Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects.

Endometriosis is a common benign pathology, characterised by the presence of endometrial tissue outside the endometrial cavity with a prevalence of 10-15% in reproductive-aged women. The pathogenesis is not completely understood, and several theories have been proposed to explain the aetiology. Our group has recently described the presence of ectopic endometrium in a consistent number of human female foetuses analysed by autopsy, reinforcing the hypothesis that endometriosis may be generated by defects during the organogenesis of the female reproductive trait. Herein, in order to identify, at molecular level, changes involved in the disease, we compared the transcriptional profiling of ectopic endometrium with the corresponding eutopic one. Statistical analyses lead us to identify some genes specifically deregulated in the ectopic endometrium, that are involved in gonad developmental process or in wound healing process. Among them, we identified BMP4 and GREM1. BMP4 was never associated before to endometriosis and is involved in the mesoderm-Müllerian duct differentiation. GREM1 is needed for the initial step of the ureter growth and perhaps could possibly be involved in Müller ducts differentiation. These molecules might be related to the endometriosis aetiology since we showed that their expression is not related to the menstrual cycle phase both at RNA and at protein levels. These data support the theory that embryological defects could be responsible of the endometriosis generation.

Vasari Scoring System in Discerning between Different Degrees of Glioma and IDH Status Prediction: A Possible Machine Learning Application?

(1) The aim of our study is to evaluate the capacity of the Visually AcceSAble Rembrandt Images (VASARI) scoring system in discerning between the different degrees of glioma and Isocitrate Dehydrogenase (IDH) status predictions, with a possible application in machine learning. (2) A retrospective study was conducted on 126 patients with gliomas (M/F = 75/51; mean age: 55.30), from which we obtained their histological grade and molecular status. Each patient was analyzed with all 25 features of VASARI, blinded by two residents and three neuroradiologists. The interobserver agreement was assessed. A statistical analysis was conducted to evaluate the distribution of the observations using a box plot and a bar plot. We then performed univariate and multivariate logistic regressions and a Wald test. We also calculated the odds ratios and confidence intervals for each variable and the evaluation matrices with receiver operating characteristic (ROC) curves in order to identify cut-off values that are predictive of a diagnosis. Finally, we did the Pearson correlation test to see if the variables grade and IDH were correlated. (3) An excellent ICC estimate was obtained. For the grade and IDH status prediction, there were statistically significant results by evaluation of the degree of post-contrast impregnation (F4) and the percentage of impregnated area (F5), not impregnated area (F6), and necrotic (F7) tissue. These models showed good performances according to the area under the curve (AUC) values (>70%). (4) Specific MRI features can be used to predict the grade and IDH status of gliomas, with important prognostic implications. The standardization and improvement of these data (aim: AUC > 80%) can be used for programming machine learning software.

Embryologic origin of endometriosis: analysis of 101 human female fetuses.

The etiology of endometriosis, a gynecological disease characterized by the presence of endometrial glands and stroma outside the uterine cavity, is still unknown. Our research group has recently demonstrated the presence of ectopic endometrium in human female fetuses at different gestational ages. In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis. The clinical and pathological implications of these findings are discussed.

HtrA1, a potential predictor of response to cisplatin-based combination chemotherapy in gastric cancer.

AIMS: HtrA1 is a member of the HtrA (high-temperature requirement factor A) family of serine proteases. HtrA1 plays a protective role in various malignancies due to its tumour suppressive properties. The aim of this study was to determine HtrA1 expression as a predictor of chemoresponse in patients with advanced gastric cancer. METHODS AND RESULTS: HtrA1 expression was determined by immunohistochemistry on specimens of primary gastric cancer from 80 patients treated consecutively with cisplatin-based combination chemotherapy. Response to chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Our population consisted of males/females [51/29; median age 64 years (range 32-82)]. A complete or partial response was observed in 71.4% [95% confidence interval (CI) 54.7-88.2], 66.7% (95% CI 47.8-85.5) and 28.6% (95 CI 11.8-45.3) of tumours showing high, medium and low HtrA1 expression, respectively. A statistically significant association between HtrA1 expression and the clinical response was observed (P = 0.002). The median overall survival for patients with high/medium expression was 17 months compared to 9.5 months for patients with low HtrA1 expression (P = 0.037). CONCLUSIONS: Identification of HtrA1 in gastric cancer prior to chemotherapy indicates that levels of HtrA1 could be used to predict response to platinum-based combination therapies. Further assessment of HtrA1 expression is highly warranted in large, prospective studies.

Pre-natal exposure of mice to bisphenol A elicits an endometriosis-like phenotype in female offspring.

Endometriosis is a chronic gynecological disease characterized by the growth of endometrial tissue outside the uterine cavity. Exposure to endocrine disruptors during critical period of development causes long-lasting effects, being the genital system one of the targets. This study describes the effects on female genital system caused by developmental exposure to the endocrine-disrupting chemical bisphenol A (BPA) during pre- and peri-natal development in mice. To this end, timed pregnant Balb-C mice were treated from day 1 of gestation to 7 days after delivery with BPA (100, or 1000 microg/kg/day). After delivery, pups were held for 3 months; then, pelvic organs were analyzed in their entirety and livers of both pups and moms were studied for the presence of BPA. We found in the adipose tissue surrounding the genital tracts of a consistent number of treated animals, endometriosis-like structure with the presence of both glands and stroma and expressing both estrogen receptor and HOXA-10. Moreover, cystic ovaries, adenomatous hyperplasia with cystic endometrial hyperplasia and atypical hyperplasia were significantly more frequent in treated animals respect to the controls. Finally, BPA was found in the livers of exposed moms and female offspring. In conclusion, we describe for the first time an endometriosis-like phenotype in mice, elicited by pre-natal exposition to BPA. This observation may induce to thoroughly reconsider the pathogenesis and treatment of endometriosis, considering the high incidence of endometriosis and the problems caused by associated infertility.

Rectovaginal septum endometriosis: an immunohistochemical analysis of 62 cases.

Deep infiltrating endometriosis of rectovaginal septum is a particular form of endometriosis located under the peritoneal surface. This kind of lesions are very active and strongly associated with pelvic pain symptoms. A study on 62 cases of rectovaginal septum endometriosis by means of immunohistochemistry was conducted in order to evaluate the oestrogen and progesterone receptor levels in these cases and to correlate them to the level of vascularization (CD34 expression) and the amount of nerve fibres (S100 expression). Data showed great heterogeneity in the expression of all the parameters analyzed. Nevertheless, by using Spearman correlation test to assess relationship among oestrogen and progesterone receptors, S100 and CD34 staining, a significant direct correlation was found between all the parameters analyzed. These observations sustain the hypothesis that oestrogen and progesterone play an important role in the genesis of endometriotic glands, in the vascularization and in the proliferation of nerves.

Pharmacogenetic-Based Interactions between Nutraceuticals and Angiogenesis Inhibitors.

Background: Angiogenesis inhibitors (AIs) have become established as an effective cancer treatment. Whereas their interactions with antineoplastic drugs have extensively been investigated, little is known of the effect of their co-administration with nutraceuticals/dietary supplements (N/DSs), which are often self-prescribed. N/DSs comprise a wide range of products such as herbs, nutrients, vitamins, minerals, and probiotics. Assessment of their interactions with cancer drugs, particularly AIs, is hampered by the difficulty of gauging the amount of active substances patients actually take. Moreover, there is no agreement on which approach should be used to determine which N/DSs are most likely to influence AI treatment efficacy. We present a comprehensive review of the metabolic routes of the major AIs and their possible interactions with N/DSs. Methods: The PubMed and Cochrane databases were searched for papers describing the metabolic routes of the main AIs and N/DSs. Results: Data from the 133 studies thus identified were used to compile a diagnostic table reporting known and expected AI-N/DS interactions based on their metabolization pathways. AIs and N/DSs sharing the cytochrome P450 pathway are at risk of negative interactions. Conclusions: Recent advances in pharmacogenetics offer exceptional opportunities to identify prognostic and predictive markers to enhance the efficacy of individualized AI treatments. The table provides a guide to genotyping patients who are due to receive AIs and is a promising tool to prevent occult AI-N/DS interactions in poor metabolizers. N/DS use by cancer patients receiving AIs is a topical problem requiring urgent attention from the scientific community.

Potential role of electrochemotherapy for the treatment of soft tissue sarcoma: first insights from preclinical studies in animals.

Local management of soft tissue sarcoma in humans generally involves multi-modality approaches whose cornerstones are surgery combined with radiation therapy. The usual radiation protocols are based on preoperative, intraoperative, or postoperative external beam treatment or adjuvant brachytherapy. The aim of these strategies is to maximize tumor control while minimizing side effects, especially in the case of limb sarcomas. Unfortunately, the rate of local wound complication associated with aggressive surgical management and radiation therapy are still elevated. Electrochemotherapy is an anticancer technique that gained popularity over the past 15 years. It involves the administration of anticancer agents to the application of permeabilizing pulses so to increase the uptake of antitumor molecules. Goal of this review is to underline the advances in this field obtained from animal studies in order to point out the possible therapeutic applications of this technique for the treatment of soft tissue sarcomas in humans.

Adjuvant carboplatin for the treatment of intestinal carcinoid in a dog.

A ten-year-old castrated male dog was presented due to a two-day history of constipation and tenesmus. At physical examination, the dog was depressed and unresponsive. Aggressive behavior was elicited by deep abdominal palpation and a mass was detected during the examination. Imaging studies evidenced a large jejunal mass. The lesion (6 cm in diameter) was surgically removed. The histopathology report gave a diagnosis of completely excised intestinal carcinoid. The patient recovered well from the procedure and was scheduled for adjuvant chemotherapy. The dog received four doses of carboplatin (300 mg/m2) every three weeks without showing signs of toxicity. The dog is still in remission after 18 months and is reassessed on a three-month schedule. This report represents the first description of long-term control of intestinal carcinoid in the dog and the first of adjuvant chemotherapy for this rare and aggressive neoplasm.

Cutaneous T-cell lymphoma in an African hedgehog (Atelerix albiventris).

A three-year-old male African hedgehog was presented for a non healing crusty proliferation on the left pinna. The lesion failed to respond to topical therapy and systemic antibiotic therapy. Whole body radiography and abdominal ultrasonograpy were within normal limits. The lesion was surgically removed. The patient recovered well from the procedure and remained in remission for nine months when he came back as an emergency case and died of an unrelated disease. The histopathology report enabled a diagnosis of completely excised cutaneous T-cell lymphoma. This report represents the first successful treatment of a cutanous T-cell lymphoma in this species and might help to plan future therapies.

Successful rescue of an apocrine gland carcinoma metastatic to the cervical lymph nodes by mitoxantrone coupled with trains of permeabilizing electrical pulses (electrochemotherapy).

Canine apocrine gland carcinoma is a locally aggressive neoplasm that can occasionally lead to metastatic spread, thus mimicking the behavior of their human counterpart. In this paper we describe the successful treatment of a cervical metastatic spread of this neoplasia by using mitoxantrone selectively driven within the tumor cells by trains of biphasic pulses. The dog experienced tumor reduction from the first cycle of electrochemotherapy (ECT) and complete remission by the time of its fourth session. Neither systemic or local toxicities were detected during the whole course of therapy. The dog is in complete remission after six months from his last treatment. Electrochemotherapy is a safe and efficacious therapy for metastatic carcinoma and warrants further investigation.

Patterns of tumor response in canine and feline cancer patients treated with electrochemotherapy: preclinical data for the standardization of this treatment in pets and humans.

Electrochemotherapy (ECT) is a novel anticancer therapy that is currently being evaluated in human and pet cancer patients. ECT associates the administration of an anti-tumor agent to the delivery of trains of appropriate waveforms. The increased uptake of chemotherapy leads to apoptotic death of the neoplasm thus resulting in prolonged local control and extended survival. In this paper we describe the histological features of a broad array of spontaneous tumors of companion animals receiving pulse-mediated chemotherapy. Multivariate statistical analysis of the percentage of necrosis and apoptosis in the tumors before and after ECT treatment, shows that only a high percentage of necrosis and apoptosis after the ECT treatment were significantly correlated with longer survivals of the patients (p < 0.0001 and p = 0.004, respectively). Further studies on this topic are warranted in companion animals with spontaneous tumors to identify new molecular targets for electrochemotherapy and to the develop new therapeutical protocols to be translated to humans.

Intraoral lymphoepithelial carcinoma of the minor salivary glands.

The occurrence of lymphoepithelial carcinoma in the oral cavity is extremely rare and a case with involvement of minor salivary glands is very uncommon. We describe a case of LELC of the oral cavity with involvement of the upper lip and of minor salivary glands. The tumour was described at the clinical and instrumental level; moreover, its histopathological phenotype was defined. Finally, the problems of differential diagnosis and the most appropriate therapeutic approaches are discussed.

Biphasic pulses enhance bleomycin efficacy in a spontaneous canine genital tumor model of chemoresistance: Sticker sarcoma.

Sticker's sarcoma (also known as transmissible venereal tumor) is a horizontally transmitted neoplasm of the dog, that is passed with coitus. It is a locally aggressive tumor with a low tendency to metastatic spread. The most common locations are the genitals, the nose, the perianal area. Standard treatment consists with chemotherapy with vincristine, however other therapies such as, cryotherapy, immunotherapy or, in selected cases, radiation therapy, have been reported. In this article we describe the outcome of a small cohort of canine patients, with chemotherapy resistant transmissible venereal tumor (TVT), treated with bleomycin selectively driven by trains of biphasic pulses (electrochemotherapy). Three canine patients, with refractory TVT, entered the study and received two sessions of ECT under sedation. The pets had local injection of bleomycin at the concentration of 1.5 mg/ml and five minutes after the chemotherapy, trains of 8 biphasic electric pulses lasting 50 + 50 mus each, with 1 ms interpulse intervals, were delivered by means of modified caliper or, for difficult districts, through paired needle electrode. All the patients responded to the treatment and are still in remission at different times. Electrochemotherapy appears as a safe and efficacious modality for the treatment of TVT and warrants further investigations.