Evaluation of PTEN, PI3K, MTOR, and KRAS expression and their clinical and prognostic relevance to differentiated thyroid carcinoma.

AIM OF THE STUDY: Important signalling pathways play fundamental roles in the pathogenesis of thyroid carcinoma (TC). PTEN, mTOR, PI3K-p85 and K-Ras are the principal factors involved in these signalling pathways. To immunohistochemically examine the expressions of PI3K, mTOR and PTEN in patients suffering from follicular TC, papillary TC or variants thereof, as well as to investigate KRAS mutations via PCR to determine their clinical and prognostic relevance to differentiated thyroid cancer. MATERIAL AND METHODS: The expression of PTEN, PI3K-p85 and mTOR was immunohistochemically examined, and the mutation of K-Ras was examined via PCR. The results obtained were compared to the clinico-pathologic characteristics of the patients. RESULTS: A significant correlation was found between p85 expression and lymphovascular invasions and between PTEN expression and multifocality (p = 0.048 and p = 0.04, respectively), and a correlation between p85 and capsular invasion was found, with a borderline statistical significance (p = 0.056). No expression of PTEN, p85 or Mtor was detected in normal tissue. K-Ras mutation was examined in 66 of the 101 patients (57.4%), and the percentage of patients exhibiting a K-Ras mutation was 17.4%. All of the patients exhibiting a K-Ras mutation were women (p = 0.047). The disease-free survival was 44.6 months (95% CI: 37.9-51.3) and was statistically significantly higher in the group that displayed level 1 or lower expression of p85 (p = 0.043). CONCLUSIONS: The expression levels of the aforementioned markers were significantly higher in TC cells than in normal tissue. A significant correlation was detected between K-Ras mutation and gender. This study demonstrates that p85 and PTEN are markers that should be evaluated in further studies of TC.

Efficacy of first-line CDK 4-6 inhibitors in premenopausal patients with metastatic breast cancer and the effect of dose reduction due to treatment-related neutropenia on efficacy: a Turkish Oncology Group (TOG) study.

The only phase 3 study on the effectiveness of CDK 4-6 inhibitors in first-line treatment in premenopausal patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer is the MONALEESA-7 study, and data on the effectiveness of palbociclib is limited. Data are also limited regarding the effectiveness of CDK 4-6 inhibitors in patients whose dose was reduced due to neutropenia, the most common side effect of CDK 4-6 inhibitors. In our study, we aimed to evaluate the effectiveness of palbociclib and ribociclib in first-line treatment in patients with premenopausal metastatic breast cancer and the effect of dose reduction due to neutropenia on progression-free survival. Our study is a multicenter, retrospective study, and factors affecting progression-free survival (PFS) were examined in patients diagnosed with metastatic premenopausal breast cancer from 29 different centers and receiving combination therapy containing palbociclib or ribociclib in the metastatic stage. 319 patients were included in the study. The mPFS for patients treated with palbociclib was 26.83 months, and for those receiving ribociclib, the mPFS was 29.86 months (p = 0.924). mPFS was 32.00 months in patients who received a reduced dose, and mPFS was 25.96 months in patients who could take the initial dose, and there was no statistical difference (p = 0.238). Liver metastasis, using a fulvestrant together with a CDK 4-6 inhibitor, ECOG PS 1 was found to be a negative prognostic factor. No new adverse events were observed. In our study, we found PFS over 27 months in patients diagnosed with premenopausal breast cancer with CDK 4-6 inhibitors used in first-line treatment, similar to post-menopausal patients. We did not detect any difference between the effectiveness of the two CDK 4-6 inhibitors, and we showed that there was no decrease in the effectiveness of the CDK 4-6 inhibitor in patients whose dose was reduced due to neutropenia.

Biosimilar filgrastim vs filgrastim: a multicenter nationwide observational bioequivalence study in patients with chemotherapy-induced neutropenia.

BACKGROUND: We studied the comparative effectiveness of biosimilar filgrastim vs original filgrastim in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: This multicenter, observational study was conducted at 14 centers. The study included 337 patients experiencing neutropenia under chemotherapy. Patients were given either filgrastim 30 MIU or 48 MIU (Neupogen®) or biosimilar filgrastim 30 MIU (Leucostim®). Data regarding age, chemotherapeutic agents used, number of chemotherapy courses, previous diagnosis of neutropenia, neutrophil count of patients after treatment, medications used for the treatment of neutropenia, and duration of neutropenia were collected. Time to absolute neutrophil count (ANC) recovery was the primary efficacy measure. RESULTS: Ambulatory and hospitalized patients comprised 11.3% and 45.1% of the enrolled patients, respectively, and a previous diagnosis of neutropenia was reported in 49.3% of the patients, as well. Neutropenia occurred in 13.7% (n=41), 45.5% (n=136), 27.4% (n=82), 11.4% (n=34), and 2.0% (n=6) of the patients during the first, second, third, fourth, and fifth cycles of chemotherapy, respectively. While the mean neutrophil count was 0.53±0.48 before treatment, a significant increase to 2.44±0.66 was observed after treatment (p=0.0001). While 90.3% of patients had a neutrophil count <1.49 before treatment, all patients had a neutrophil count ≥1.50 after treatment. Neutropenia resolved within ≤4 days of filgrastim therapy in 60.1%, 56.7%, and 52.6% of the patients receiving biosimilar filgrastim 30 MIU, original filgrastim 30 MIU, and original filgrastim 48 MIU, respectively. However, there was no significant difference between the three arms (p=0.468). Similarly, time to ANC recovery was comparable between the treatment arms (p=0.332). CONCLUSION: The results indicate that original filgrastim and biosimilar filgrastim have comparable efficacy in treating neutropenia. Biosimilar filgrastim provides a valuable alternative; however, there is need for further studies comparing the two products in different patient subpopulations.

Tc-99m MIBI uptake in traumatic vertebral fractures and metastatic vertebral lesions: comparison with Tc-99m MDP.

This study compared technetium-99m-hexakis-2-methoxyisobutyl-isonitrile (Tc-99m MIBI) with technetium-99m methylene iphosphonate (Tc-99m MDP) to determine whether Tc-99m MIBI could distinguish vertebral metastases from traumatic vertebral fractures. Twenty patients with traumatic vertebral fracture (and no malignant disease) and 14 patients with metastatic vertebral lesions were evaluated. Three to 4 hours after intravenous injection of Tc-99m MDP, images of the vertebrae in all patients were obtained. Corresponding Tc-99m MIBI images were acquired within 4 days after the Tc-99m MDP bone images were obtained. Computed tomography and magnetic resonance imaging demonstrated 24 vertebral traumatic fractures and 44 vertebral metastases. On conventional bone scans, Tc-99m MDP activity was increased in 92% of vertebral fractures and in 100% of vertebral metastases. However, on MIBI scans, no abnormal findings were observed in the vertebrae with fracture, although increased activity was seen in 73% of vertebral metastases. In this study, traumatic vertebral fractures tended to display no pathologic increases in Tc-99m MIBI uptake, whereas bone metastases usually appeared with high uptake. In light of the excellent specificity of Tc-99m MIBI scans compared with Tc-99m MDP bone scans, imaging studies that use Tc-99m MIBI scans may play an important complementary role in differentiating vertebral metastases from traumatic vertebral fractures.

An implementation on the social cost of hospital acquired infections.

Hospital Acquired Infections (HAIs) are defined as infections developing in relation to health services at inpatient treatment facilities in general. Although health services improve, HAIs continue to be seen both in underdeveloped and developed countries. HAIs result in a range of negative externalities. Negative externalities include factors such as an increase in morbidity and mortality, extension of the hospitalization duration, impaired quality of life, loss of working power and performance. HAIs pose a big burden regarding population and community health care. This study aims to calculate the financial burden of HAIs by evaluating it within the scope of negative externality. The communal costs of HAIs patients were calculated by using a genuine approach with reference to samples obtained from the Duzce University Research and Application Hospital. This approach includes 4 stages and the results of each stage is sorted according to the data of 2013 as follows: (i) HAIs expenditure undertaken by the Social Security Institution is 5,832,167 TL, (ii) the monetary value of the work power loss of the HAIs patients who are at a working age is 126,154 TL, (iii) the relative cost of HAIs patients compared to a group of normal patients is 21,507 TL and (iv) HAIs patients' communal cost is 6,013,101 TL. Based on the received results, the annual communal cost of the estimated HAIs patients in Turkey is predicted to be 3,640,442,057 TL. In addition to these findings, HAIs patients experience 14 times longer in-patient stay at the hospitals as compared to normal patients, and their treatment expenditures are 23 times higher than the normal patients. In the conclusion part of the study, regarding the preventability (internalization) of HAIs, which was evaluated as part of negative externality, alternative applicable political suggestions are presented for the use of policymakers.

99mTc tetrofosmin scintigraphy in acute leukaemia: the relationship between marrow uptake of tetrofosmin and P-glycoprotein and chemotherapy response.

BACKGROUND: The non-invasive detection of P-glycoprotein (Pgp) and multidrug resistance related proteins in vivo, will represent the greatest challenge in overcoming multidrug resistance. Although 99mTc tetrofosmin has been used previously as a myocardial perfusion agent, it is now also being used in the imaging of various tumours. In the current study, Tc tetrofosmin was used in the investigation of acute leukaemia. AIM: To show the uptake pattern of 99mTc tetrofosmin in the bone marrow of patients with acute leukaemia, and to ascertain the relationship between 99mTc tetrofosmin uptake and the level of Pgp expression and their relation to the response to chemotherapy. In addition, CD95, which is an indicator of apoptosis (programmed cell death), has also been assessed. MATERIALS AND METHODS: Pgp and CD95 were detected by using flow cytometry. Of the 27 acute leukaemia patients assessed, nine had previously received chemotherapy, and 18 had had an initial diagnosis. All patients had undergone 99mTc tetrofosmin scintigraphy, and their Pgp and CD95 levels had been determined. The same parameters were studied again for 14 patients. The responses to chemotherapy were assessed by patients' clinicians. A control group of 37 patients without bone marrow pathology was also studied in order to provide comparisons for the scintigraphy results. The control images were assessed only qualitatively. RESULTS: In leukaemia patients the uptake of 99mTc tetrofosmin into bone marrow was found to be considerably higher than in control patients (P=0.000). An analysis of the relationship between Pgp, CD95, and the qualitative and quantitative tetrofosmin uptake ratios (URs) showed that there was an inverse correlation only between Pgp and the quantitative uptake ratio (P=0.016, r=-0.461). When the patients were grouped as 'good' and 'poor', as related to the chemotherapy response, there were no meaningful differences between these two groups regarding Pgp, CD95 and tetrofosmin URs (P>0.05). By evaluating the scintigraphic findings of the 'repeated' 14 patients, we showed that if the 99mTc tetrofosmin UR in the second imaging test was reduced by >0.08, the response to chemotherapy tended to be good. This method, based on follow-up scanning with tetrofosmin, showed a sensitivity of 83% and a specificity of 62% in the prediction of a 'good' response, if a decrease of 0.08 was taken into consideration. CONCLUSION: In this study, patients with acute leukaemia showed significant uptake of tetrofosmin into the bone marrow. The addition of basal and repeated 99mTc tetrofosmin scintigraphy to the management protocol for leukaemia could lead to the preferential determination of responses to chemotherapy, by evaluating whole bone marrow non-invasively. This method seems promising, but it needs further support from various similar investigations comprising more patients in order to confirm our results.

Analysis of PTEN, VEGF, HER2 and P53 status in determining colorectal cancer benefit from bevacizumab therapy.

BACKGROUND: No factor has thus far been identified to predict the efficacy of bevacizumab therapy for colorectal cancer. We here therefore studied PTEN, VEGF, HER2 and p53 by immunohistochemistry as possible prognostic and predictive factors. MATERIALS AND METHODS: A total of 34 retrospectively collected tumor samples were evaluated, all from patients receiving bevacizumab-based regimens. VEGF-A, PTEN, HER2, p53 were assessed and data was compared with clinicopathologic characteristics of patients and the bevacizumab response rate. RESULTS: In this study, the median age of the 34 metastatic colorectal cancer patients was 55.5 (24-75), twelve (35.3%) being women and 22 (64.7%) men. PTEN, VEGF, HER2, p53 expressions were compared with bevacizumab response and other chacteristics of disease. Statistical significant differences were not found between bevacizumab response rates and different expression levels of VEGF, PTEN, HER2 and p53 (respectively p=0.256, p=0.832, p=0.189, p=0.131). However, a survival difference was noted in the VEGF expression negative group (median OS:55 months; 95%CI, 22-88 months) (p=0.01). There was no statistically significant OS difference in other groups (PTEN p=0.6, HER2 p=0.189, p53 p=0.13). CONCLUSIONS: We did not find any predictive factor for BV therapy in our study. VEGF negative expression could be an important prognostic factor in metastatic colorectal carcinoma.

Retrospective analysis of 498 primary soft tissue sarcomas in a single Turkish centre.

BACKGROUND: Soft tissue sarcomas (STS) must be managed with a team involving pathologists, radiologists, surgeons, radiation therapists and medical oncologists. Treatment modalities and demographic characteristics of Turkish STS were analysed in the current study. MATERIAL-METHODS: Primary adult STS followed between 1999- 2010 in Cukurova University Medical Faculty Department of Medical Oncology were analyzed retrospectively. RESULTS: Of the total of 498 patients, 238 were male and 260 female. The most seen adult sarcomas were leomyosarcoma (23%). Localization of disease was upper extremity (8.8%), lower extremity (24.7%), head-neck 8.2%, thoracic 8%, retroperitoneal 5.6%, uterine 12.4%, abdominal 10%, pelvic region 3.6 and other regions 10%. Some 13.1% were early stage, 10.2% locally advanced, 8.2% metastatic and 12.2% recurrent disease. Patients were treated with neoadjuvant/adjuvant (12%) or palliative chemotherapy (7.2%) and 11.4% patients did not receive chemotherapy. Surgery was performed as radical or conservative. The most preferred regimen was MAID combination chemotherapy in the rate of 17.6%. The most common metastatic site was lung (18.1%). The overall survival was 45 months (95%CI 30-59), 36 months in men and 55 months in women, with no statistically significant difference (p=0.5). The survival rates were not different between the group of adjuvant and palliative chemotherapy (respectively 28 versus 18 months) (p=0.06), but radical surgery at 37 months was better than 22 months for conservative surgery (p=0.0001). No differences were evident for localization (p=0.152). Locally advanced group had higher overall survival rates (72 months) than other stages (p=0.0001). CONCLUSION: STS can be treated successfully with surgery, chemotherapy and radiotherapy. The survival rates of Turkish people were higher in locally advanced group; these results show the importance of multimodality treatment approach and radical surgery.

The value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in carcinoma of an unknown primary: diagnosis and follow-up.

BACKGROUND: The management of the patients with carcinoma of an unknown primary represents a difficult challenge in oncology. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has provided new insights in the diagnosis, staging, and follow-up of oncological patients. AIM: This study aimed to investigate the value of FDG PET/CT in clarifying the primary site in our patients with histologically proven tumor metastasis (HPM) or with a high clinical suspicion of malignancy, and the clinical impact of this technique on the management of these patients. METHODS: In total 94 patients from two centers underwent FDG PET/CT imaging; 78 patients with HPM and 16 patients with a clinical suspicion of malignancy. The histology and/or follow-up data were used as the gold standard. Hypermetabolic findings at the site of the pathological CT changes or at physiological FDG uptake sites were the criteria for malignancy. PET/CT findings were analyzed for the identification of the primary tumor site, for the relationship with survival, and also for the effect in chemotherapy monitoring. RESULTS: Primary malignancy was discovered in 53 of 90 patients (59%) histologically and 37 (41%) patients' primary tumor sites were not found during the study period. Amongst 90 patients, five (6%) were normal on FDG PET/CT. Of 85 patients (94%) with pathological findings on FDG PET/CT, 27 patients (32%) had solitary and 58 (68%) patients had multiple organs affected. Regarding the whole study population, a sensitivity of 74% and a specificity of 78% were calculated for FDG PET/CT imaging. Regarding the patients with HPM, the sensitivity and specificity values were 84 and 81%, respectively. The mean survival time of the patients with disseminated disease was significantly shorter than those of the patients with single or no lesion (13.44+/-1.61, 20.98+/-2.0 and 26.67+/-2.73 months, respectively, P=0.014). In seven of eight patients, follow-up FDG PET/CT scans effectively monitored the patients' therapies. CONCLUSION: Whole-body FDG PET/CT has to be considered a useful method, especially in an early phase of the diagnostic workup of patients with carcinoma of an unknown primary syndrome, to optimize the management.