Prognostic nutritional index is an independent prognostic factor for treatment response, survival and drug choice in metastatic castration-resistant prostate cancer treated with abiraterone acetate or enzalutamide.

PURPOSE: We designed this study to identify the prognostic value of baseline prognostic nutritional index (PNI) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide. METHODS: 101 mCRPC patients were included. PNI was calculated using formula 10 x serum albumin value (gr/dL) + 0.005 × total lymphocyte count (per mm3). ROC analysis was used for determining prognostic PNI value. RESULTS: The statistically significant cut-off value for PNI was 46.62. Initial PSA response and PSA kinetics (early PSA response and 30 %-50%-90% PSA response at any time) were much better in PNI > 46.62 group than the PNI ≤ 46.62 group (p < 0.01). In multivariate analysis, baseline PNI level >46.62 was an independent predictor of PSA-PFS (HR: 0.42, p < 0.01), radiologic PFS (HR: 0.53, p < 0.01), and OS (HR: 0.42, p < 0.01). In the PNI ≤ 46.62 group, median OS was 7.4 months (95% CI: 4.1-10.7) for the abiraterone acetate subgroup vs. 17.6 months (95% CI: 10.1-25.1) for enzalutamide subgroups (p < 0.01). CONCLUSION: PNI is a useful, independent prognostic marker for mCRPC patients treated with either abiraterone acetate or enzalutamide. Using pre-treatment PNI may help clinicians in the prediction of survival and decision making based on abiraterone acetate or enzalutamide.

Systematic Review: Clinical Symptoms and Laboratory and Radiology Findings in Children with COVID-19.

Coronavirus disease 2019 (COVID-19) caused by the new [novel] coronavirus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic with exceeding 72 million cases and 1.2 million deaths by the end of November 2020. We aimed to evaluate clinical, laboratory, and radiology findings of COVID-19 in children as reported worldwide and thereby to increase the clinical knowledge about the disease. Bibliographic searches were conducted in December 2020 using PubMed and Google Scholar. The search was limited to children [below 18 years of age]. The search strategy yielded a total of 336 potential articles but finally a total of 25 valid studies covering a total of 2446 (China: 1109, Europe: 663, North America: 674) pediatric patients. In the studies covered by this review, it was observed that the median age was calculated at various values between the ages of 1 and 7 years. In the studies, overall rate of the asymptomatic patients was 24.8% (ranging between 10.7 and 56.6). Acute upper respiratory tract infection (URTI) [mild disease] was observed in 40.7 (ranging between 22 and 50.6%), mild pneumonia in 27% (ranging between 9.5 and 40.6%), and severe pneumonia in 5.3% (ranging between 1.9 and 10.6%). A total of 3% (ranging between 0.7 and 5.1%) of the patients had critical severity. Among the most common clinical symptoms and findings; 61.7% (ranging between 57.4 and 64.3%) of the patients had fever, 53.2% (ranging between 30.6 and 75.1%) had cough, 16.8% (ranging between 4.6 and 27.2%) had diarrhea or nausea, and 15% had lymphopenia. Abnormal radiological findings were detected in 47.2 of the children with COVID-19 and ground glass opacity was in 22.2%. COVID-19 manifests milder and the clinical signs and symptoms vary widely in children. Laboratory and radiological findings of COVID-19 in pediatric patients are not mostly disease-specific, except lymphopenia may have a limited value, and ground glass opacity may have a significant diagnostic value.

Relation between sarcopenia and dose-limiting toxicity in patients with metastatic colorectal cancer who received regorafenib.

BACKGROUND: Sarcopenia is related to poor prognosis and drug toxicities in solid tumors. The aim of our study is to investigate the predisposition of patients with metastatic colorectal carcinoma who started regorafenib treatment to sarcopenia and prolonged survival. METHODS: Patients with metastatic colorectal carcinoma who receives regorafenib were search retrospectively. Dose-limiting toxicity was defined as dose reduction or toxicity requiring drug withdrawal. Sarcopenia evaluation was made with computed tomography performed within a month before treatment. Progression-free survival and overall survival were estimated. RESULTS: Thirty-six patients were found as suitable for the study. 63.9% of patients were found as basally sarcopenic. Dose-limiting toxicity occured 13 of 23 patients (56.5%) with basal sarcopenia, whereas only 1 of 13 patients (7.6%) with no sarcopenia exhibited dose-limiting toxicity (p = 0.005). Three patients suffered from grade 3-4 toxicity. Hand-foot syndrome, hypertension, and mucosal rash were the most seen side effects. Mean regorafenib treatment duration was 3.36 months. There was no significant difference in the progression-free survival (PFS) and the overall survival (OS) between sarcopenic patients and patients with no sarcopenia. Durations were as OS 24.2 weeks in patients with sarcopenia (95% CI 16.7-31.7), 28.1 weeks in patients with no sarcopenia (95% CI 20.5-35.7) (p = 0.36), and as PFS 14.2 weeks in patients with sarcopenia (95% CI 12.1-16.4), 14.8 weeks in patients with no sarcopenia (95% CI 9.7-20.1) (p = 0.65). CONCLUSION: Dose-limiting toxicity was significantly higher in basally sarcopenic patients who were started regorafenib as treatment of metastatic colorectal carcinoma. There was no significant relationship between overall survival and progression-free survival with sarcopenia.

Skeletal muscle loss during anti-EGFR combined chemotherapy regimens predicts poor prognosis in patients with RAS wild metastatic colorectal cancer.

PURPOSE: We aimed to assess whether anti-EGFR combined chemotherapy regimens are related with loss of skeletal muscle mass and to compare cetuximab and panitumumab therapies in the aspect of skeletal muscle area change as well as to assess whether skeletal muscle mass loss has prognostic significance in the RAS wild mCRC patients. MATERIALS AND METHODS: A total of 56 patients (30 patients in cetuximab arm and 26 patients in panitumumab) who had computed tomography images were retrospectively evaluated at the diagnosis and follow up during the treatment period before progression. RESULTS: During treatment period 24 patients (42.8%) had muscle loss. Of these, 7 (29.2%) patients were treated at first-line and 17 (70.8%) patients were treated at second-line setting. There was no significant difference in the aspect of skeletal muscle loss among cetuximab and panitumumab combined treatment regimens. Median PFS was 9.1 (8.6-9.6) months in muscle loss group and 13.9 (7.2-20.6) months in muscle stable group (p = 0.001). Median OS was 23.4 (95% CI 15.8-31.0) months in muscle stable group and 19.1 (95% CI 17.0-21.3) months in muscle loss group (p = 0.57) at first-line setting. For second-line, median OS was 21.2 (14.7-27.7) months in muscle stable group and 14.4 (6.0-22.4) months in muscle loss group (p = 0.003). CONCLUSIONS: Decrease in skeletal muscle mass before progression on CT imaging is an independent indicator for shorter PFS value in RAS WT mCRC patients who received anti-EGFR combined chemotherapy regimens at both the first and second-line settings. Beside that shorter overall survival values also were significantly seen in patients who had muscle loss during anti-EGFR therapy in the second-line setting.

AT-101 acts as anti-proliferative and hormone suppressive agent in mouse pituitary corticotroph tumor cells.

PURPOSE: Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. METHODS: Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT-101. ACTH was measured by ACTH-EIA Kit. RESULTS: AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7-, 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. CONCLUSION: AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells.

Depression and socio-economical burden are more common in primary caregivers of patients who are not aware of their cancer: TURQUOISE Study by the Palliative Care Working Committee of the Turkish Oncology Group (TOG).

In this study, we aimed to determine the personal, social and economic burden and the frequency of depression, as well as in caregivers of cancer patients who are being treated with chemotherapy in Turkey. The study is designed as a cross-sectional survey study using a 5-point Likert-type response scale, and the last part of the questionnaire includes the Beck Depression Inventory. The depression rate was found to be 64% (n = 476) among all subjects (n = 968), with 91% of those with depression demonstrating signs of mild depression. In this study, a significant difference was found between the presence of depression and age (young), sex (female), educational level (high), economic status (low), financial loss during treatment, patient's lack of knowledge about his/her diagnosis, metastatic disease and short survival time. In addition, 64% of all subjects had concerns of getting cancer, and 44% of all subjects had feelings of anger/rage against other people. In a multivariate regression analysis, the patient's lack of knowledge of the diagnosis was the independent risk factor. In conclusion, depression incidence and burden rate increased among cancer caregivers, and care burden was highly associated with depression. Accordingly, approaches to reducing the psycho-social effects of cancer should focus intensively on both the patients and their caregivers in Turkey.

The access rate to diagnosis and treatment modalities in breast cancer patients in Turkey; multicenter observational study.

PURPOSE: To determine the time elapsed between the first notification of the disease and the access to the diagnosis and treatment modalities and the associated factors in female patients with breast cancer in Turkey. METHODS: Data was acquired from a questionnaire involving 535 patients who applied to 14 various oncology clinics in Turkey between 1st and 28th of February 2010. Analyses were performed by the participating clinics and were divided into 3 groups: centers located in metropolitan areas formed group 1 (n=161), those located in Marmara and central Anatolia region formed group 2 (n=189), and centers located in Karadeniz and East-Southeast Anatolia region formed group 3 (n=185). The groups of these centers were formed according to the socioeconomic development of the provinces. RESULTS: The median patient age was 48 years, 56.1% of patients were less than 50 years of age. Eighty-five percent of the patients detected a mass in their breast by self examination and 27% of the patients older than 50 years never had breast imaging until the definite diagnosis was established. The median time elapsed between disease noticed by the patient and application to a health care center was 10 days, between application and biopsy 19 days, between biopsy and surgery 10 days, and between surgery and systemic therapy 31 days. The median time elapsed between patients applying for surgery in groups 1 and 2 centers was 11 and 21 days, respectively (p=0.01). The median time elapsed between biopsy and surgery in groups 1,2 and 3 centers was 14,1.5, and 12 days, respectively (p<0.05). CONCLUSION: A high level of awareness regarding breast cancer in our country is related with the time that is defined as 10 days between disease recognition and medical application. The time elapsed between the application and biopsy, surgery and systemic therapy was longer compared with the corresponding figures in developed countries.

Radiosensitization of hormone-refractory prostate cancer cells by gossypol treatment.

PURPOSE: many drugs have been tested to increase the sensitivity of prostate cancer cells to radiotherapy. Gossypol, a natural polyphenolic compound extracted from the cotton plant, is one of the agents the efficacy of which has been investigated in the treatment of prostate cancer for this purpose. The main aim of this study was to investigate the best gossypol application with irradiation, when gossypol was applied either sequentially (24 h before and after irradiation) or concurrently in PC-3 hormone-refractory and radioresistant prostate cancer cells. METHODS: The XTT viability assay was used to evaluate the cytotoxicity of different concentrations of gossypol in PC- 3 cells. Irradiation was applied to PC-3 cells via 6 MV photon linear accelerator and delivered 24 h before, 24 h after radiation or at the same time with gossypol administration. RESULTS: gossypol caused radiosensitization of PC-3 cells that are known to be radioresistant, with high Bcl-2 levels. Among different applications of gossypol and irradiation (before, after and concurrent) in prostate cancer cells, the best results were observed by the application of gossypol 24 h before irradiation. CONCLUSION: our study suggests that gossypol represents a promising novel anticancer treatment for radiosensitization of human hormone-refractory prostate cancer cells.

Apoptosis-mediated cytotoxic effects of ibandronic acid on hormone- and drug-refractory prostate cancer cells and human breast cancer cells.

Over 80% of patients with advanced breast and prostate cancer ultimately develop bone metastases. Ibandronic acid has proven efficacy for treatment of bone metastasis secondary to breast cancer. This study was designed to investigate the cytotoxic and apoptotic effects of ibandronic acid on hormone- and drug-refractory prostate carcinoma DU-145 and human breast cancer MCF-7 cell lines. Cytotoxicity was evaluated using an XTT cell proliferation kit, and apoptosis was assessed by enzyme-linked immunosorbent assay (histone-DNA fragmentation) and measurement of caspase 3/7 activity. With increasing concentrations of ibandronic acid there was a dose- and time-dependent decrease in cell numbers. MCF-7 cells were more resistant than DU-145 cells (half maximal inhibitory concentrations of 122 and 90 microM, respectively). Ibandronic acid induced apoptosis in both cell lines. The study showed an apoptosis-mediated cytotoxic effect for ibandronic acid (in addition to the already known osteoclast inhibiting effect) in breast cancer patients with bone metastases; which was also observed in prostate cancer cells. Further clinical studies involving breast and prostate cancer patients with bone metastases are warranted to confirm these findings.

The effect of racemic gossypol and at-101 on angiogenic profile of ovcar-3 cells: a preliminary molecular framework for gossypol enantiomers.

AIM: To compare the effect of racemic gossypol with its (-)/(-) enantiomer (AT-101) on expression profiles of angiogenic molecules by mRNA levels in human ovarian cancer cell line OVCAR-3. METHODS: Cell viability assay (2,3-bis (2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) was used to detect cytotoxicity of gossypol enantiomers. DNA fragmentation by an enzyme-linked immunosorbent (ELISA) assay was used to evaluate the rate of apoptosis. The mRNA expression levels of angiogenic molecules were investigated by Human Angiogenesis RT2 ProfilerTM PCR Array (SuperArray, Frederick, MD). RESULTS: Both racemic form and AT-101 resulted in a significant cytotoxicity and induced apoptosis. This effect was observed in a dose- and time dependent manner. However, AT-101 was much more potent. In addition, the treatment of 10 microM of racemic gossypol alone and 3 microM of AT-101 alone resulted in significant down-regulation (>or= 3 fold) in mRNA levels of some pivotal angiogenic molecules in OVCAR-3, but altered gene profiles were different by the treatment of each enantiomer. CONCLUSION: The efficacy of two gossypol enantiomers in OVCAR-3 cells showed distinction. AT-101 was much more potent than racemic gossypol, not only by means of cell death and apoptosis, but also by modulation of angiogenic molecules released from OVCAR-3 cells. Further studies with endothelial cells should be done to verify the anti-angiogenic effect of gossypol enantiomers in cancer treatment.

Enhancement of taxane-induced cytotoxicity and apoptosis by gossypol in human breast cancer cell line MCF-7.

PURPOSE: Gossypol is a natural polyphenolic compound extracted from cotton plant (Gossypium species) which has shown potent inhibitory effect on cell growth of many types of cancers. In this study, we aimed to evaluate the interaction of gossypol with some conventional drugs known to be effective in the treatment of breast cancer, like taxanes, doxorubicin, gemcitabine, cisplatin and vinorelbine, in MCF-7 breast cancer cells. MATERIALS AND METHODS: The XTT viability assay was used to evaluate the cytotoxicity of various cytotoxic agents alone and in combination with gossypol in MCF-7 breast cancer cells. The combination effect analysis of Chou and Talalay was used to identify the most synergistic drug combinations. The possible synergistic effects of the combination of drugs on apoptosis were also evaluated by using two different apoptosis assays. RESULTS: We identified strong synergistic cytotoxic and apoptotic activity of gossypol with taxanes among all other studied cytotoxic drugs. CONCLUSION: This study provides proof that gossypol combined with taxanes may have potential as a novel future treatment for breast cancer.

Targeting apoptosis in the hormone- and drug-resistant prostate cancer cell line, DU-145, by gossypol/zoledronic acid combination.

Possible synergistic cytotoxic and apoptotic effects of gossypol with zoledronic acid on DU-145 cells were explored, along with the rationale behind any observed synergism due to the different apoptotic proteins involved. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 activity were measured to verify apoptosis. Human Apoptosis Array was used to evaluate apoptotic proteins. The synergistic cytotoxic combination treatment had a versatile effect on apoptotic proteins, through inhibition of anti-apoptotic proteins (including cIAP-1, cIAP-2, survivin, livin, claspin, p53, p21, PON-2 and heat shock proteins) and concurrently the induction of pro-apoptotic proteins (Bad, Bax, Fas, FADD, cleaved caspase-3 and p27). Both drugs had a minimal toxicity profile comparing to cytotoxic agents. Combination treatments targeting many pivotal apoptosis-related proteins may be a rationale option for treatment of prostate cancer.

Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic Bcl-2 protein level in hormone-refractory prostate cancer cells.

Docetaxel, a semi-synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti-tumoral effects on prostate cancer cells. We have explored the possible additive/synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC-3 and DU-145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC-3 and DU-145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl-2 in PC-3 and DU-145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer.

Evaluation of the association between null genotypes of glutathione-S-transferases and Behcet's disease.

Glutathione S-transferases (GST) play an important role in oxidative stress related syndromes. An imbalance of the oxidant and antioxidant systems is important in the pathogenesis of Behcet's disease (BD). The objective of this study was to evaluate the association of null genotypes of GST-M1 and GST-T1 with BD since some preliminary molecular genetic data were recently published. Ninety-four Turkish BD patients (42 male, 52 female, 37.1+/-10.4 years) and 140 healthy volunteers (70 male, 70 female, 36.8+/-11.7 years) matched for age and gender with the patients as the control group were included in the study. Distributions of GST-M1 and GST-T1 genotypes were determined by multiplexed PCR using three sets of primers for GST-M1, GST-T1, and beta-globulin genes. There was no association between BD and the frequencies of GST-M1 and GST-T1 null genotypes when compared to controls by separate analysis. However, by cross and pooled combination analysis there was a significant association between the frequencies of pooled GSTs with one or both null genotypes in BD and controls. This is the first evidence that the association between the frequencies of GST-M1 and GST-T1 null genotypes and BD might be dependent on the interaction of multiple null allele polymorphisms rather than a single null allele of GST-M1 and GST-T1.

High-dose exposure to valsartan with suicidal intention.

Valsartan is a strong angiotensin receptor inhibitor specific for the angiotensin I receptor, which has been proven safe and well-tolerated in clinical trials. We were able to confirm its safety and tolerability in a case of high-dose exposure to valsartan with suicidal intention. A 25-year-old, fully conscious, female patient was brought to our hospital by relatives on July 24, 2001, at 9:15 p.m. following intake of a high dose of valsartan. It was established that she had taken 28 Diovan 80 mg tablets (2.24 g) 5 hours before admission to the hospital. Her clinical condition at the time of admission was good and did not deteriorate after admission. During the follow-up, her blood pressure never fell below 90/60 mmHg. The only complaint she had were painful muscle cramps which, with only supportive therapy, disappeared spontaneously over 2 days, and her blood pressure also returned to normal during this period. This report demonstrates the effect/side effect profile of valsartan when taken at a high dose, not achievable in a clinical trial.

Up-regulation of serine/threonine protein phosphatase type 2A regulatory subunits during methylprednisolone-induced differentiation of leukaemic HL-60 cells.

Serine/threonine protein phosphatase 2A (PP2A) may play a role in leukaemic cell differentiation of the HL-60 myeloid leukaemic cell-line after methylprednisolone induction. We have investigated the specific enzyme activity and expression of catalytic and regulatory subunits of PP2A. The resulting specific enzyme activity and immunoblots showed an increase in enzyme activity and the expression of regulatory subunits after methylprednisolone treatment. There was no change in the expression of PP2A catalytic subunits. It is suggested that the effect of methylprednisolone on leukaemic differentiation may be the result of PP2A upregulation.

Augmentation of methylprednisolone-induced differentiation of myeloid leukemia cells by serine/threonine protein phosphatase inhibitors.

To elucidate the roles of serine/threonine protein phosphatases type 1 (PP1) and type 2A (PP2A) in methylprednisolone-induced differentiation of HL60 cells into granulocytes and K562 cells into monocytes, we examined the effect of serine/threonine protein phosphatase inhibitors, okadaic acid and Cal-A on the proliferation/differentiation of HL60 and K562 cells. Okadaic acid and Cal-A augmented methylprednisolone induced granulocytic differentiation and cell death of HL60 cells and monocytic differentiation and cell death of K562 cells in different dose ranges, respectively. These data suggest an important role of PP1 and PP2A in the mechanism leading to differentiation of leukemic cells.

Synthesis and activities of 5-substituted-2-(p-substituted phenyl)-1-dialkylaminomethyl benzimidazole derivatives.

Nine 1,2,5-trisubstituted benzimidazole derivatives were prepared and their structure have been elucidated by IR, NMR spectral data and elemental analyses. Analgesic activity of the compounds prepared was investigated in mice by modified KOSTER test. Anti-inflammatory activity of these compounds was investigated by a carregeenan-induced hind paw edema model in mice. Their antibacterial activities were examined against S. aureus, E. faecalis, E. coli, P. aeruginosa, and antifungal activity against three kinds of yeast-like fungi (C. albicans, C. parapsilosis, C. stellatoidea).