Purpose
To evaluate the efficacy of alpha-lipoic acid (ALA) administration on hormonal and metabolic parameters of obese PCOS patients.
Methods
A group of 32 obese PCOS patients were selected after ...informed consent. 20 patients referred to have first grade relatives with diabetes type I or II. Hormonal and metabolic parameters as well as OGTT were evaluated before and after 12 weeks of ALA integrative administration (400 mg per os every day).
Results
ALA administration significantly decreased insulin, glucose, BMI and HOMA index. Hyperinsulinemia and insulin response to OGTT decreased both as maximal response (Δmax) and as AUC. PCOS with diabetes relatives showed the decrease also of triglyceride and GOT. Interestingly in all PCOS no changes occurred on all hormonal parameters involved in reproduction such as LH, FSH, and androstenedione.
Conclusions
ALA integrative administration at a low dosage as 400 mg daily improved the metabolic impairment of all PCOS patients especially in those PCOS with familiar diabetes who have a higher grade of risk of NAFLD and predisposition to diabetes.
The putative role and use of dehydroepiandrosterone (DHEA) as replacement therapy for menopausal women has been under consideration during the latest years. DHEA is one of the main adrenal hormones ...that progressively reduces its plasmatic levels from the beginning of ageing. This phenomenon implies not only the reduction of the plasmatic androgens but also the decrease of a peculiar category of hormones, named neurosteroids, in particular one: allopregnanolone. This review aims to elucidate the peculiar aspects of DHEA administration and its putative use as substitutive/integrative hormonal treatment alone or in combination with the traditional hormone replacement therapy.
Abstract
Phosphatase and tensin homolog (PTEN), a potent downregulator of the PI3K-Akt pathway, has been shown to mediate the interaction between poly (ADP-ribose) polymerases (PARPs) and the ...mismatch repair (MMR) complex in endometrial and ovarian cancer. Drugs inhibiting PARPs (iPARPs) are currently considered promising therapeutic tools in a subset of PTEN-defective tumors. Regrettably, the frequency and significance of MMR alterations in breast cancer is debated, and their relationship with PTEN status has not been investigated in the breast. Furthermore, many of the studies on the DNA damage response and its therapeutic implications in breast cancer focus on inherited syndromes (e.g. Lynch syndrome and hereditary breast-ovarian cancer syndrome).
Aims: We sought to explore the interplay between PTEN and the MMR system and to define whether PTEN immunohistochemistry (IHC) is a predictor of MMR proficiency in non-familial breast cancers.
Methods: 373 cases of non-familial breast cancers, including a representative number of no special (n=295) and special types (n=78), carefully characterized from clinical and pathological standpoints, were reviewed and used to construct 14 tissue microarrays (TMAs). For each case, a mean of 4.5 tumor tissue cores (range 3 to 6 cores) was sampled, incorporating distinct topographic areas of the tumor, as well as matched non-neoplastic breast tissue. Taken together, 1876 spots were generated. Each TMA was subjected to IHC for PTEN and the DNA MMR proteins MLH1, MSH2, MSH6 and PMS2. In order to minimize human-related biases, each stained slide was digitalized and two pathologists blindly analyzed each tumor spot using a dedicated software able to segment and randomize TMA cores. The pattern of expression was therefore annotated manually on a digital database using a specific add-on module to reconstruct the original topography.
Results: According to clinicopathologic surrogate definition of intrinsic subtypes, PTEN protein loss or heterogeneous expression was more frequent in estrogen receptor negative cancers. Furthermore, 100% of the MMR-proficient luminal B-like (HER2+) and triple-negative breast cancers displayed strong and diffuse homogeneous PTEN expression, while PTEN-positive status identified MMR-proficient luminal A-like and luminal B (HER2-) like tumors with accuracy rates of 89.3% and 92.7%, respectively (p=0.001, Fisher's exact test).
Conclusions: The present study is the first to investigate PTEN protein loss in a large set of non-familial breast carcinomas based on their DNA MMR status by IHC. Here, we demonstrated that PTEN strong and homogeneous expression by IHC is able to capture the vast majority of MMR-proficient non-familial breast cancers. Our findings broaden the understanding of the biology underpinning these tumors, suggesting that PTEN is likely play a role in the development of MMR alterations. Given that PTEN-defective breast cancers have the propensity to develop additional somatic alterations in the MMR system, our results suggest that IHC for PTEN and MMR proteins may be emplyed as an ancillary study to define new subclasses of sporadic breast cancers potentially eligible for iPARPs therapies.
Citation Format: Fusco N, Gambini D, Runza L, Lopez G, Ercoli G, Despini L, Bosari S. PTEN immunohistochemistry is a predictor of mismatch repair status in breast cancer abstract. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-07.
Abstract
Breast cancer related lymphoedema (BCRL) occurs in a substantial proportion of breast cancer survivors and is a major contributor to disability, representing a long-term threat to these ...patients. Given the extremely high incidence of breast cancer worldwide, and the increasing number of long-term survivors, the reduction of BCRL burden represents an urgent clinical need in women's healthcare. However, there are no validated predictive biomarkers, diagnostic tools, and strong evidence-supported therapeutic strategies for BCRL management. Here, we provide a comprehensive clinicopathological characterization of a large series of women with node-positive breast cancers and identify new bona fide predictors of BCRL occurrence.
332 cases of surgically-treated node-positive breast cancers were retrospectively collected (2-10.2 years of follow-up). Among them, 62 patients developed BCRL. To identify demographic and clinicopathologic features related to BCRL, Fisher's exact test or Chi-squared test were carried out for categorical variables; the Wilcoxon rank-sum was employed for continuous variables. Factors associated with BCRL occurrence were assessed using a Cox proportional hazards regression model.
En-bloc dissection of the axillary lymph nodes but not the type of breast surgery impacted on BCRL development. Most of BCRL patients had a Luminal A-like neoplasm. The median number of lymph nodes involved by metastatic deposits was significantly higher in BCRL compared to the control group (p=0.04). Both peritumoral lymphovascular invasion (LVI) and extranodal extension (ENE) of the metastasis had a negative impact on BCRL-free survival (p=0.01). Specifically, patients with LVI and left side localization harbored 4-fold higher risk of developing BCRL, while right axillary nodes metastases with ENE increased the probability of BCRL compared to ENE-negative patients.
Here, we document that LVI and ENE have a strong predictive value for BCRL occurrence. Furthermore, we confirm that the full excision of the axillary nodes is one of the major determinants of BCRL, regardless of the extent of the surgical procedure involving the breast. In conclusion, our results suggest that the pathologic data on LVI and ENE should be integrated with information on the laterality of the tumor and the type of surgical procedure. This new integrative approach could be extremely beneficial to improve BCRL risk stratification.
Citation Format: Fusco N, Corti C, Lopez G, Michelotti A, Despini L, Gambini D, Lorenzini D, Guerini-Rocco E, Maggi S, Noale M, Invernizzi M. Proposal for integrating the pathologic assessment of lymphovascular invasion and extranodal tumor extension in breast cancer-related lymphedema clinical management abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-12-09.
Abstract
Despite the approval of pembrolizumab in all tumors showing mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI), there are currently no companion diagnostics for MMR ...status assessment in breast cancer. Here, we sought to define the diagnostic and prognostic role of MMR and MSI testing in breast cancer patients.
We subjected 444 breast cancers to MMR immunohistochemistry (IHC) and MSI analysis. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and MMR-heterogeneous (hMMR) based on the loss of immunoreactivity; MSI was defined by the instability in the five indicators recommended by the National Cancer Institute for endometrial and colorectal cancers. Correlation of MMR status with patients' survival was assessed using the Kaplan-Meier estimator.
In 75 patients (17%) the loss of MMR proteins was homogeneous, classified as dMMR, while 55 cases (12%) were hMMR. The prevalence of cancers with loss of the MMR proteins was homogeneous across ER+ breast cancers (15-19% for dMMR and 10-18% for hMMR tumors). The level of overlap between IHC and MSI analysis was 9% (p<0.0001). Among ER+/HER2- carcinomas, pMMR and hMMR patients displayed better survival rates (p=0.008). In chemo-treated ER-/HER2- breast cancers, the dMMR status was a marker of good prognosis (p<0.001).
Our study documents the clinical impact of MMR testing in a large series of breast cancers, using the most commonly adopted diagnostic tools and criteria. We show that MMR protein loss is a rather common event in breast cancer and has a remarkable degree of intra-tumor heterogeneity, therefore making the analysis of a small area of the tumor, or a small biopsy, of little clinical value. Our investigation supports the concept that MSI occurs rarely in breast cancer and demonstrate that this condition is restricted to a minority of tumors with MMR protein loss. These data suggest that MMR IHC and MSI analysis should not be considered as interchangeable tests in the diagnostic workup of breast carcinomas. Finally, our observations indicate that the complete loss of at least one of the MMR proteins assessed by IHC is able to identify high-risk ER+/HER2- breast cancers that can potentially benefit from pembrolizumab therapy, whereas first-line chemotherapy shows comparatively good results in dMMR ER-/HER2- breast cancers.
Citation Format: Fusco N, Lopez G, Corti C, Pesenti C, Colapietro P, Ercoli G, Gaudioso G, Faversani A, Gambini D, Despini L, Blundo C, Vaira V, Miozzo M, Ferrero S, Bosari S. Mismatch repair protein loss is a prognostic and predictive biomarker in breast cancers regardless of microsatellite instability abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-21.
Aim With the aim of reducing recurrence after perineal surgery for full‐thickness rectal prolapse, a new operation consisting of a trans‐obturator colonic suspension during Altemeier’s operation has ...been developed.
Method Eighteen women with full‐thickness rectal prolapse were examined clinically, with validated quality of life and continence scores, colonoscopy, anorectal manometry, anal EMG and sacral reflex latency. Ten had a newly diagnosed and eight a recurrent prolapse. The Altemeier operation was combined with a levatorplasty in all cases using two porcine collagen prostheses sutured to the descending colon and passed through the trans‐obturator space bilaterally. The operation was completed by a manual or stapled colo‐anal anastomosis. Clinical examination, with quality of life and continence scores, anorectal manometry, EMG and sacral reflex latency, was scheduled during follow up, with the recurrence of prolapse as the primary outcome measure.
Results There were no recurrences at 30 months. There was no mortality and no complications. All patients experienced significant improvement in quality of life and faecal continence scores (P < 0.01). Surgery did not affect anorectal pressures or sacral reflex latencies.
Conclusion The new technique appears to be relatively easy to perform and is complication free with no recurrence after a short period of follow up. A larger study with appropriate controls and longer follow up is now needed to assess its real effectiveness in reducing the risk of recurrence.
Selected primary lung cancers less than 2
cm from the carina or invading the tracheo-bronchial angle, formerly considered inoperable, can be amenable to tracheal sleeve pneumonectomy (TSP). Such a ...delicate technique, can entail remarkable post-operative morbidity and mortality, and only few clinical series are reported. Purpose of this paper is to examine complications and long-term survival of our personal series and those reported in literature. At our academic department from 1983 to December 2004, out of 99 patients with NSCLC less than 2
cm from the carina, 35 (35.4%) were deemed inoperable after conventional staging; the remaining 64 underwent surgery. Since 1993 in every patient with lung cancer we perform a thoracoscopic exploration as the first step of the intervention. Unexpected causes of inoperability were found at thoracotomy in nine patients (14.1%) and at thoracoscopy in two other patients. Of the remaining 53 patients, 52 had a right TSP and one a left TSP. Intraoperative mortality was nil. Perioperative mortality was 7.5%. Major complications occurred in 11.3% of the patients. Thirty (56.6) patients are alive and disease-free 23–97 months after surgery; for 18 (33.4%) of these, more than 5 years have elapsed after the operation. TSP is the only concrete option for treating lung cancer originating less than 2
cm from the carina. The review of our experience and of other reported series suggests that, with careful selection of patients and meticulous surgical technique, operative mortality and complications are acceptable. Long-term survival and prognosis are encouraging.
Introduction/ Background Loss of phosphatase and tensin homolog (PTEN) expression and alterations in mismatch repair (MMR) genes are regarded as early oncogenic events in breast cancer. It has ...recently been hypothesized that the polyadenosine tract in PTEN might be a target for mutation in MMR-deficient endometrial tumors. However, the frequency and significance of MMR alterations in breast cancer is debated, and their relationship with PTEN status has not been investigated in the breast. Aims In this study, we sought to explore the relationships between PTEN expression and MMR alterations and to define whether PTEN immunohistochemistry is a predictor of MMR status in breast cancer. Methods 309 cases, including 261 invasive ductal carcinomas, no special type, 32 invasive lobular carcinomas, and 16 invasive ductal carcinomas, mixed types, carefully characterized from clinical and pathological standpoints, were reviewed and used to construct 11 tissue microarrays (TMAs). For each case, a mean of 4.5 tumor tissue cores (range 3 to 6 cores) was sampled, incorporating distinct topographic areas of the tumor, as well as matched non-neoplastic breast tissue, and, when present, associated in situ carcinoma. Taken together, 1381 spots were generated. Each TMA was subjected to immunohistochemical analysis of PTEN and the DNA MMR proteins MLH1, MSH2, MSH6 and PMS2. In order to allow a quick navigation within each TMA, and to minimize human-related biases, each stained slide was digitalized and blindly analyzed by two pathologists using a dedicated software able to segment TMA cores. The pattern of expression was therefore annotated manually on a digital database using a specific add-on module. Results According to clinicopathologic surrogate definition of intrinsic subtypes, PTEN protein loss was more frequent in luminal A-like and triple negative groups compared to luminal B-like carcinomas, as recently observed in other studies. MMR status in Luminal B-like tumors did not differ significantly between PTEN-retained and PTEN-loss groups, regardless HER2 amplification. In particular, retained PTEN expression was a predictor of MMR proficiency in approximately 35% of cases for this group. However, in luminal A-like and triple negative breast cancer groups, retained positive expression of MMR proteins was observed in 100% of cases showing PTEN wild-type immunohistochemical expression. Discussion: The present study is the first to investigate PTEN protein loss in a large set of breast carcinomas based on DNA MMR status by immunohistochemistry. Our findings broaden the understanding of the biology underpinning breast cancer, suggesting that MMR alterations are likely to be independent of PTEN status in the majority of luminal B-like breast cancers and that, in a way akin to endometrial carcinoma, MMR deficiency could play a part in the development of PTEN alterations in luminal A-like and triple negative breast cancers. The integration of traditional pathology with cutting-edge digital tools allowed a rapid quantification of immunohistochemistry and effective data organization in this wide cohort multi-variable study. Conclusion: PTEN immunohistochemistry is a useful adjunct in the clinical evaluation of breast cancer patients, being able to capture all MMR-proficient luminal A-like and triple negative tumors.
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