Differential transcriptional and protein expression of thyroid-stimulating hormone receptor in ovarian carcinomas.

OBJECTIVE: Thyroid-stimulating hormone (TSH) regulates normal thyroid function by binding to its receptor (thyroid-stimulating hormone receptor -TSHR) that is expressed at the surface of thyroid cells. Recently, it has been demonstrated that TSHR is abundantly expressed in several tissues apart from the thyroid, among them the normal ovarian surface epithelium. The role of TSHR expression outside the thyroid is not completely understood. The current study examines possible alterations of TSHR expression in ovarian carcinomas and its implication in ovarian carcinogenesis. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction and immunohistochemistry analysis of TSHR expression were performed in 34 ovarian carcinoma specimens and 10 normal ovarian tissues (controls). RESULTS: Significant reduction in TSHR messenger RNA (mRNA) expression was detected in ovarian carcinomas (mean [SD]: 0.518 [0.0934] vs normal, 49.4985 [89.1626]; P < 0.001, Mann-Whitney U test), whereas TSHR protein levels were significantly increased (percentage of positive cells: cancer, 73.55% [20.09%], vs normal, 54.54% [21.14%]; intensity: cancer, 2.52 [0.508], vs normal 1 [0]; P = 0.012, Mann-Whitney U test). No significant differences in TSHR mRNA were found according to history of thyroid disease. CONCLUSIONS: Our study describes for the first time alterations in TSHR expression both at mRNA and protein levels in ovarian carcinomas. The discrepancy between the decreased levels of the TSHR mRNA and the increased protein expression has already been described in thyroid carcinomas and might be due to alterations in its degradation by the ubiquitin system or other unknown mechanisms. Further analysis could elucidate the role of these findings in ovarian carcinogenesis.

Convalescent plasma therapy in an immunocompromised patient with multiple COVID-19 flares: a case report.

Convalescent plasma (CP) transfusion has been utilized as a salvage therapy in immunocompromised patients with severe COVID-19 pneumonia. We describe the case of a 45-year-old immunocompromised patient, who received CP, in order to control multiple COVID-19 flares and prolonged SARS-CoV-2 viraemia lasting for 2 months after the initial diagnosis.

A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study.

BACKGROUND: Platinum-based combinations are the standard second-line treatment for platinum-sensitive ovarian cancer (OC). This randomized phase II study was undertaken in order to compare the combination of carboplatin and pegylated liposomal doxorubicin (LD) with carboplatin and paclitaxel (CP) in this setting. METHODS: Patients with histologically confirmed recurrent OC, at the time of or more than 6 months after platinum-based chemotherapy, were randomized to six cycles of CP (carboplatin AUC5 + paclitaxel 175 mg/m2, d1q21) or CLD (carboplatin AUC5 + pegylated LD 45 mg/m2, d1q28). RESULTS: A total of 189 eligible patients (CP 96, CLD 93), with a median age of 63 years, median Performance Status (PS) 0 and a median platinum free interval (PFI) of 16.5 months, entered the study. Discontinuation due to toxicity was higher in the CP patients (13.5% versus 3%, P = 0.016). The overall response rate was similar: CP 58% versus CLD 51%, P = 0.309 (Complete Response; CR 34% versus 23%) and there was no statistical difference in time-to-progression (TTP) or overall survival (OS; TTP 10.8 months CP versus 11.8 CLD, P = 0.904; OS 29.4 months CP versus 24.7 CLD, P = 0.454). No toxic deaths were recorded. Neutropenia was the most commonly seen severe toxicity (CP 30% versus CLD 35%). More frequent in CLD were severe thrombocytopenia (11% versus 2%, P = 0.016), skin toxicity and Palmar-plantar erythrodysesthesia (PPE) grade 1-2 (38% versus 9%, P< 0.001), while grade 3 neurotoxicity and alopecia were higher in CP (7% versus 0%, P = 0.029, 20% versus 5%, P = 0.003). PS and PFI were independent prognostic factors for TTP and OS. CONCLUSIONS: The combination of pegylated LD with carboplatin is effective, showing less neurotoxicity and alopecia than paclitaxel-carboplatin. It thus warrants a further phase III evaluation as an alternative treatment option for platinum-sensitive OC patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000436279.

Immunohistochemical study of PTEN and phosphorylated mTOR proteins in familial and sporadic invasive breast carcinomas.

AIMS: Loss of phosphatase and tensin homologue (PTEN) leads to activation of several kinases, including mammalian target of rapamycin (mTOR), which promotes cell cycle progression. The aim was to study the expression of PTEN and phosphorylated (p)-mTOR in familial and sporadic invasive breast carcinomas and their relation to clinicopathological features, molecular indices (Wnt1) and patients' survival. METHODS AND RESULTS: PTEN and p-mTOR were detected immunohistochemically in 215 sections of invasive breast carcinomas (112 with a familial history of breast cancer). Image analysis was used and univariate and multivariate analyses employed for statistical evaluation of results. PTEN was detected in the nucleus (73.5%) and p-mTOR in the cytoplasm (44.2%) of cancer cells. Loss of PTEN protein was more frequently detected in women with a familial history of breast cancer (72%) (P < 0.0001), while its expression was negatively correlated with Wnt1, in total (P = 0.049). p-mTOR showed a positive association with lymph node status (P = 0.010) and was found to have a negative impact on patients' overall survival (P = 0.016). CONCLUSIONS: Loss of PTEN protein expression appears to occur more frequently in women with a family history of breast cancer, whereas activation of mTOR protein seems to be related to a more aggressive phenotype.

Secondary Alopecia Neoplastica Mimicking Alopecia Areata following Breast Cancer.

Cutaneous metastases from visceral carcinomas are relatively uncommon, with an overall incidence ranging from 0.7 to 9%. Diagnosis of scalp metastases usually escapes clinicians and dermatologists due to the fact that these metastases are mimicking other benign dermatological conditions. Herein, we present an uncommon case of scalp alopecia neoplastica mimicking alopecia areata due to breast cancer; a 43-year-old woman diagnosed with lobular cancer 3 years previously presented with acute loss of hair in well-circumscribed areas of the scalp and was diagnosed with alopecia areata by a private-practice dermatologist. She was then reevaluated, and due to her history of breast cancer, a biopsy from the scalp was performed and revealed alopecia neoplastica. At the same time that the skin lesions were recognized as disease involvement, the patient presented with dyspepsia, and endoscopy of the upper and lower gastrointestinal tract also revealed metastasis to the stomach and bowel. Gastrointestinal metastasis may occur with several types of cancer, but the stomach and bowel are rare metastatic sites for breast cancer.

Treatment of early uterine sarcomas: disentangling adjuvant modalities.

Uterine sarcomas are a rare group of neoplasms with aggressive clinical course and poor prognosis. They are classified into four main histological subtypes in order of decreasing incidence: carcinosarcomas, leiomyosarcomas, endometrial stromal sarcomas and "other" sarcomas. The pathological subtype demands a tailored approach. Surgical resection is regarded as the mainstay of treatment. Total abdominal hysterectomy and bilateral salpingo-oophorectomy represents the standard treatment of uterine sarcomas. Pelvic and para-aortic lymph node dissection in carcinosarcomas is recommended, given their high incidence of lymph node metastases, and may have a role in endometrial stromal sarcomas. Adjuvant radiation therapy has historically been of little survival value, but it appears to improve local control and may delay recurrence. Regarding adjuvant chemotherapy, there is little evidence in the literature supporting its use except for carcinosarcomas. However, more trials are needed to address these issues, especially, their sequential application. Patients with uterine sarcomas should be referred to large academic centers for participation in clinical trials.

Monophasic synovial sarcoma as a cause of obstructive ileus: A case report.

Synovial sarcoma is a high-grade soft tissue sarcoma, divided histologically into 3 types: Monophasic, biphasic and poorly differentiated. An extremely rare case of obstructive ileus due to monophasic synovial sarcoma in a 54-year-old male patient is reported in the present study. The patient presented to the emergency department with signs and symptoms of obstructive ileus. Computer Tomography (CT)scan showed a pelvic mass (20×17×12 cm) causing obstruction at the sigmoid colon. An exploratory laparotomy through a midline incision was performed. The described mass was unresectable as it was infiltrating major vessels. Therefore, a diverting loop descending colostomy and biopsy of the solid mass were performed. Pathological examination revealed a monophasic synovial sarcoma. The patient was referred to the Department of Oncology and started treatment with doxorubicin and ifosfamide.

Treatment with granulocyte colony stimulating factor is associated with improvement in endothelial function.

PRIMARY OBJECTIVE: Granulocyte-colony stimulating factor (G-CSF) is used for the mobilization of bone marrow and endothelial progenitor cells, though G-CSF-induced inflammation may cause endothelial dysfunction. We examined the effects of G-CSF on endothelium, C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha) and anti-inflammatory cytokines namely interleukin 10 (IL-10). RESEARCH DESIGN: We studied 60 women with breast cancer, who were randomized to either subcutaneous G-CSF (5 microg/kg), o.d. for 5 days after adjuvant chemotherapy (n = 40) or placebo (n = 20). EXPERIMENTAL INTERVENTIONS: We measured flow-mediated dilatation (FMD%) of the brachial artery by ultrasonography, CRP, TNF-alpha, IL-10 and the ratio TNF-alpha/ IL-10 blood levels before, 2-h and 5-days after the G-CSF or placebo treatment. MAIN OUTCOMES AND RESULTS: There was a greater increase of FMD, IL-10 and reduction of TNF-alpha/ IL-10, 2 h and 5 days after the G-CSF treatment compared to placebo. Although, CRP and TNF-alpha were higher, TNF-alpha/IL-10 was lower at the end of G-CSF treatment compared to placebo. Improvement of FMD was related to changes of IL-10 and TNF-alpha/IL-10. CONCLUSIONS: Treatment with G-CSF improves endothelial function in vivo, possibly by shifting the balance between the pro- and anti-inflammatory cytokines.

Predictors of colorectal cancer screening awareness among people working in a hospital environment.

BACKGROUND: Compliance rates for colorectal cancer (CRC) screening are much lower than those desired. Appropriate information on CRC risks and screening methods is supposed to stimulate motivation for screening. We aimed to identify parameters associated with the decision for CRC screening and colonoscopy in a population expected to have high awareness of disease prevention. METHODS: In a single-center, cross-sectional study, we used an anonymous questionnaire (AQ) to record the demographics, habits and screening behavior for cancers and other common diseases of all employees older than 50 years in our hospital. RESULTS: Among 287 active employees, 83% (n=237) answered the AQ (age 55±4 years). Thirty percent (n=70) underwent colonoscopy while 17% (n=40) underwent CRC screening (39/40) colonoscopy). Comparatively, among women 97% had a Pap-smear, 92% a mammography, while among men 83% had been tested for serum prostate-specific antigen. Age, male sex, alcohol consumption and university education correlated positively with CRC screening (P<0.05 for all). After multivariate analysis, university education remained an independent determinant of CRC screening (OR 2.488, 95%CI 1.096-5.648; P=0.029). Among subjects who had not undergone colonoscopy in the past, ignorance of the need for CRC screening (OR 0.360, 95%CI 0.150-0.867; P=0.023) and indifference to undergo such a procedure (OR 0.188, 95%CI 0.066-0.537; P=0.002) were independent determinants for not planning a future screening colonoscopy. CONCLUSIONS: Education was the most important factor in the decision to undergo CRC screening. Colonoscopy was the preferred screening method. Ignorance of and indifference to CRC risks were the major obstacles for a future screening colonoscopy.

Untreated newly diagnosed essential hypertension is associated with nonalcoholic fatty liver disease in a population of a hypertensive center.

PURPOSE: Recent studies have demonstrated that hypertension (HTN) is associated with nonalcoholic fatty liver disease (NAFLD) in treated hypertensive patients. The aim of this study was to investigate the association between newly diagnosed essential HTN and NAFLD in untreated hypertensive patients. PATIENTS AND METHODS: A consecutive series of 240 subjects (143 hypertensives and 97 normotensives), aged 30-80 years, without diabetes mellitus were enrolled in the study. Subjects with 24-hour systolic blood pressure (SBP) values ≥130 mmHg and/or diastolic BP values ≥80 mmHg were defined as hypertensives. NAFLD was defined as the presence of liver hyperechogenicity on ultrasound. RESULTS: Body mass index (P=0.002) and essential HTN (P=0.016) were independently associated with NAFLD in the multivariate logistic regression model. Furthermore, the multivariate analysis revealed that morning SBP (P=0.044) was independently associated with NAFLD. CONCLUSION: Untreated, newly diagnosed essential HTN is independently associated with NAFLD. Ambulatory BP monitoring could be used for the diagnosis of essential HTN in patients with NAFLD.

Two cycles of carboplatin-based adjuvant chemotherapy for high-risk clinical stage I and stage IM non-seminomatous germ cell tumours of the testis: a HECOG trial.

BACKGROUND: We investigated the efficacy and safety of 2 cycles of adjuvant chemotherapy with carboplatin, etoposide and bleomycin (CEB90) in patients with high-risk clinical stage I or stage IM non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: A total of 52 consecutive patients (22 patients with high-risk histological features [vascular invasion, presence of embryonal carcinoma, absence of yolk sac tumour] and 30 with tumour marker activity post-orchidectomy-stage IM) were entered into this prospective study. Chemotherapy consisted of carboplatin 400 mg/m2 or AUC 5 (day 1), etoposide 165 mg/m2 (days 1-3) and bleomycin 30 mg (days 1, 8, 15). Chemotherapy was repeated every 3 weeks. RESULTS: During a median follow-up of 112 months (range, 10 to 174 months), two patietns with stage IM relapsed. These cases had a disseminated, marker-positive germ cell tumour (GCT), extensively involving both liver and lungs in the first case and para-aortic lymph nodes and lung in the second one; both patients died of the tumour after a number of salvage chemotherapy (including high-dose therapy) regimens. Fifty patients (96%) are alive and disease-free. Two cycles of CEB90 were well tolerated and the only side-effects were myelotoxicity and alopecia. CONCLUSION: Despite the general consensus that ciplatin-based chemotherapy is superior to carboplatin-containing regimens in testicular cancer, 2 cycles of CEB90 may be an equally effective treatment option as adjuvant therapy for high-risk clinical stage I and IM patients.

Expression of angiogenic markers in the peripheral blood of docetaxel-treated advanced breast cancer patients: a Hellenic Cooperative Oncology Group (HeCOG) study.

It is well known that low-dose metronomic chemotherapy has antiangiogenic activity. The aim of the present trial was to investigate the antiangiogenic properties of weekly docetaxel in patients with metastatic breast cancer. In total, 157 metastatic breast cancer patients received 35 mg/m2 docetaxel weekly as a recommended treatment. Blood samples were collected before the start of chemotherapy (baseline) and during treatment. Nitric oxide (NO) and vascular endothelial growth factor A (VEGF-A) plasma levels were measured at baseline and during treatment, while VEGF-A, endothelial nitric oxide synthase (eNOS) and thrombospondin-1 (THBS-1) peripheral blood mRNA levels were measured at baseline, in 127 patients and 39 female healthy controls. In general, the treatment was well-tolerated. Sixty-one patients (38%) achieved an objective response (4% complete and 34% partial response), while 52 (33%) had stable disease and 27 (17%) progressed. At a median follow-up of 33.5 months (range 2.8-45.0), 118 patients (74%) demonstrated disease progression and 94 (59%) had died. Median progression-free survival (PFS) was 8.8 months and median overall survival (OS) was 27.7 months. Median baseline level of plasma NO was significantly lower in patients than in healthy controls (p=0.010), while none of the plasma markers significantly changed upon docetaxel treatment. In addition, the median relative quantification value for THBS-1 mRNA was significantly higher (p<0.001) in patients as compared to healthy controls. NO plasma levels were positively associated with the number of organs involved (p=0.008). In multivariate analysis, low eNOS mRNA levels showed adverse prognostic significance for OS and high THBS-1 mRNA levels were found to be associated with shorter OS and PFS, independently from established clinical prognostic factors. Although an antiangiogenic activity of weekly docetaxel was not demonstrated in the present study, some interesting observations regarding the prognostic role of a number of blood angiogenic markers could be made.

Common breast cancer susceptibility loci are associated with triple-negative breast cancer.

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

Periodic therapeutic plasma exchange in patients with moderate to severe chronic myasthenia gravis non-responsive to immunosuppressive agents: an eight year follow-up.

Few patients with moderate or severe myasthenia gravis (MG) do not respond to immunosuppressive treatment. We present our experience with periodic therapeutic plasma exchange (TPE), in 11 patients with MG resistant to intravenous immunoglobulin (IVIg) therapy, who had frequent relapses even whilst on high doses of immunosuppressive drugs, over a period of 8 years. All patients underwent TPE until control of their symptoms was achieved, and afterwards TPE sessions were continued periodically in an attempt to achieve remission of the disease, without immunosuppressant therapy. Two of the patients were progressively weaned off immunosuppressive agents, as well as TPE, and they are now symptom free. The other nine patients are still under a periodic TPE regime. Seven of them were weaned off all medications and required an average of 3.7 TPE sessions per year during the last 5 years. In the other two patients, those with the most severe form of the disease, the immunosuppressant dosage has been decreased and a TPE session every 2-3 weeks is required in order to control their symptoms. Through all these years TPE has been well tolerated and only minor side-effects were observed in two patients. Finally, during this 8 year follow-up period, nine of the patients treated with periodic TPE have been in good control of their symptoms over the last 5 years, and the other two patients live a normal life without any treatment in the last 3 years. Our results suggest that periodic TPE is safe and effective in the control of symptoms in patients with moderate to severe MG who do not respond to immunosuppressive therapies.

The combination of estramustine, vinorelbine, and mitoxantrone in hormone-refractory prostate cancer: a Phase II feasibility study conducted by the Hellenic Cooperative Oncology Group.

OBJECTIVES: To evaluate the safety profile and therapeutic value of the combination of estramustine, mitoxantrone, and vinorelbine in the treatment of hormone-refractory prostate cancer. METHODS: Fifty-two patients with hormone-refractory prostate cancer were included in the study. Median age was 70 years (range, 49 to 100 years), World Health Organization performance status ranged from 0 to 2. The treatment schedule consisted of estramustine capsules (140 mg 3 times daily on days 1 to 3 and days 8 to 10 per os), intravenous mitoxantrone (12 mg/m2 on day 2), and intravenous vinorelbine (25 mg/m2 on day 2 and day 9), given in a 3-week cycle. RESULTS: Thirty-one percent of patients with measurable soft-tissue disease demonstrated an objective response, which included six complete and ten partial responses in all involved organs (bone responses not included). Twenty-nine patients (56%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 6.9 months, and the median survival for all patients was 14.5 months. CONCLUSIONS: The combination of estramustine, vinorelbine, and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer.

Aberrant expression of the costimulatory molecule CD40 ligand on monocytes from patients with systemic lupus erythematosus.

CD40 ligand (CD40L, CD154) is overexpressed on T and B cells in systemic lupus erythematosus (SLE). Monocytes have been shown to contribute to immune-mediated pathology in SLE and to express CD40L under certain conditions. Therefore, we studied CD40L expression on lupus monocytes ex vivo, as well as after activation in vitro. A highly significant sevenfold increase in the frequency of CD40L-expressing peripheral monocytes from 23 SLE patients, compared to 16 healthy individuals (mean percentage of CD40L(+)CD14(+) among CD14(+) cells, 11.7 versus 1.6), was found by flow cytometry. Increased CD40L expression on monocytes correlated significantly with disease activity, elevated gamma-globulin serum levels, as well as increased CD40L expression on T cells. CD40L expression by lupus monocytes was verified at both the mRNA and protein levels, while LPS stimulation was found to upregulate CD40L mRNA accumulation and surface protein expression. CD40L expression on activated lupus monocytes within anti-CD3-stimulated, mononuclear cell cultures was also enhanced compared to control-derived monocytes. These novel findings underscore the multiplicity of pathways through which monocytes may contribute to SLE pathology and suggest that T cell-independent CD40L-mediated cell to cell interactions may be also involved in humoral immune activation in SLE.