Perfluorooctanoic acid alters progesterone activity in human endometrial cells and induces reproductive alterations in young women.

Female fecundity is finely regulated by hormonal signaling, representing a potential target for endocrine-disrupting chemicals. Among the chemicals of most concern are the perfluoroalkyl substances (PFAS), widely used in consumer goods, that are associated with adverse effects on reproductive health. In this context, the endometrium clearly represents an important fertility determining factor. The aim of this study was to investigate PFAS interference on hormonal endometrial regulation. This study was performed within a screening protocol to evaluate reproductive health in high schools. We studied a cohort of 146 exposed females aged 18-21 from the Veneto region in Italy, one of the four areas worldwide heavily polluted with PFAS, and 1080 non-exposed controls. In experiments on Ishikawa cells included UV-Vis spectroscopy, microarray analysis and qPCR. We report a significant dysregulation of the genetic cascade leading to embryo implantation and endometrial receptivity. The most differentially-expressed genes upon PFOA coincubation were ITGB8, KLF5, WNT11, SULT1E1, ALPPL2 and G0S2 (all p < 0.01). By qPCR, we confirmed an antagonistic effect of PFOA on all these genes, which was reversed at higher progesterone levels. Molecular interference of PFOA on progesterone was confirmed by an increase in the intensity of absorption spectra at 250 nm in a dose-dependent manner, but not in the presence of ß-estradiol. Age at menarche (+164 days, p = 0.006) and the frequency of girls with irregular periods (29.5% vs 21.5%, p = 0.022) were significantly higher in the exposed group. Our results are indicative of endocrine-disrupting activity of PFAS on progesterone-mediated endometrial function.

AKT1(E17K) in human solid tumours.

The serine-threonine kinase AKT1 is a central player in the oncogenic pathway controlled by PI3K. Recently, a somatic mutation in AKT1 (E17K) has been detected in breast, colorectal, lung and ovarian cancers. The E17K change results in constitutive AKT1 activation and induces leukaemia in mice. We determined the occurrence of the E17K variant in a panel of 764 tumour samples. These included breast, lung, ovarian, colorectal and pancreatic carcinomas as well as melanomas and glioblastomas. Despite the fact that these tumours are known to bear alterations in genes involved in the PI3K signalling pathway, AKT1(E17K) was detected only in breast (16/273), colorectal (1/88) and lung (1/155) cancers. Within the neoplasms of breast origin, the AKT1(E17K) variant was mutually exclusive with respect to the PIK3CA(E454K or H1047R) alleles and was present only in ductal and lobular histotypes. Our results, showing that AKT1 mutations seem to occur in a tissue-specific fashion have basic and clinical implications. First, the activity of mutated AKT1 in oncogenic PI3K signalling could be strictly dependent on the cell and tissue milieu. Second, therapeutic efforts aimed at selective targeting the AKT1(E17K) variant could be effective mainly in specific cancer types.

Intra-arterial hepatic chemotherapy: management of liver tumors by percutaneous port-a-cath positioning.

In the past, intrahepatic arterial locoregional chemotherapy was performed by surgical approach via gastroduodenal artery; early use of percutaneously placed arterial port was complicated by clotting and bleeding in 50% of pts. More recently, permanent catheters were positioned percutaneously in GDA by Japanese group and fixed to the artery by means of bucrylate in order to reduce dislocation. We present the technique and the preliminary results of percutaneous implantation of intraarterial catheters connected to a subcutaneous infusion reservoir for prolonged regional chemotherapy of hepatic tumors. Two hundred patients underwent to percutaneous arterial port implant, for loco-regional chemotherapy for liver primary or metastatic tumors. Catheter dislodgments were observed in 14,5%, but in 90% the catheters could be reinserted. No case of catheter related mortality was registered. Percutaneous positioning of arterial port is a safe and effective technique to deliver loco-regional treatment for hepatic tumors. Complication rates are similar to the surgical series and to other percutaneous interventional radiological reports. This percutaneous approach in the hands of a skilled team allows intra-arterial infusion in a wide percentage of pts, improving the accuracy of clinical trials by a faster and optimal balanced comparison between systemic and arterial arm.

Chemohyperthermia for advanced abdominal malignancies: a new procedure with closed abdomen and previously performed anastomosis.

ChemoHyperthermic Peritoneal Perfusion (CHPP) after cytoreductive surgery is a relatively new procedure in the treatment of abdominal carcinomatosis or sarcomatosis. An assessment of the CHPP technique performed on 20 patients suffering from abdominal malignancies was carried out. After surgical debulking and gastrointestinal anastomosis, two Tenckhoff catheters were positioned for the immediate performance of CHPP, which was carried out at 42-43 degrees C for 1 h, after closing the abdomen. In 19 assessable patients, 47.3% and 36.8% complete responses (CR) were recorded at 1 and 6 months, respectively, with responses of 37.5% in patients affected with gastrointestinal cancer and 50% in patients affected with ovarian cancer. CR were obtained only in patients who had undergone accurate peritoneal debulking. Survival rate for gastrointestinal and ovarian cancer was 68% at 12 months. Patients who underwent radical cytoreductive surgery are all alive at a follow-up median time of 17 months. Two anastomotic leakages with spontaneous recovery were observed, along with one hydrothorax, which was immediately drained during the procedure, three cases of chemotherapic gastrointestinal toxicity, one sepsis, one renal failure that required a transient dialysis, and one cholecystitis that required cholecystectomy. One patient died 30 days after CHPP of a cardiac ischaemia not strictly related to the surgical procedure. In the authors' experience, CHPP with closed abdomen after reconstructive gastrointestinal surgery is a safe and feasible treatment with acceptable side effects.

Limits of aortic stop flow infusion chemotherapy in the treatment of advanced cancer.

BACKGROUND: Advanced and relapsed tumors remain a challenging disease with a poor and dismal prognosis. Our choice for inoperable tumors consists in a percutaneous treatment strategy involving intra-arterial chemotherapy and hemofiltration, with previous blood stop-flow, which allows high doses of Cisplatin-cisplatinum, cis-diammine-dichloroplatinum (CDDP) and Mitomycin C (MMC) in the tumor-bearing area with minimal systemic toxicity. METHODS: We analyse the morbidity and mortality associated with stop-flow in 20 patients with unresectable and/or metastatic thoraco- abdominal tumors, non responders to prior systemic chemotherapy. RESULTS: In our experience, the rate of major side effects of the procedure was 31% with a mortality of 5%. The side effects were related to the radiological procedure and to the chemotherapic treatment. A 74-year-old patient died for acute kidney toxicity within 15 days after the procedure. The other transient toxicity symptoms recorded were: nausea, vomiting, increasing of creatinine levels, diplopia and appearance of necrotic ulcer associated to chemotherapic drugs. Concerning the complications related to the radiological technique, the main problem was the rupture of the balloon stop-flow catheter in four patients. CONCLUSIONS: Stop-flow is a new procedure that could develop in the future, thanks to the possibility of obtaining a higher dose intensity of chemotherapic drugs in districts or organs affected by advanced tumors, with less systemic side effects. Unfortunately, the uncertain results in terms of increasing survival and the default of effective devices are to be resolved for a wider application of the procedure.

Combined regional and systemic chemotherapy by a mini-invasive approach for the treatment of colorectal liver metastases.

From February 1996 to December 1998, 95 patients affected with colorectal liver metastases underwent the positioning of an intraarterial hepatic catheter by a transcutaneous subclavian access, under local anesthesia. All patients were evaluated for catheter implantation complications. Moreover, 61 patients of 95 treated at our center were retrospectively evaluated for results of chemotherapy performed with two different schedules of hepatic artery infusion (HAI) combined with systemic chemotherapy (SC). Eleven patients (group A) were treated with combined SC (5-fluorouracil continuous infusion) and HAI (floxuridine). A subsequent 50 patients underwent HAI (floxuridine, 4 cycles) followed, if a response or stable disease were observed, by combined SC and HAI (group B). Three cases of aneurysm of subclavian artery occurred, which were treated by the positioning of a radiologic arterial stent and the reimplantation of the catheter by a femoral access. Thrombosis of the hepatic artery was registered in four cases. We observed 10.5% occurrence of dislocation of the catheter, which was always moved again in the hepatic artery. In group A, with 45% clinical objective response rate and 10% stable disease rate, median survival time and median time to extrahepatic progression were 9 and 6 months, respectively. In group B, we observed 44% clinical objective responses and 26% stable disease after HAI. Patients without disease progression and therefore submitted to sequential SC and HAI had a median survival time of 21 months and a median time to extrahepatic progression of 16 months. The development of the mini-invasive technique of implantation of an arterial port can avoid laparotomy for HAI. Percutaneous implantation of an arterial port has a low rate of technical complications. HAI followed by combined systemic and regional chemotherapy has good results in terms of survival and time to extrahepatic progression.

Intra-arterial continuous infusion for treatment of pancreatic and biliary tract cancer.

BACKGROUND: Systemic chemotherapy does not satisfactorily improve the poor prognosis of pancreas and biliary tract cancer unresectable or metastatic to the liver. Intra-arterial infusion of antineoplastic agents can give higher concentrations to the tumor and slighter concentrations to the whole body, with a potential of efficacy and lower toxicity, due to the hepatic clearance. METHODS: Based on a safe and ambulatorial technique of transcutaneous arterial port implantation, this study was designed to evaluate feasibility and toxicity of 5-fluorouracil (5-FU) intra-arterial continuous infusion combined with systemic gemcitabine with dose escalation. Seventeen patients affected by pancreatic (14) or biliary tract (3) cancer received up to six cycles of treatment. Treatment consisted of intravenous gemcitabine on d 1 and 8 and intra-arterial 5-FU continuous infusion on d 1-14 every 21 d. Dose-escalation levels were 900 and 1000 mg/m2 for gemcitabine and 8, 10, 12, 15, and 17 mg/kg/d for 5-FU. Consecutive cohorts of three patients were planned at each dose level. RESULTS: Gastrointestinal toxicity (vomiting and diarrhea [3rd-4th degree] and gastritis), constituted the dose-limiting toxicity, with a maximum-tolerated dose of 1000 mg/m2 for gemcitabine and 15 mg/kg/d for 5-FU. Hematological toxicity was present in a minority of patients. No patient had acute or later complications such as arterial thrombosis related to the implanted arterial port, sclerosis cholangitis, or chemical cholecistitis. CONCLUSION: 5-Fluorouracil intra-arterial continuous infusion, combined with systemic gemcitabine, seems to be a feasible and safe regimen that could give interesting results in pancreatic cancer.

Technetium-99m labelled macroaggregated albumin arterial catheter perfusion scintigraphy: prediction of gastrointestinal toxicity in hepatic arterial chemotherapy.

Gastrointestinal toxicity from hepatic arterial infusion (HAI) of floxuridine in patients with liver metastases is probably due to extrahepatic perfusion or to partial escape of the drug from first-pass liver extraction. The aim of this study was to verify the role of technetium-99m-labelled macroaggregated albumin (99mTc-MAA) arterial catheter perfusion scintigraphy at the beginning of each chemotherapy cycle in decreasing or preventing gastrointestinal toxicity. We studied 167 consecutive patients. On the basis of the scintigraphic follow-up and the presence or absence of an intrahepatic arteriovenous shunt (IHAVS), we classified our patients into the following groups: (1) FU+ hepatic distribution pattern (DP), comprising 29 patients with regular scintigraphic follow-up who showed the expected distribution pattern at each control or a distribution pattern with transient alterations (extrahepatic escape) promptly reversed by the replacement of the catheter. Among these 29 patients there was one case of gastrointestinal toxicity. (2) FU- hepatic DP, comprising 128 patients who were evaluated with 99mTc-MAA only at the beginning of the first chemotherapy cycle, showed the expected distribution pattern and underwent HAI with no further scintigraphic evaluation. Among these 128 patients there were 28 cases of gastrointestinal toxicity. (3) FU+ pulmonary DP, comprising three patients with abnormally elevated pulmonary uptake (higher than 5%) and with regular scintigraphic follow-up. There were two cases of gastrointestinal toxicity among these three patients. (4) FU- pulmonary DP, comprising seven patients with abnormally elevated pulmonary uptake and without regular scintigraphic follow-up. There were four cases of gastrointestinal toxicity among these seven patients. The incidence of toxicity was significantly higher in group FU- hepatic DP than in group FU+ hepatic DP (21.9% vs 3.4%, P<0.05). In both the FU+ pulmonary DP and FU- pulmonary DP groups, the incidence of gastrointestinal toxicity was higher than 50%, with no significant difference between them. We conclude that, when performing 99mTc-MAA perfusion scintigraphy, the presence of an abnormally elevated pulmonary uptake (IHAVS higher than 5%) is the most relevant positive prognostic index for the development of gastrointestinal toxicity. Furthermore, in the absence of abnormal pulmonary uptake (IHAVS lower than 5%), strict scintigraphic follow-up is useful since it is able to promptly diagnose the presence of extrahepatic abdominal perfusion and thus to prevent the occurrence of gastrointestinal toxicity.

Percutaneous implantation of a catheter with subcutaneous reservoir for intraarterial regional chemotherapy: technique and preliminary results.

PURPOSE: We present the technique and the preliminary results of percutaneous implantation of intraarterial catheters connected to a subcutaneous infusion reservoir for prolonged regional chemotherapy of hepatic and extrahepatic tumors. METHODS: Two hundred patients with primary or secondary hepatic neoplasms, pelvic, pancreatic, renal, lingual, and breast cancer underwent the procedure. The access was the left axillary artery (188 patients) and the femoral artery (12 patients). The catheter tip was placed in the hepatic (170 patients), hypogastric (18), splenic (4), internal thoracic (2), gastroduodenal (3), renal (2) or the external carotid artery (1). The catheter was connected to a subcutaneous reservoir and filled with heparin; chemotherapeutic infusion was subsequently started. RESULTS: One hundred percent immediate technical success was obtained. Forty-three of 200 (21.5%) patients had a complication: 29 patients had a catheter dislodgment, nine had arterial thrombosis, three had a pseudoaneurysm of the left axillary artery and two had a port pocket hematoma. Most complications (37/43, 86%) were treated percutaneously without interruption of chemotherapy. In only six cases (3% of the total population) was chemotherapy discontinued due to the complication itself. The mean duration of catheter patency was 7.2 months. CONCLUSION: Percutaneous placement of an intraarterial catheter is feasible and causes less discomfort to the patient than the surgical approach. The technique has an acceptable complication rate (21.5%), similar to that for surgical implantation (17.8%), with the advantage that in most cases the complications can be resolved percutaneously. This technique represents an alternative to surgical implantation in the treatment of liver metastases from colorectal cancer and opens new therapeutic possibilities for the local prolonged treatment of other kinds of tumor, though its clinical efficacy must be assessed in selected trials.

[A case of presacral myelolipoma]. / Un caso di mielolipoma presacrale.

Myelolipoma is a rare benign pathology whose pathogenesis is still unclear. It is most frequently localised in the adrenal gland, followed by the presacral region, mediastinum, and perirenal and hepatic region. It varies in size from a few millimetres to several centimetres. The lesion is usually capsulated, detachable from the surrounding tissues and hypovascularised. In histological terms, it is composed of lipomatous and hematopoietic tissues. A 65-year-old female patient was referred to our unit after the finding of a nonbiopsied, pelvic mass during earlier surgery. The patient was in considerable pain owing to the extrinsic compression of the mass on abdominal and pelvic organs. Preoperative tests confirmed the presence of a voluminous presacral neoformation that appeared to have a possible medullary origin (chordoma or schwannoma). During surgery, the lesion was found to be capsulated and mainly adherent to the rectum. Histological analysis confirmed the myelolipomatous nature of the lesion. A review of 21 cases reported in the literature is presented.

Sorbitol removal by the metastatic liver: a predictor of systemic toxicity of intra-arterial chemotherapy in patients with liver metastases.

BACKGROUND/AIM: Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine. METHODS: Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Student's t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability). RESULTS: Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy. CONCLUSIONS: Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.

Extrahepatic regional chemotherapy: use of technetium-99m labeled macroaggregated albumin.

The purpose of this study was to verify the applicability of nuclear techniques with technetium-99m labeled macroaggregated albumin (Tc-99m-MAA) in extrahepatic regional chemotherapy. Of 98 patients in whom arterial Port-a-caths were implanted by transcutaneous access, 13 were treated by regional extrahepatic chemotherapy (breast, one; pancreas, four; kidney, one; uterus, three; vagina, two; bladder, two). In all 13 patients, Tc-99m-MAA was slowly infused intraarterially. The examination showed the perfusion of the area with the neoplasm and excluded the presence of important misperfusions of Tc-99m-MAA to the nearest areas. To detect the presence of an arteriovenous shunt with systemic misperfusion, an anterior image of the thorax was obtained in all patients and an index of misperfusion was calculated. In 12 patients, the index was < 5%; in one patient it was about 40%. In conclusion, our preliminary experience concerns the monitoring of intraarterial infusion chemotherapy of extrahepatic districts. In all 13 patients, we evaluated the correct positioning of the intraarterial catheter and the distribution pattern of the arterial flow, with a semiquantitative indication of arteriovenous shunting. This method gave us an instrument of study that was inexpensive, harmless, and free of collateral complications.

Percutaneous implantation of arterial Port-a-cath via trans-subclavin access.

BACKGROUND: Hepatic artery infusion is the best choice of treatment for colorectal liver metastases, but it could be suggested for other hepatic tumors or locally advanced pancreatic cancer. The need of a laparotomy for the positioning of the arterial catheter has been the limiting factor for the diffusion of regional treatments. MATERIALS AND METHODS: 170 patients suffering from primary or secondary liver tumours and pancreatic or bile ducts cancer, underwent the positioning of intra-arterial hepatic part-a-cath by a transcutaneous subclavian access in local anaesthesia. In 163 patients, a catheter was placed into the hepatic artery, 4 into the splenic and 3 into the gastroduodenal artery. RESULTS: The procedure was performed successfully in all patients. We observed 5 aneurysms of the subclavian artery and 9 thrombosis of the hepatic artery. Only in 7 patients was arterial infusion suspended for technical complications. We observed 10.6% of dislocation, but dislodged catheters were always moved again into the hepatic artery. CONCLUSIONS: The development of percutaneous techniques of arterial port-a-cath implantation could enlarge the indication of regional chemotherapy.

[Abdominal aortic aneurysm associated with non-neoplastic abdominal disease. Therapeutic approach]. / Aneurismi dell'aorta addominale associati a patologia addominale non neoplastica. Strategia terapeutica.

BACKGROUND: Personal experience concerning the treatment of 8 patients with infrarenal aortic aneurysms associated with extravascular non-neoplastic abdominal diseases is presented. METHODS AND RESULTS: In all 7 cases which underwent combined surgical procedures (aneury-smectomy + cholecystectomy in 4 patients and aneurysmectomy + groin hernia repair in 3 patients) early and late postoperative complications were not recorded. CONCLUSIONS: The main therapeutic guidelines concerning the pathologic association of infrarenal aortic aneurysms associated with extravascular non-neoplastic abdominal diseases are discussed on the basis of a literature review and of personal experience.

Flow cytometry in breast cancer: prognostic and surgical indications of the sparing of axillary lymph node dissection.

The lymph node status is still regarded as the most important prognostic factor in breast cancer. However, the utility of axillary lymph node dissection in clinically node-negative patients with breast cancer as a therapeutic approach rather than a pathologic staging procedure has been recently discussed. DNA index (DI) and S-phase fraction (SPF), evaluated by flow cytometric analysis, are two prognostic factors used especially in the assessment of the adjuvant therapy in stage N0 tumors. By studying a large number of cases, the authors aimed to assess the potential role of flow cytometry in predicting lymph node status. Two hundred eleven patients with breast cancer were included. Each tumor specimen was freshly analyzed by flow cytometry to assess DI and SPF. The authors also evaluated TNM status of patients, estrogen- and progesterone-receptor (ER and Pgr) status, and histologic grades. A group of patients with negative axillary lymph nodes was identified by means of association of tumor size of 2 cm or less, DI of 1, and SPF less than 7%. The ER and PgR status as well as histologic grade were significantly more favorable in this group of patients. These findings indicate that association of DI, SPF value, and tumor size may be predictive of axillary lymph node status in breast cancer.

Italian population data on the polymarker system and on the five short tandem repeat loci CSF1PO, TPOX, TH01, F13B, and vWA.

A population study on five short tandem repeat (STR) loci and five sequence specific polymorphism loci was performed on unrelated Italian Caucasians. Separation and detection of the amplified STR fragments were carried out by high resolution vertical denaturing polyacrylamide gel electrophoresis (PAGE) and silver staining, respectively. The sequence specific loci were analyzed using the AmpliType PM Typing Kit (Perkin Elmer, Foster City, CA). All loci, except Gc (p = 0.031), meet Hardy-Wienberg expectations. In addition, there is no evidence for association of alleles between pairs of loci. The combined power of discrimination for the five STR loci is 0.9999862 and for the PM loci is 0.99503. The results suggest that these loci may be useful for human identification cases in Italy.