Novel anticoagulants for stroke prevention in patients with atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia that can potentially result in stroke. Vitamin K antagonists (VKA) like warfarin were for many decades the only oral anticoagulants available for stroke prevention in patients with non-valvular atrial fibrillation (AF) at high risk of stroke. Recently, new oral anticoagulants (NOACS) have been introduced that act via direct inhibition of thrombin (dabigatran) or activated factor X (edoxaban, rivaroxaban and apixaban). Unlike VKAs, these anticoagulants do not require routine INR monitoring and posses favorable pharmacological properties. NOACs act rapidly, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. Phase III trials comparing these agents to warfarin for stroke prevention in patients with non-valvular AF demonstrated that they are at least as efficacious and safe as warfarin. Evolution of clinical guidelines to incorporate the new anticoagulants for stroke prevention in non-valvular AF may result in a reduction in the incidence of AF-related strokes. Safe and effective use of these new drugs in clinical practice requires understanding of their distinct pharmacological properties.

Use of octreotide, a long-acting somatostatin analogue, in the treatment of chylothorax of idiopathic etiology.

We describe a case of chylothorax of idiopathic etiology, treated with octreotide, a long-acting somatostatin analogue. A 30-year-old man with a left supraclavicular mass, and chylothorax, initially diagnosed by outpatient thoracentesis, underwent diagnostic surgery to ascertain the etiology of the pleural effusion. Biopsies of the left supraclavicular mass, lymphatic tissue and lymph nodes were benign. Triglyceride level in the pleural fluid was 396 mg/dL, diagnostic of chylothorax. Treatment included intravenous total parenteral nutrition (TPN) and a nil per os (NPO) diet. Subsequent surgical interventions included left lung decortication and glue-mediated control of chylothorax, combined with TPN and a strict low-fat diet. Given the persistency of chylothorax, thoracic duct ligation was also performed, and octreotide subcutaneous injections were started, with dramatic resolution of pleural effusion, after 1 week of treatment, in absence of any side effects. The patient fully recovered, and no relapse has been observed during a follow-up period of over 1 year. In conclusion, octreotide showed to be a valid and safe noninvasive approach for the treatment of chylothorax, whose early clinical use may also reduce the need for surgical intervention.

Metabolic and hemodynamic features of elderly patients undergoing beating heart coronary artery bypass graft surgery.

AIM: Coronary artery bypass graft (CABG) surgery, nowadays, is increasingly performed in patients who are older and have more comorbidities than subjects operated on a decade ago. In this study, we investigated metabolic and hemodynamic features of elderly patients with single vessel coronary artery disease (CAD), undergoing beating heart coronary artery bypass graft (BHCABG) surgery. METHODS: Twenty-five elderly patients, ages 73-78 years, with isolated left anterior descending artery (LAD) disease, were enrolled and compared to a younger similar group of 25 patients, mean age 48+/-1.2 years. A single vessel left internal mammary artery (LIMA) to LAD BHCABG was performed in all patients. Duration of temporary LAD occlusion was 9.8+/-0.5 min in the elderly group, and 10+/-0.4 min in the younger group. Myocardial arterial-venous differences in glucose, lactate, and creatine phosphokinase (CPK) were performed at different time points: preoperatively in the operating room (T0); at the end of the grafting procedure (T1); and before closing the chest (T2). Left ventricular stroke work index (LVSWI), as an indicator of global function of left ventricle, were recorded at T0, T1, T2, 6 (T3) and 48 (T4) hours postoperatively. RESULTS: Preoperative glucose extraction, observed in both groups, did not augment during and after surgery. In addition, neither lactate nor CPK were released in the coronary sinus during temporary LAD occlusion and following reperfusion in either group. Similarly, no significant changes in LVSWI were observed intra- and perioperatively between the two groups. CONCLUSIONS: Cardiac metabolism, hemodynamic parameters and global left ventricular function were not affected in either group by brief LAD occlusion during BHCABG, suggesting that BHCABG is a well-tolerated surgical approach, which can be safely attempted in patients of any age.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.

Secondary cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma.

OBJECTIVE: The aim of this prospective study was to evaluate the influence of secondary cytoreductive surgery on survival of patients with recurrent epithelial ovarian cancer. METHODS: Between June 1993 and June 1999, 149 patients after primary treatment underwent secondary cytoreductive surgery: 69 (46.3%) had recurrence-free interval (RFI) 7-12 months, 59 (39.6%) RFI 13-24 months, and 21 (14.1%) RFI >24 months. Exclusion criteria included secondary cytoreduction during second-look laparotomy, interval cytoreduction, and palliative surgery in patients with intestinal obstruction or progressive disease. RESULTS: The median follow-up was 27 months. According to multivariate analysis, RFI groups, prior chemotherapy combination, and residual tumor after secondary surgery were associated independently with overall survival. Residual tumor after secondary surgery was by far the most strongly predictive factor for patient's survival (hazard ratio (HR) 2.65; 95% confidence interval (CI) 1.43-4.92). The 2-year survival rates were 22.3, 62.9, and 22.7%, respectively, for patients with RFI 7-12, 13-24, and >24 months. The 5-year survival was 29% for patients with RFI 13-24 months. No patients with RFI 7-12 and >24 months outlived the 4-year estimate. Unexpectedly, RFI >24 months was not correlated significantly with overall survival. However, 17 patients (81%) with RFI >24 months were heavily treated with chemotherapy before secondary surgery. CONCLUSIONS: Patients who have documented gross disease preoperatively should be selected for a secondary debulking operation; the entity of surgical effort would be modulated in relation to previous treatment.

Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer.

PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds. PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients). CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

Determination of tamoxifen and its metabolites in the endometrial tissue of long-term treated women.

Concentrations of tamoxifen and its metabolites were analysed in the endometrium of 23 post-menopausal asymptomatic breast cancer patients who were on chronic tamoxifen therapy. Small endometrial samples were collected during diagnostic hysteroscopy. Analysis of both serum and tissue for these compounds was performed by mass spectrometry. Tamoxifen and its metabolites were far more concentrated in the endometrium than in serum; tamoxifen was also significantly more concentrated in endometrium with hyperplastic changes than in atrophic endometrium. Endometrial polyps of an additional 9 women showed a trend to a lesser concentration of compounds. Increased concentration of tamoxifen compounds could possibly be explained by the avidity of these compounds for oestrogen receptors (ER).

Feasibility and pain control in outpatient hysteroscopy in postmenopausal women: a randomized trial.

BACKGROUND: Three methods of diagnostic hysteroscopy have been tested for both women's compliance and feasibility of procedures in postmenopause. METHODS: Three hundred and sixty-two postmenopausal women were enrolled in a three-arm study: 5 mm diagnostic sheath (Group 1, 119 women), 5 mm sheath with paracervical block (Group 2, 121 women), and 3.5 mm sheath (Group 3, 121 women). CO2 was the distention medium. Both feasibility of hysteroscopy (procedures failed due to stenosis or incomplete distention of cavity) and discomfort of women have been recorded. Pain perception has been measured on a visual numerical rating scale. Statistical analysis was performed by t-test for unpaired samples and chi-square test. RESULTS: Paracervical block was per se painful in 18.2% and bleeding from injection site occurred in 38.8%. Hysteroscopy failure due to stenosis occurred in 9%, 10% and 0.4% of the three groups respectively (p<0.01). Intolerable pain was reported by 17% of women in Group 1, 6% in Group 2 (p<0.05) and in none of Group 3 (p<0.01). Pain score improved from Group 1 to Group 3 (p<0.01). Hysteroscopy was incomplete because of gas leakage in 1.7% of both Group 1 and 2 and in 13.2% of Group 3 (p<0.01). CONCLUSIONS: Pain perception in postmenopausal women was reduced when paracervical block was used, but discomfort was even less with the narrow sheath hysteroscope. The narrow sheath will expose to a high percentage of inconclusive procedures but it can be overcome by changing to the large sheath hysteroscope without affecting patient pain perception.

Primary Hodgkin's disease of the vagina.

We describe a patient with primary Hodgkin's disease (HD) of the vagina presenting with stage IEB. To our knowledge, this is the first case reported so far. Based on morphological and immunophenotypic features, the HD was classified as nodular sclerosis subtype, "syncytial" variant. The patient, a 64-year old woman, received chemotherapy followed by radiation therapy. She is still disease-free 14 months after diagnosis.

Different patterns of postoperative bleeding following cytoreductive surgery for gynecological cancer.

PURPOSE OF INVESTIGATION: To study the possible causes of postoperative bleeding following maximal cytoreductive surgery for gynecological cancers. METHOD: We have retrospectively reviewed all our cases of postoperative bleeding following major abdominal and pelvic cytoreductive surgery within a 48-hour period. In the postoperative period, replacement therapy was ineffective in achieving hemodynamic stability. During re-operation, the entire abdominal cavity was evaluated for bleeding sites that were adequately ligated or electrocoagulated. RESULTS: Of 942 women undergoing major cytoreductive surgery 22 women (2.3%) were re-operated for postoperative bleeding after a mean of 14.2 hours. Bleeding was either localized from a vessel in 9 women (40.9%) or diffuse (capillary oozing) in 13 women (59.1). Operative deaths have been as high as 36.8%. CONCLUSION: Postoperative bleeding following cytoreductive surgery can be from a single group of vessels or a capillary oozing from the edges or denuded areas of excised peritoneum.

Clinical value of intraoperative gross examination in endometrial cancer.

We present the largest multicenter study evaluating whether intraoperative visual estimation can accurately assess the depth of myometrial invasion in patients with endometrial cancer. The study population consisted of 403 consecutive women who underwent total hysterectomy for endometrial cancer. After the uterus was removed, a visual estimate of depth of gross myometrial invasion was recorded. The uterus was opened, the endometrial cavity was inspected, and one or more full-thickness incisions were made through the tumor, myometrium, and serosa. An intraoperative estimation of gross myometrial invasion was made and classified as more or less than 50% of the uterine wall. Gross visual estimation accurately identified the microscopic myometrial invasion in 85.3% (344/403) of cases. Sensitivity, specificity, and positive and negative predictive values of gross estimation in determining a microscopic myometrial invasion greater than 50% were 73.0, 92.5, 85.0, and 85.5%, respectively. Among patients in whom the myometrial invasion was underestimated at gross examination the tumoral invasion was limited to the inner two thirds of the myometrium in 45% (18/40) of cases and the distance from the tumor-myometrial junction to the uterine serosa was greater than 3 mm in 65% (26/40) of cases. We conclude that gross estimation of myometrial invasion is a reliable and inexpensive method for evaluating the invasiveness of uterine carcinomas and that deciding to perform an extensive surgical staging upon gross estimation will be in accordance with the final histopathologic report in about 9 of 10 cases.

Primary cytoreductive surgery with rectosigmoid colon resection for patients with advanced epithelial ovarian carcinoma.

BACKGROUND: The impact of radical bowel resection with multiple organ resection on the survival if patients with advanced ovarian carcinoma has not been well defined. The authors investigated whether primary cytoreductive surgery including rectosigmoid colon resection would affect the recurrence free interval and survival of these patients. METHODS: Between April 1990 and April 1997, 66 previously untreated Stage IIIC-IV ovarian carcinoma patients with macroscopic involvement of the rectosigmoid colon were enrolled. All patients underwent cytoreductive surgery with rectosigmoid colon resection to remove residual tumor less than 2 cm in greatest dimension and received 6 cycles of cisplatin-based postoperative chemotherapy. RESULTS: The median follow-up was 26 months (range, 7-104 months). In multivariate analysis, residual disease and depth of tumor infiltration of the bowel wall were independently associated with overall survival and recurrence free interval. Disease stage was independently associated only with overall survival. Residual tumor was the most strongly predictive factor for recurrence or death. The 2-year estimated survival rates according to the amount of residual tumor were 100% for 24 patients with no macroscopic residual disease and 77.3% for 28 patients with residual disease less than 1 cm. None of the 14 patients with residual disease larger than 1 cm were alive 2-years after operation. Overall, 48 patients (72.7%) developed disease recurrence: 43 (65.1%) in the abdomen, 19 (29.8%) in the liver, and 3 (4.5%) in the pelvis. CONCLUSIONS: The current findings suggest that cytoreductive surgery with rectosigmoid colon resection should be considered for ovarian carcinoma patients with bulky pelvic disease to help ensure that they are left with no residual disease after debulking surgery.

Treatment of vaginal intraepithelial neoplasia (VAIN) with the carbon dioxide laser.

The increasing incidence of VAIN especially in young women, the frequent relapses, and renewed interest in maintaining sexual function have prompted gynecologists to a conservative management of the disease. Over the last decades, surgery, 5-fluorouracil, chemosurgery, electrocautery and cryotherapy were used. Carbon dioxide laser ablation therapy of VAIN has been reported from various authors with different results. From June 1991 through December 1998, 39 patients affected by VAIN were treated with laser surgery (35 vaporizations and 4 excisions). To achieve complete elimination of all lesions, seven patients had two vaporizations and one patient three. One patient was submitted to six combined repeated treatments. Five patients were not evaluable and three presented persistence of VAIN. One patient died because of AIDS. The remaining 30 patients, treated with laser surgery, were lesion free: 7 patients were negative at 12-24 months, 10 at 24-36 months and 13 at 37-90 months. No important complications occurred. Sexual function was not compromised. Carbon dioxide laser is a safe and efficacious tool in the treatment of pre-neoplastic lesions of the vagina.

[Percutaneous endoscopic gastrostomy (PEG) in upper gastrointestinal tract occlusion in gynecologic oncology]. / La gastrostomia percutanea endoscopica (PEG) nelle occlusioni dell'alto tratto intestinale in ginecologia oncologica.

BACKGROUND AND AIMS: Intestinal obstruction is a frequent cause of death in patients suffering from gynecological cancer, who have undergone multiple treatment in the form of surgery and/or chemotherapy and/or radiotherapy. The usual form of rescue treatment consists in the use of a nasogastric tube to administer support and analgesic treatment. Surgical gastrostomy is not a viable proposition in these extremely weak patients with large masses compressing and displacing the stomach. Percutaneous endoscopic gastrostomy (PEG), a technique first introduced for nutritional purposes, can be beneficially used to achieve decompression in these patients. METHODS: PEG was performed in a total of 67 patients who had already undergone multiple treatment for abdominal-pelvic neoplasia with upper gastrointestinal obstruction, who could no longer be operated and who had a life expectancy of less than sixty days. In three cases positioning was not possible owing to the lack of transillumination of the gastric and abdominal wall. 54/64 patients had previously undergone at least two operations. RESULTS: Esophagogastric lesions were found in 29% of patients, some of which were attributed to the nasogastric tube. Symptomatic wellbeing was obtained in 76.5% a few days after PEG. PEG remained in situ from 4 to 472 days. Slight peristomal infection was observed in 9% of cases. In seven cases it was necessary to add octreotide owing to the reappearance of symptoms. CONCLUSIONS: PEG is relatively easy to use and allows obstructive symptoms to be resolved in the majority of patients. Special medical skills are not required and the patient may be easily managed at home together with support therapy and pain management. Once PEG has been performed, it is possible to take fluids and semi-liquid foods, offering the patient a chance to taste flavours which have often been forgotten. PEG enables neoadjuvant chemotherapy to be performed in patients with previously untreated intestinal obstruction.

Maximal cytoreductive surgery as a reasonable therapeutic alternative for recurrent endometrial carcinoma.

OBJECTIVE: The objective was to determine if maximal cytoreductive surgery could carry any benefit in pelvic and abdominal recurrent endometrial carcinoma. METHODS: Twenty women at their first large pelvic or abdominal recurrence from endometrial carcinoma were treated with maximal cytoreductive surgery. Women were classified as R1 (residual tumor) or R0 (no residual tumor) by tumor left at the end of surgery. Adjuvant postoperative therapy was undertaken upon clinical judgement. Progression-free, overall, and cancer-related survivals were analyzed with the product-limit method and compared with the log-rank test. The Cox regression model was used to study the variables involved in progression-free and overall survival. RESULTS: Complete macroscopic resection of tumor was feasible in 13 women (65%). R0 group women had a significant both progression-free (median reached at 9.1 months) and overall survival (median reached at 11.8 months) compared to R1 group women. There were 2 (10%) perioperative deaths. Eight women died of cancer, 5 in the R1 group and 3 in the R0 group. There were four intercurrent deaths in women still free from the disease. Local control of neoplasia was achieved in 84.6% of R0 women and their survival was affected mostly by distant recurrences or intercurrent deaths. Residual tumor at the end of surgery was the only significant variable to affect both progression-free and overall survival. CONCLUSION: Intensive surgery is a valid treatment option in women with large pelvic or abdominal recurrence from endometrial carcinoma. Tumor can be completely resected and local control of the disease can be achieved in most of the patients, although survival could be affected by distant recurrence and intercurrent deaths.

Risk factors for endometrial cancer according to familial susceptibility.

Endometrial cancer (EC) shares some environmental or genetic risk factors with colorectal cancer (CRC). It represents a risk factor for CRC. Furthermore, EC is the most frequent extracolonic neoplasm in HNPCC (hereditary nonpolyposis colorectal cancer) and, in this syndrome, it has the same inheritance pattern as CRC. Neoplastic family history and clinical features were evaluated in women with EC in a health care district (Pordenone Province) in Northeastern Italy from 1990 to 1995, to examine the proportion of patients with hereditary cancer and the relation with clinical characteristics of EC. We interviewed 215 patients with EC (average age 61 years, range 35-88) in relation with some risk factors (age, weight, diabetes, menstrual and reproductive pattern, synchronous and metachronous neoplasms) and we obtained their family pedigree. Twenty-nine patients (13.5%) had a CRC family history, 66 (30.7%) showed an aspecific cancer aggregation in their families and more than half (120, 55.8%) had a negative cancer family history. Family pedigrees were consistent with a dominant inherited cancer pattern in 8 patients (3.7%) belonging to the CRC-related family history group. A different pattern of family history distribution emerged in relation with age (< 55 vs. > or = 55, p < 0.001) and body mass index (BMI) (< 26 vs. > or = 26, p = 0.002). Patients with a CRC pedigree were more numerous in the younger group, in the group with lower BMI and in pre-menopausal women.