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Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFβ and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors’ proliferative index (Ki67) increased from 5–6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.

Many investigations exist regarding the effect of the DNA repair enzyme MGMT (O 6 -methylguanine- DNA-methyltransferase)-encoding gene methylation on the antineoplasticity of temozolomide in glioblastoma patients. However, there exist surprisingly lesser studies regarding the associations between MGMT enzyme biochemistry with glial carcinogenesis. MGMT involves in risk of malignancies associated with ionizing radiation, smoking, exposure to polycyclic aromatic hydrocarbons, chlorinated solvents, vinylchloride and hairdyes. All these factors are also proposed to link with gliomagenesis, yet MGMT interactions with these carcinogens in gliomagenesis are not studied yet. In future, MGMT sequencing may be employed in vulnerable populations working in industries associated with exposure to these carcinogens to develop preventive strategies. Given that MGMT is involved in DNA repair, a polymorphism may simultaneously modify the risk of gliomas while enhancing temozolomide cytotoxicity in both marrow and tumor cells.

WOS:000518031100008 PMID: 31970972 Background: The synthesis of CDK4/6 inhibitors with endocrine treatment in two series of treatment has been widely accepted as the standard for patients with estrogen receptor-positive metastatic breast cancer. In spite of this, the activity of CDK4/6 inhibitors in patients with metastatic breast cancer who have progressed despite receiving multiple lines of treatment is not well understood. Aims: To report the activity and safety of a CDK4/6 inhibitor (palbociclib) in patients in whom at least three lines of treatment for ER+ metastatic breast cancer had failed. Study Design: Multicenter retrospective observational cohort study. Methods: In this retrospective observational cohort study, we included 43 patients who received palbociclib after at least three lines of systemic treatment for ER+/HER2- metastatic breast cancer. Results: The median progression-free survival in our population was 7 months (25th-75th percentile, 4-10), and the median overall survival was 11 months (25th-75th percentile, 6-19). Although there were some adverse events, palbociclib was generally well tolerated, so dose reduction was needed for only six patients (14%). Conclusion: The efficacy of palbociclib among heavily treated hormone receptor-positive/HER2- patients with advanced breast cancer was acceptable in terms of clinical benefit, and it was generally well tolerated among this population.

Bone is the most common site of distant metastases in breast cancer that can cause severe and debilitating skeletal related events (SRE) including hypercalcemia of malignancy, pathologic fracture, spinal cord compression and the need for palliative radiation therapy or surgery to the bone. SRE are associated with substantial pain and morbidity leading to frequent hospitalization, impaired quality of life and poor prognosis. The past 25 years of research on the pathophysiology of bone metastases led to the development of highly effective treatment options to delay or prevent osseous metastases and SRE. Management of bone metastases has become an integral part of cancer treatment requiring expertise of multidisciplinary teams of medical and radiation oncologists, surgeons and radiologists in order to find an optimal treatment for each individual patient. A group of international breast cancer experts attended a Skeletal Care Academy Meeting in November 2012 in Istanbul and discussed current preventive measures and treatment options of SRE, which are summarized in this evidence-based consensus for qualified decision-making in clinical practice. (C) 2014 Elsevier Ltd. All rights reserved.

Aim: Thromboembolism is common in patients with cancer and may be considered a major cause of morbidity and mortality. We studied the most common genetic polymorphism characteristics that may have roles in the development of thrombosis in patients with cancer. Methods: A total of 158 patients with cancer who had had any thrombotic event were included, together with a control group of 134 patients with cancer without a thromboembolic event. The presence of mutations (Factor V Leiden G1691A, prothrombin G20210A) and polymorphisms (methylenetetrahydrofolate reductase [MTHFR] C677T and plasminogen activator inhibitor (PAI-1) 4G/5G) were analysed. Results: A heterozygous polymorphism for Factor V Leiden G1691A was found in 48 patients (30.3%) and a homozygous polymorphism in only one (0.63%), compared to 32 heterozygous (23.8%) and one homozygous (0.74%) polymorphism in the control group (P = 0.462). Prothrombin G20210A heterozygous polymorphism was observed in 11(6.9%) and four (2.5%) in the patients and controls, respectively. The MTHFR C677T heterozygous polymorphism was found in 48 (30.3%) and 24 (15.1%) and the homozygous polymorphism was observed in 15 (9.4%) and 12 (7.5%) in the study and control group, respectively (P = 0.04). Conclusion: Although we found a statistically significant difference between patients with and without thrombosis in respect to MTHFR C677T gene mutation, our data suggest that we do not have enough evidence yet to recommend performing genetic analysis.

Tumor growth and angiogenic factors are usually overexpressed in colorectal carcinomas. We aimed to assess the prognostic role of VEGF, bFGF, PDGF-AA, EGF, HGF, and E-selectin in patients with metastatic colorectal cancer treated with capecitabine and oxaliplatin (XELOX) chemotherapy protocol. Thirty-eight colorectal cancer patients who had evidence of distant metastasis were enrolled in the study. Angiogenic factors were measured before and after third cycle of chemotherapy. Patients were randomized into three groups, partial response (PR), stable disease (SD), and progressive disease (PD) groups, according to their clinical and radiologic evaluation after three cycles of XELOX chemotherapy. Eighteen patients (47.3 %) achieved partial response, 10 (26.3 %) stable disease, and 10 (26.3 %) progressive disease. VEGF (63.20 Pg/ml vs. 19,79 Pg/ml; p < 0.001), EGF (7.29 +/- A 3.08 Pg/ml vs. 4.79 +/- A 2.05 Pg/ml; p < 0.011), HGF (618.16 +/- A 340.39 Pg/ml vs. 452.02 +/- A 217.18 Pg/ml; p < 0.049), and PDGF-AA (691.68 +/- A 187.10 Pg/ml vs. 404.89 +/- A 168.47 Pg/ml; p < 0.001) were significantly decreased in PR group. PDGF-AA levels were also decreased in SD group (706.66 +/- A 206.66 Pg/ml vs. 389.79 +/- A 143.16 Pg/ml; p < 0,001). HGF levels were significantly increased in PD disease group (449.99 Pg/ml vs. 682.22 Pg/ml; p < 0.046). The baseline E-selectin levels were inversely proportional with overall survival that could be an important prognostic factor at the time of diagnosis. This study demonstrated that tumor growth factors can be helpful to determine colorectal cancer prognosis and overall survival in patients with metastatic disease. VEGF, HGF, EGF, and PDGF-AA levels were decreased in PR group. However, meaningful increment was seen HGF levels in PD group. Angiogenic factors and E-selectin provided unique prognostic information in advanced colorectal carcinoma patients.

Purpose: The purpose of this retrospective analysis was to describe the clinical course of patients with breast cancer with liver metastases alone who were treated on doxorubicin/cyclophosphamide or taxane-containing chemotherapy protocols at the M. D. Anderson Cancer Center. Patients and Methods: A total of 2,193 patients with metastatic breast cancer were treated on prospective clinical protocols at the University of Texas M. D. Anderson Cancer between 1973 and 2003. Among those, 132 were identified as having the liver as the first site of metastatic disease. The following information was obtained from the medical records: gender, age, race, performance status, menopausal status, hormonal receptor status, laboratory data, primary treatment, prior systemic treatment, disease-free interval, extent of metastatic disease, response to chemotherapy, site of progression, time to tumor progression, overall survival, and cause of death. Results: Of the patients 62% received anthracycline-based regimens and 38% received anthracycline- and taxane-based regimens on various clinical protocols as the initial therapy for metastatic disease. The median follow-up of the patients was 52 months. The overall objective response rate was 66.4%; 16.4% of the patients achieved complete responses. The median time to progression was 14 months. Progression-free survival rates were 56% and 30% at 12 and 24 months, respectively. The median overall survival was 25 months. Sixteen patients (12.1%) survived longer than 60 months. There was a statistically inverse relation between a high lactate dehydrogenase level and achieving a complete response (P < 0.05). Age≥50 years, extent of liver metastases, performance status, and lactate dehydrogenase and albumin levels are significantly related to progression-free survival (P < 0.05). Year of liver metastases diagnosis, extent of liver metastases, performance status, and albumin level are significantly related to overall survival (P < 0.05). Conclusions: This retrospective analysis demonstrated that patients with liver metastases only had high objective response rates and encouraging results for median survival obtained with currently available cytotoxic agents.

The more metastatic sites and bone marrow metastasis in small cell lung cancer (SCLC), the worse the prognosis. Diagnosing the bone marrow invasion at the beginning of the therapy is important for determining of the prognosis and planning the treatment. Abnormalities of some blood parameters may help to estimate the extent of bone marrow invasion by cancer cells. In this retrospective review, the changes in routine laboratory tests that may indicate bone marrow invasion, the predictive values of these tests, and the prognostic importance of bone marrow invasion were evaluated in SCLC patients who were being followed up according to a protocol. One hundred and forty-four patients with SCLC were enrolled in this study. Retrospectively, it was evaluated that 25 (17.4%) of the patients had bone marrow metastasis. According to univariate analysis, there was a significant difference between hemoglobin, white blood cell count, platelet count, lactate dehydrogenase, alkaline phosphatase and uric acid of the patients with and without bone marrow involvement. Among the biochemical parameters, the elevated LDH and AP had the highest sensitivity and specificity as indicators of bone marrow invasion (0.80–0.82 and 0.84–0.78, respectively). The median overall survival of extensive-stage disease with and without bone marrow metastasis were 4.0 ± 1.0 months (95% CI 2.2–5.7) and 7.0 ± 1.2 months (95% CI 4.7–9.3), respectively (P = 0.03). Bone marrow metastasis was found to be an indicator of a bad prognosis. Bone marrow biopsy, that is an invasive procedure, can be performed on selected patients who have changes of routine laboratory tests suggesting bone marrow invasion.

The effect of medroxyprogesterone acetate (MPA) on the mitotic activity of bone marrow and testis during chemotherapy was investigated experimentally in an animal study. A total of 120 male Swiss albino mice were included in this study. Six groups were formed, each consisting of 20 mice. Low-dose MPA (LD-MPA) (15 mg/kg), high-dose MPA (HD-MPA) (100 mg/kg), LD-MPA plus cyclophosphamide (CP) (65 mg/kg), HD-MPA plus CP (65 mg/kg), and CP (65 mg/kg) were administered to the test groups and no drug was administered to the control group. Bone marrow samples and testis were examined for mitotic activity rate (MAR) on days 0, 18, 22, 26, and 30. In groups with regimens containing CP, MAR of hematopoietic cells in bone marrow was suppressed significantly (p 0.05). Mitotic activity rate of the testis cells was significantly suppressed in groups with regimens containing MPA (p

Carcinogenesis and tumor cell biology are very complex subjects. Recent findings on cancer stem cells may have a great impact on the understanding of the biology of malignancies and the development of future treatment approaches. Cancer stem cells are defined by their potential to self-renew and differentiate. Identification of cancer stem cells is possible by detecting expression of a certain combination of various cell surface markers and also by functional assays. The cancer stem cell concept was originally developed for hematological malignancies but is now becoming accepted for solid tumors as well. Emerging data indicates that cancer stem cells are responsible for the growth and spread of tumors. There is still a long way to go in characterizing cancer stem cells and understanding their role in carcinogenesis. Further studies should lead to a greater understanding of the biology of these cells with significant implications for diagnosis, treatment, and prevention of cancer. The recent studies regarding stem cell origin of various solid tumors will be discussed briefly in this review.

TO THE EDITOR: In the July 15, 2004, issue of the Journal of Clinical Oncology, Dahut et al showed that the addition of thalidomide to docetaxel resulted in an encouraging prostatespecific antigen decline and overall median survival rate in patients with metastatic androgen-independent prostate cancer. In this study, low-molecular-weight heparin (LMWH) was offered to patients in the combination arm for median 6 months, but not offered to patients in the control arm. Preclinical evidence suggests that angiogenesis is important for tumor progression in prostate cancer. LMWH inhibits angiogenesis, and this effect seems to be independent of the anticoagulant actions. In a recent randomized study, we tested the effect on patient mortality of a prophylactic dose of LMWH (dalteparin; 5,000 U/d subcutaneously) given in combination with chemotherapy versus chemotherapy alone in patients with small-cell lung cancer (42 patients per group). This trial demonstrated an improvement in overall survival for those patients randomly assigned to receive LMWH. In another recent randomized study, the FAMOUS (Fragmin Advanced Malignancy Outcome Study) Trial, 385 patients with advanced solid cancers were randomly assigned to receive a prophylactic dose of the dalteparin or placebo for up to 1 year. There was suggestion of a marked survival advantage for patients with a better prognosis receiving LMWH therapy. We think that LMWH could provide a therapeutic and survival advantage for patients in the thalidomide arm in the Dahut et al study. To understand whether this survival advantage is depending on thalidomide, the authors should have used LMWH on the control arm as well.

OBJECTIVES The aim of this study was to determine the protective effect of carvedilol in anthracycline (ANT)-induced cardiomyopathy (CMP). BACKGROUND Despite its broad effectiveness, ANT therapy is associated with ANT-induced CMP. Recent animal studies and experimental observations showed that carvedilol prevented development of CMP due to chemotherapeutics. However, there is no placebo-controlled clinical trial concerning prophylactic carvedilol use in preventing ANT-induced CMP. METHODS Patients in whom ANT therapy was planned were randomized to administration of carvedilol or placebo. We enrolled 25 patients in carvedilol and control groups. In the carvedilol group, 12.5 mg once-daily oral carvedilol was given during 6 months. The patients were evaluated with echocardiography before and after chemotherapy. Left ventricular ejection fraction (EF) and systolic and diastolic diameters were calculated. RESULTS At the end of 6 months of follow-up, 1 patient in the carvedilol group and 4 in the control group had died. Control EF was below 50% in 1 patient in the carvedilol group and in 5 in the control group. The mean EF of the carvedilol group was similar at baseline and control echocardiography (70.5 vs. 69.7, respectively; p = 0.3), but in the control group the mean EF at control echocardiography was significantly lower (68.9 vs. 52.3; p < 0.001). Both systolic and diastolic diameters were significantly increased compared with basal measures in the control group. In Doppler study, whereas E velocities in the carvedilol group decreased, E velocities and E/A ratios were significantly reduced in the control group. CONCLUSIONS Prophylactic use of carvedilol in patients receiving ANT may protect both systolic and diastolic functions of the left ventricle.