Randomized Trial Comparing Resection of Primary Tumor with No Surgery in Stage IV Breast Cancer at Presentation: Protocol MF07-01.

BACKGROUND: The MF07-01 trial is a multicenter, phase III, randomized, controlled study comparing locoregional treatment (LRT) followed by systemic therapy (ST) with ST alone for treatment-naïve stage IV breast cancer (BC) patients. METHODS: At initial diagnosis, patients were randomized 1:1 to either the LRT or ST group. All the patients were given ST either immediately after randomization or after surgical resection of the intact primary tumor. RESULTS: The trial enrolled 274 patients: 138 in the LRT group and 136 in the ST group. Hazard of death was 34% lower in the LRT group than in the ST group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.49-0.88; p = 0.005). Unplanned subgroup analyses showed that the risk of death was statistically lower in the LRT group than in the ST group with respect to estrogen receptor (ER)/progesterone receptor (PR)(+) (HR 0.64; 95% CI 0.46-0.91; p = 0.01), human epidermal growth factor 2 (HER2)/neu(-) (HR 0.64; 95% CI 0.45-0.91; p = 0.01), patients younger than 55 years (HR 0.57; 95% CI 0.38-0.86; p = 0.007), and patients with solitary bone-only metastases (HR 0.47; 95% CI 0.23-0.98; p = 0.04). CONCLUSION: In the current trial, improvement in 36-month survival was not observed with upfront surgery for stage IV breast cancer patients. However, a longer follow-up study (median, 40 months) showed statistically significant improvement in median survival. When locoregional treatment in de novo stage IV BC is discussed with the patient as an option, practitioners must consider age, performance status, comorbidities, tumor type, and metastatic disease burden.

Expression of FHIT, p16, p53 and EGFR as prognostic markers in thyroid tumors of uncertain malignant potential.

PURPOSE: Thyroid tumors of uncertain malignant potential (TT-UMP) constitute a relatively new diagnosis. The purpose of this study was to analyze the relationship between immunohistochemical panels, prognostic parameters and TT-UMP. METHODS: Group I was composed of patients diagnosed as differentiated thyroid carcinoma (DTC) and Group II of patients diagnosed as TT-UMP. The prognostic scores of patients were calculated using data according to the well-known prognostic scoring systems MACIS, AMES, AGES. Evaluations of antibodies were based on the presence of nuclear staining for p16 and p53, membranous and cytoplasmic staining for epidermal growth factor receptor (EGFR) and cytoplasmic staining for fragile histidine triad (FHIT). RESULTS: Statistically significant difference was noted (p< 0.05) between Group I and Group II according to MACIS and AMES. No statistical difference was found in terms of immunostaining between groups when stained with p16, p53 and FHIT. On the other hand, in Group II a moderate positive correlation was detected between MACIS and EGFR. CONCLUSION: According to our findings p53 was not important in tumor genesis at early stages in well-differentiated thyroid carcinomas and p16 loss of expression could be used as a finding to help in difficult microscopic diagnosis. TT-UMP is a gray zone of lesions requiring specific therapeutic procedures and postoperative follow-up. A positive correlation was detected between EGFR and TT-UMP, leading to assume that this situation could be used as a new tool in the follow-up of these patients in the future.

Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies.

BACKGROUND: One of the most important factors in breast cancer (BC) mortality is treatment delay. The primary goal of this survey was to identify factors affecting the total delay time (TDT) in Turkish BC patients. METHODS: A total of 1031 patients with BC were surveyed using a uniform questionnaire. The time between discovering the first symptom and signing up for the first medical visit (patient delay time; PDT) and the time between the first medical visit and the start of therapy (system delay time; SDT) were modelled separately with multilevel regression. RESULTS: The mean PDT, SDT and TDT were 4.8, 10.5 and 13.8 weeks, respectively. In all, 42% of the patients had a TDT >12 weeks. Longer PDT was significantly correlated with disregarding symptoms and having age of between 30 and 39 years. Shorter PDT was characteristic of patients who: had stronger self-examination habits, received more support from family and friends and had at least secondary education. Predictors of longer SDT included disregard of symptoms, distrust in success of therapy and medical system and having PDT in excess of 4 weeks. Shorter SDT was linked to the age of >60 years. Patients who were diagnosed during a periodic check-up or opportunistic mammography displayed shorter SDT compared with those who had symptomatic BC and their first medical examination was by a surgeon. CONCLUSION: TDT in Turkey is long and remains a major problem. Delays can be reduced by increasing BC awareness, implementing organized population-based screening programmes and founding cancer centres.

The impact of Ramadan on peptic ulcer perforation.

BACKGROUND: Medical treatment has played an important role in the reduction of peptic ulcer perforation (PUP). The goal of this study was to evaluate the effect of fasting on PUP. METHODS: A retrospective analysis of 229 patients who were operated due to PUP between 1999-2009 was made. Patients were divided into two groups. Group I (n=188) included the patients who were operated in other periods of the year, while Group II (n=41) included the patients who were operated during Ramadan, the Muslim period of fasting. Patients in Group II were analyzed in terms of duration of fasting. RESULTS: The increase in surgeries per group was higher in Group II than Group I (p<0.05). Predisposing factors, anti-ulcer drug usage and demographic variables were seen to have no role in this difference. Duration of fasting may have a minimal effect on the perforation. CONCLUSION: The results of this study demonstrate that PUP is detected as relatively higher during Ramadan among those who are fasting for more than 12 hours daily. We suggest that people with predisposing factors should be informed before making a decision to fast.

Effects of Ramadan fasting on peptic ulcer disease as diagnosed by upper gastrointestinal endoscopy.

BACKGROUND AND STUDY AIMS: The diagnostic methods such as upper gastrointestinal endoscopy (UGE) have played an important role in the evaluation of peptic ulcer (PU). Every year, millions of Muslims fast in Ramadan month. The aim of this study was to evaluate the effect of fasting on PU via UGE. PATIENTS AND METHODS: A total of 321 patients in the period from 2009 to 2011, who underwent UGE as a diagnostic work-up mainly for epigastric pain, were analysed. Patients were divided into three groups: Patients who have been evaluated by UGE, in the month just before Ramadan (group I, n=69), in Ramadan month (group II, n=132) and in the month just after Ramadan (group III, n=120). Continuous data were expressed as the mean±SD, and were compared with one-way analysis of variance (ANOVA) test amongst groups. Categorical data were given as percentages and were compared with the chi-squared test. RESULTS: Epigastric pain was the most common indication for referral in each group. Interestingly, the indication 'bleeding' was found to be the least in group II, but was far from statistical significance. The highest prevalence of duodenal ulcers and duodenitis was found in group II; the differences to the other groups were statistically significant. CONCLUSION: Duodenal ulcers and duodenitis were found more during Ramadan month. We recommend that, the patients with epigastric pain may fast by taking their medications.

Management of neuroendocrine carcinomas of the breast: A rare entity.

Neuroendocrine (NE) carcinoma of the breast is extremely rare and constitutes less than 0.1% of all breast tumors. Only a few studies are currently available in the literature and a standard approach to treating this tumor has yet to be established. The aim of this study was to apply pathological treatment modalities in clinical practice and to select the most appropriate treatment accordingly. Six female patients were diagnosed with primary NE carcinoma of the breast. The patients underwent modified radical mastectomy with axillary dissection. Pathological specimens were stained with hematoxylin and eosin and an immunohistochemical panel of antibodies [neuron-specific enolase (NSE), chromogranin, synoptophysin, estrogen and progesterone receptor, c-erbB2 and Ki-67]. The results showed that tumor size ranged from 2 to 4.5 cm in diameter. Lymph node metastasis was detected in 4 (67%) patients. Estrogen and progesterone receptor expression was found in 5 (83%) patients. None of the patients expressed c-erbB2. Chromogranin was found to be positive in 5 (83%) patients. Synoptophysin expression was detected in 5 (83%) patients. NSE was stained in 4 (67%) patients. An intraductal component was found in 5 (83%) patients. Lymphovascular invasion was found in 5 (83%) patients. Adjuvant chemotherapy was administered to patients with a Ki-67 index of ≥10%. Radiotherapy was administered to 4 (67%) patients, and 4 (67%) patients received hormonal therapy. The mean follow-up time was 31.1 months (range 12-52). All 6 patients survived, although following chemotherapy and tamoxifen, the disease progressed in 1 patient who received second-line hormonal therapy. In conclusion, NE carcinoma of the breast is a distinct entity. Management of this rare tumor may include surgery and radiotherapy depending on the size of the tumor and lymph node status. However, the exact role of chemotherapy and hormonal therapy has yet to be established. Adjuvant chemotherapy is recommended for patients with a Ki-67 index of ≥10%, and hormonal treatment appears to be feasible in patients who are positive for estrogen and/or progesterone receptor.

Breast cancer risk factors in Turkey: a hospital-based case-control study.

BACKGROUND: Regional disparities in breast cancer (BC) outcomes have been reported in Turkey. METHODS: In a hospital-based case-control study in Sivas, Turkey, 172 patients with histologically confirmed BC were compared with 383 controls, recruited from visitors in various departments of the same hospital, who had not been previously diagnosed with BC. Information was collected from both groups using a questionnaire and logistic regression analysis was applied to assess associations between each risk factor and BC risk with adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In multivariable models, family history of BC (OR=4.67, 95% CI: 2.23-9.76), history of smoking (OR=1.75, 95% CI: 1.08-2.84), and higher education level (OR=2.88, 95% CI: 1.64-5.07) were the strongest predictors of BC in the study population. A separate analysis studying only postmenopausal women using hormone replacement therapy (HRT) (comparing duration of use, >36 months versus ≤36 months, P<0.05) found that use of HRT was also a risk factor for BC. Duration of HRT use (P<0.05) was significantly associated with the elevated risk. On the other hand, certain factors such as first full-term pregnancy before age 30 (χ2=5.755 P<0.05) and higher parity (χ2=20.731, P<0.05) were found to be protective factors for BC. CONCLUSION: The findings of the present study indicate that family history of BC, history of smoking, education, and HRT are factors significantly associated with increased BC risk among Turkish women within the area of Central Anatolia, Turkey.

The Evaluation of Microcarcinoma in Differentiated Thyroid Cancers According to Old and New TNM Classification.

OBJECTIVE: In this study, we aimed to evaluate the tumor size for proximal and distant metastases when the new and old TNM classification is taken into account in differentiated thyroid cancers. MATERIAL AND METHODS: Two hundred sixty eight patients diagnosed with thyroid carcinoma, undergoing bilateral total or subtotal thyroidectomy treated with high doses of I-131 were examined retrospectively. The data of these patients were compared after classification, according to tumor size <1 cm and <2 cm, lymph node metastases thyroid and tumor capsule invasion at the time of diagnosis, and accumulation of abnormal activity in post I-131 treatment whole-body scan. I-131 uptakes besides physiological and thyroid bed were considered as abnormal activity uptakes. RESULTS: A total of 268 patients with average age of 19-82 yrs (mean: 47.0±13.8 yrs) were included in the study. At postoperative histopathological evaluation, 228 (85.1%) of patients were reported as papillary, 13 (4.9%) as follicular, 23 (8.6%) as well differentiated tumor of unknown malignant potential, 2 (0.7%) as insular and 2 (0.7%) as Hürthle-cell carcinoma. In patients with known tumor size, 96 of 207 (46.4%) patients' tumor size was <1 cm and in 111 (53.6%) >1 cm. In the same group, according to the revised TNM classification, in 149 of 207 patients (72%) the tumor size was <2 cm, whereas in 58 (28%) >2 cm. Of 187 patients with negative lymph nodes, 15 (8%) showed abnormal activity accumulation in the first post I-131 treatment whole-body scan and 10 (40% of 25 patients) positive lymph node (p<0.05) involvement. CONCLUSION: Since the treatment of patients with microcarcinoma is controversial, tumor size should not be the only factor considered in patients with differentiated thyroid cancer Tissue tumor invasion, age, gender and multifocality should also be taken into account. CONFLICT OF INTEREST: None declared.

Effects of proton pump inhibitors and h(2) receptor antagonists on the ileum motility.

Objectives. To investigate the effects of proton pump inhibitors (PPIs) and H(2) receptor antagonists on ileum motility in rats with peritonitis and compare changes with control group rats. Methods. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another of 8 rats underwent a sham operation and were accepted as controls. Twenty-four hours later after the operation, the rats were killed, and their ileum smooth muscle was excised and placed in circular muscle direction in a 10 mL organ bath. Changes in amplitude and frequency of contractions were analyzed before and after PPIs and H(2) receptor blockers. Results. PPI agents decreased the motility in a dose-dependent manner in ileum in both control and intraabdominal sepsis groups. While famotidine had no significant effect on ileum motility, ranitidine and nizatidine enhanced motility in ileum in both control and intraabdominal sepsis groups. This excitatory effect of H(2) receptor antagonists and inhibitor effects of PPIs were significantly high in control group when compared to the peritonitis group. The inhibitor effect of pantoprazole on ileum motility was significantly higher than the other two PPI agents. Conclusions. It was concluded that H(2) receptor antagonists may be more effective than PPIs for recovering the bowel motility in the intraabdominal sepsis situation.

Could total thyroidectomy become the standard treatment for Graves' disease?

PURPOSE: Graves' disease is the most frequent cause of hyperthyroidism. Although treatment with antithyroid drugs or radioactive iodine is effective, surgery remains the preferred treatment for many patients. We analyzed the results of 55 prospectively followed patients who underwent total thyroidectomy for Graves' disease. METHODS: Total thyroidectomy was performed by experienced endocrine surgeons in all 55 patients. We monitored the patients postoperatively for early and late complications. RESULTS: There were 19 men, with a mean age of 42 years (range, 34-68 years) and 36 women, with a mean age of 38 years (range, 19-78 years). One patient suffered postoperative hemorrhage and subsequent wound infection, two patients had transient recurrent laryngeal nerve palsy, and 24 patients had transient hypocalcemia. The mean follow-up time was 4 years (range, 10 months to 6 years). Recurrence of hyperthyroidism was not reported in this period. CONCLUSION: Removal of all thyroid tissue offers the best chance of preventing recurrent hyperthyroidism. Total thyroidectomy is the most effective surgery for achieving the goal of treatment of Graves' disease to ensure that hyperthyroidism will not recur.

Effects of contrast media on the hepato-pancreato-biliary system.

AIM: To determine the effects of high osmolarity contrast media (HOCM) and iso-osmolar contrast media (CM) application, with or without pressure, on hepato-pancreato-biliary (HPB) system. METHODS: Sixty rats were divided into six equal groups as follows: Group 1: (0.9% NaCl, control), Group 2: (diatrizoate meglumine Na, ionic HOCM, Urographin), Group 3: (iodixanol, iso-osmolar non-ionic CM, Visipaque); each of which was applied without pressure, whereas the animals of the remaining three groups (1p, 2p, 3p) were subjected to the same CM with pressure. We performed a duodenal puncture and introduced a catheter into the ampulla. After the catheterization, 0.2 mL CM or 0.9% NaCl was injected with or without pressure. Blood samples were taken for biochemical evaluations. The histopathological examinations of liver, common bile duct, and pancreas were performed. RESULTS: There were no significant differences between the six groups for blood amylase, alanine aminotransferases, aspartate aminotransferases, bilirubin levels (P > 0.05). Alkaline phosphatase and gamma glutamyl transaminase levels were higher (P < 0.05) in the Urographin groups (2, 2p) than the Visipaque groups (3, 3p), or control groups (1, 1p). Hepatocyte necrosis, portal area inflammation, and Kupffer's cell hyperplasia were higher (P < 0.05) in the study groups than the control group. However, there were no significant differences (P > 0.05) between HOCM (2, 2p) and iso-osmolar CM (3, 3p) groups. Bile duct proliferation and regeneration in the Urographin groups (2, 2p) were significantly higher (P < 0.05) than the Visipaque groups (3, 3p) or the control groups (1, 1p). Although CM caused minor damage to the pancreas, there were no statistically significant differences (P > 0.05) between the groups. Application of the CM with pressure did not cause additional damage to the HPB system. CONCLUSION: Iso-osmolar, non-ionic CM could be more reliable than the ionic HOCM, whereas the application of pressure during the CM application had no effect on the HPB system.

Altered spontaneous contractions of the ileum by anesthetic agents in rats exposed to peritonitis.

AIM: To investigate in vitro effects of propofol, midazolam and dexmedetomidine, which are commonly used anaesthesic or sedatives, on spontaneous contractions of the ileum both in normal rats and those exposed to hyperdynamic peritonitis. METHODS: Spontaneous contractions of isolated ileum muscle segments from sham operated rats and those exposed to peritonitis, were studied in vitro. The amplitude and the frequency of spontaneous contractions of ileum muscle segments were studied after adding dexmedetomidine, propofol, and midazolam to the organ bath in a cumulative manner. RESULTS: Both amplitude (85.2 +/- 6.6 vs 47.4 +/- 7.1) and frequency (32.8 +/- 4.6 vs 20.2 +/- 3.9) of spontaneous contractions in ileum smooth muscle segments were decreased significantly in the peritonitis group compared to the control group (P < 0.05). Dexmedetomidine significantly increased the amplitude of spontaneous contractions (85.2 +/- 6.6 vs 152.0 +/- 5.4, P < 0.05) whereas, propofol (85.2 +/- 6.6 vs 49.6 +/- 4.8, P < 0.05) and midazolam (85.2 +/- 6.6 vs 39.2 +/- 4.5, P < 0.05) decreased it in both control and peritonitis groups. The frequency of spontaneous contractions were significantly decreased by propofol in both control (32.8 +/- 4.6 vs 18.2 +/- 3.4, P < 0.05) and peritonitis groups 20.2 +/- 3.9 vs 11.6 +/- 3.2, P < 0.05). Dexmedetomidine and midazolam did not cause significant changes in the number of spontaneous contractions in both control and the peritonitis groups (P > 0.05). CONCLUSION: Propofol, midazolam and dexmedetomidine have various in vitro effects on spontaneous contractions of the rat ileum. While dexmedetomidine augments the spontaneous contraction of the rat ileum, propofol attenuates it. However, the effects of these compounds were parallel in both control and peritonitis groups.

Effects of NO/L-arginine pathway on gallbladder contractility in bile duct ligated guinea pigs.

BACKGROUND: Common bile duct ligation (CBDL) produces gallbladder distension and acute inflammation similar to that seen in human acute acalculous cholecystitis. CBDL in the guinea pig affects smooth muscle contractility. The aim of this study was to determine whether the nitric oxide-L-arginine pathway plays a role in the inflammatory process and abnormal gallbladder contractility that occur after CBDL. MATERIALS AND METHODS: Contractility of gallbladder muscle from CBDL and sham-operated guinea pigs was studied in vitro. Animals were treated with saline, aminoguanidine (AG), or an aminoguanidine + L-arginine combination (AG + L-Arg) in vivo. Potassium chloride, carbachol, and electric field stimulation (EFS) were used for contracting the gallbladder muscle strips or activating intrinsic nerves. Hematoxylin and eosin-stained slides of muscle strips were scored for inflammation. RESULTS: Contraction responses to carbachol and EFS were decreased significantly in CBDL guinea pigs compared with those in the sham-operated group. AG partly reversed the smooth muscle contractile response to carbachol and EFS, but did not reduce the inflammation score. Treatment with AG + L-arg did not reverse either the contraction response or the inflammation score. CONCLUSIONS: These findings suggest that AG and AG + L-Arg treatments have no beneficial effect on inflammation in guinea pigs after CBDL, although AG significantly reversed the effect on muscle contractility (P < 0.05). This improvement was independent of inflammation and may be due to a decreased level of NO and its diminished relaxant effect.

Efficacy of chlorhexidine gluconate during surgery for hydatid cyst.

BACKGROUND: Dissemination of protoscolices-rich fluid during surgery for hydatid cyst disease is a major cause of recurrence. Instillation of a scolicidal agent into a hepatic hydatid cyst before opening is the most commonly employed measure to prevent this serious complication. In this clinical study, the efficacy of 0.04% chlorhexidine gluconate (Chx-Glu) during hydatid cyst surgery was tested, and early-term results were evaluated. METHODS: A total of 30 consecutive patients with 45 liver cysts were studied. Only type I and type II cysts were included. Cysts were punctured, and fluid was aspirated. The viability of protoscolices in this fluid was determined. Chx-Glu 0.04% was instilled into the cyst cavity. After 5 minutes of exposure, the cyst fluid was reaspirated and evaluated for the viability of protoscolices. Imprints of the germinative membranes were determined for protoscolices viability. RESULTS: All protoscolices in 45 cysts evaluated were killed by 5 minutes of exposure to 0.04% Chx-Glu. The whole of the germinative membrane imprints contained dead protoscolices. Chx-Glu 0.04% did not cause any adverse effect on biliary tracts in communication with cysts. There was no recurrence during the 2-year follow-up period. There were also no mortality and no cavity-related complications. CONCLUSIONS: This study shows that intracystic injection of 0.04% Chx-Glu is an effective measure against the dissemination of viable protoscolices. In addition, Chx-Glu is the most convenient scolicidal agent as per the criteria defined by the World Health Organization. Therefore, it can be used safely during hydatid cyst surgery. However, there remains the need to perform advanced comparative clinical studies on the efficacy of Chx-Glu and other scolicidal agents.

Lack of nitrate tolerance in isosorbid dinitrate- and sodium nitroprusside-induced relaxation of rabbit internal anal sphincter.

AIM: To investigate the tolerance development against the relaxant effect of nitric oxide donating drug isosorbide dinitrate (ISDN) and sodium nitroprusside (SNP) in internal anal sphincter (IAS) smooth muscle. METHODS: Relaxation responses of ISDN, and electrical field stimulation (EFS) were obtained before and after tolerance induction by ISDN incubation. RESULTS: ISDN (10(-7)-10(-4) mol/L) and SNP (10(-8)-10(-4) mol/L) caused a concentration-dependent relaxation on the basal tonus of the isolated rabbit IAS strips. After a period of 2 h incubation of the 6 multiply 10(-4) mol/L ISDN the relaxation effects of ISDN and SNP did not change compared to control strips. EFS evoked frequency-dependent relaxation in internal anal sphincter smooth muscle and E(max) obtained from control strips were not changed in ISDN tolerance-inducing condition. In this study nitrate tolerance was not observed in rabbit IAS smooth muscle. CONCLUSION: This result shows that nitric oxide donating drugs relaxes the internal anal sphincter of the rabbits without the development of tolerance.

Effect of angiotensin-converting enzyme inhibition on experimental hepatic fibrogenesis.

The renin-angiotensin system is suggested to be important in liver fibrogenesis. It induces hepatic stellate cell proliferation and up-regulates transforming growth factor beta-1 (TGF-beta1) expression. Matrix metalloproteinase-2 (MMP-2) is involved in extracellular matrix remodelling. Fibrosis, a consequence of most chronic liver diseases, may be the result of a disturbed balance between fibrogenesis and fibrolysis. The aim of this study was to investigate the effect of enalapril on liver fibrogenesis induced in rats by bile-duct ligation. Forty-seven rats were divided into two groups: bile-duct ligated (BDL) (n = 24) and BDL + enalapril (n = 23). Fibrosis was evaluated by the Knodell scoring system, and TGF-beta1 and MMP-2 were assessed with immunohistochemistry at the second, fourth and sixth weeks after bile-duct ligation. In the BDL group, TGF-beta1 increased by the second week and this increase continued through weeks 4 and 6. In the BDL + enalapril group, TGF-beta1 was significantly lower than the other group (P < 0.05). MMP-2 progressively decreased after week 2 in the BDL group. In the BDL + enalapril group, MMP-2 was significantly higher than the BDL group at the fourth and sixth weeks. These results suggest that enalapril reduces the liver tissue TGF-beta1 and has an ameliorating effect on the fibrosis markers TGF-beta1 and MMP-2.