit of quantification, precision and accuracy, and carryover. The method proved to be selective, linear, precise and accurate for the determination of silybin. To the best of our knowledge, this presents the first analytical method with the capacity to quantify the major bioactive components of milk thistle in three different biological matrices with a lower limit of quantification of 0.5 ng/mL for plasma. Silybin phosphatidylcholine, taken orally, can deliver high blood concentrations of silybin, which selectively accumulates in breast tumor tissue.

Benefit of low-dose tamoxifen in a large observational cohort of high risk ER positive breast DCIS.

Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings.

Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial.

Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.

Laryngeal Leishmaniasis: A Neglected, Emerging Disease in Northern Italy.

Leishmaniasis represents an emerging public health issue in Mediterranean countries. The incidence of this condition has progressively risen in Northern Italy due to the growing number of immunocompromised people and probably due to climate changes. We hereby describe a case of relapsing laryngeal leishmaniasis in a female immunocompetent patient, presenting as aspecific chronic laryngitis. She was affected by severe asthma treated by inhaled steroid therapy, likely responsible for the parasite's diffusion through a locus minori resistentiae. The aspecific clinical presentation led to a delayed diagnosis and the lack of guidelines for the treatment caused multiple relapses. Biopsies of laryngeal lesions in the follow-up were performed by operative flexible videolaryngoscopy, thus avoiding general anesthesia and reducing associated healthcare costs. The aim of this report is to underline the diagnostic and therapeutic challenges that patients with this condition face and to present what is, to the best of our knowledge, the first application of prophylactic aerosolized pentamidine for relapsing laryngeal leishmaniasis.

Evolving paradigms in breast cancer screening: Balancing efficacy, personalization, and equity.

Breast cancer remains a significant global health challenge, with projections indicating a troubling increase in incidence. Breast cancer screening programs have long been hailed as life-saving initiatives, yet their true impact on mortality rates is a subject of ongoing debate. Screening poses the risk of false positives and the detection of indolent tumors, potentially leading to overtreatment. Bias factors, including lead time, length time, and selection biases, further complicate the assessment of screening efficacy. Recent studies suggest that AI-driven image analysis may revolutionize breast cancer screening, maintaining diagnostic accuracy while reducing radiologists' workload. However, the generalizability of these findings to diverse populations is a critical consideration. Personalized screening approaches and equitable access to advanced technologies are essential to mitigate disparities. In conclusion, the breast cancer screening landscape is evolving, emphasizing the need for risk stratification, appropriate imaging modalities, and a personalized approach to reduce overdiagnosis and focus on cancers with the potential to impact lives while prioritizing patient-centered care.

A Mediation Analysis of Obesity and Adiponectin Association with Postmenopausal Breast Cancer Risk: A Nested Cohort Study in the International Breast Cancer Intervention Study II (IBIS-II) Prevention Trial.

Obesity is a risk factor for postmenopausal breast cancer (BC), and evidence suggests a role for adiponectin in the relationship between obesity and BC. We investigated whether adiponectin or other biomarkers mediate the effect of body mass index (BMI) on postmenopausal BC risk in a cohort study nested in the IBIS-II Prevention Trial. We measured adiponectin, leptin, IGF-I, IGFBP-1, high-sensitivity C-reactive protein, glycemia, insulin, HOMA-IR index, and SHBG in baseline and 12-month serum samples from 123 cases and 302 matched controls in the placebo arm of the IBIS-II Prevention trial. We conducted the main mediation analysis considering baseline BMI as an exposure and the 12-month adiponectin increase as a mediator after adjustment for the Tyrer-Cuzick score and the lipid-lowering medications/supplements use. In the multivariable Cox model, both the 12-month adiponectin increase (HR, 0.60; 95%CI, 0.36-1.00) and BMI were associated with BC risk (HR, 1.05; 95%CI, 1.00-1.09), with a 40% reduction in women with a 12-month increase in adiponectin. A significantly higher cumulative hazard of BC events was observed in obese women (BMI > 30) with decreased adiponectin (p = 0.0087). No mediating effect of the adiponectin increase on the total effect of BMI on BC risk was observed (natural indirect effect: HR, 1.00; 95%CI, 0.98-1.02). Raising adiponectin levels might be an attractive target for postmenopausal BC prevention.

Prognostic Value of PCSK9 Levels in Premenopausal Women at Risk of Breast Cancer-Evidence from a 17-Year Follow-Up Study.

BACKGROUND AND AIM: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. METHODS: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. RESULTS: The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170-252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999-1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = -0.305), maintained even after partial adjustment for BMI and age (r = -0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. CONCLUSIONS: In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.

Fenretinide in Young Women at Genetic or Familial Risk of Breast Cancer: A Placebo-Controlled Biomarker Trial.

Fenretinide, a retinoid with a low-toxicity profile that accumulates in the breast, has been shown to prevent second breast cancer in young women. Fenretinide exhibits apoptotic and antiinvasive properties and it improves insulin sensitivity in overweight premenopausal women with insulin resistance. This study aimed to further characterize its role in cancer prevention by measuring circulating biomarkers related to insulin sensitivity and breast cancer risk.Sixty-two women, ages 20 to 46 years, healthy or who had already undergone breast cancer surgery, with a known BRCA1/2 mutation or a likelihood of mutation ≥20% according to the BRCAPRO model, were randomly assigned to receive fenretinide (200 mg/day) or placebo for 5 years (trial registration: EudraCT No. 2009-010260-41). Fasting blood samples were drawn at baseline, 12 and 36 months, and the following biomarkers were analyzed: retinol, leptin, adiponectin, retinol-binding protein 4 (RBP-4), total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, glucose, insulin, insulin-like growth factor (IGF-1), IGF-binding protein 3, sex hormone binding globulin (SHBG), testosterone, and vascular endothelial growth factor (VEGF).After 12 months of treatment, we observed a favorable effect of fenretinide on glucose (decrease; P = 0.005), insulin (decrease; P = 0.03), homeostatic model assessment index (decrease; P = 0.004), HDL cholesterol (increase; P = 0.002), even though these effects were less prominent after 36 months. Retinol and retinol-binding protein 4 markedly decreased (P < 0.0001) throughout the study. None of the other measured biomarkers changed. PREVENTION RELEVANCE: Fenretinide exhibits beneficial effects on the metabolic profile, supporting its clinical use in breast cancer prevention especially in premenopausal women with a positive family history and pathogenic variants in BRCA1/2 genes. This finding requires further investigations in larger trials to confirm its role in breast cancer prevention.

Expression of immune-related genes and breast cancer recurrence in women with ductal carcinoma in situ.

BACKGROUND AND AIM: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with highly variable clinical behavior, but risk stratification is still challenging. We sought to identify immune-related gene expression signatures of pure DCIS associated with different risks of breast cancer recurrence. METHODS: A retrospective nested case-control study of 143 pure DCIS was performed including 70 women with subsequent ipsilateral breast event (IBE, in situ or invasive; cases) and 73 DCIS women with no IBE and matched for age, tumor size, treatment, hormone receptors/HER2 status, and follow-up time (controls). RNA was extracted from DCIS samples and subjected to next-generation sequencing gene expression analysis of 395 immune-related genes. Correlations between DCIS immune-related gene expression and IBE were analyzed using weighted Cox regression for nested case-control data. RESULTS: Eight immune-related genes were differentially expressed between cases and controls. MAGEA10 expression (present vs. absent) and high expression levels of IFNA17 and CBLB (Q4 vs. Q1) were observed more frequently in DCIS of women with subsequent IBE, mainly invasive (p-valueFDR < 0.05). Conversely, expression of IL3RA1, TAGAP, TNFAIP8, and high expression levels of CCL2 and LRP1 were associated with a lower risk of IBE (p-valueFDR < 0.05). CONCLUSION: This exploratory analysis of pure DCIS showed significant differences in immune-related gene expression profiles between women with and with no subsequent IBE, particularly as invasive IBE. These results, after additional validation, could improve risk stratification and management of DCIS patients.