Advancing Colorectal Cancer Diagnosis with AI-Powered Breathomics: Navigating Challenges and Future Directions.

Early detection of colorectal cancer is crucial for improving outcomes and reducing mortality. While there is strong evidence of effectiveness, currently adopted screening methods present several shortcomings which negatively impact the detection of early stage carcinogenesis, including low uptake due to patient discomfort. As a result, developing novel, non-invasive alternatives is an important research priority. Recent advancements in the field of breathomics, the study of breath composition and analysis, have paved the way for new avenues for non-invasive cancer detection and effective monitoring. Harnessing the utility of Volatile Organic Compounds in exhaled breath, breathomics has the potential to disrupt colorectal cancer screening practices. Our goal is to outline key research efforts in this area focusing on machine learning methods used for the analysis of breathomics data, highlight challenges involved in artificial intelligence application in this context, and suggest possible future directions which are currently considered within the framework of the European project ONCOSCREEN.

Genetic Predisposition to Male Breast Cancer: A Case Series.

BACKGROUND/AIM: Male breast cancer (MBC) is a very rare disorder affecting approximately 1 in 833 men. Genetic predisposition is one of the most important risk factors of MBC with BRCA2 being the most commonly mutated gene in males diagnosed with breast cancer. However, a large part of MBC heritability is still unexplained. This study sought to add to the data already available on the genetics of MBC. MATERIALS AND METHODS: Our study initially involved comprehensive analysis of BRCA1 and BRCA2, followed by analysis of 43 genes implicated in cancer predisposition in a series of 100 Greek patients diagnosed with MBC between 1995-2015. RESULTS: Pathogenic variants were identified in 13 patients, with BRCA2 being the most commonly affected gene, followed by BRCA1, RAD50, RAD51B, and MSH3. CONCLUSION: In agreement with previous reports, BRCA2 is the most important genetic factor of MBC predisposition, while the remaining known cancer predisposition genes are each very rarely involved, rendering conclusions as to their cumulative effect difficult to draw.

Characteristics and outcomes of cancer patients who develop pulmonary embolism: A cross-sectional study.

Pulmonary embolism (PE), along with deep vein thrombosis, are collectively known as venous thromboembolism (VTE). Predisposing factors for PE include post-operative conditions, pregnancy, cancer and an advanced age; of note, a number of genetic mutations have been found to be associated with an increased risk of PE. The association between cancer and VTE is well-established, and cancer patients present a higher risk of a thrombotic event compared to the general population. In addition, PE is a significant cause of morbidity and mortality among cancer patients. The aim of the present study was to illustrate the clinical characteristics, laboratory findings, radiology features and outcomes of cancer patients who developed PE, collected from an anticancer hospital. For this purpose, adult cancer patients diagnosed with PE by imaging with computed tomography pulmonary angiography were enrolled. The following data were recorded: Demographics, comorbidities, type of cancer, time interval between cancer diagnosis and PE occurrence, the type of therapy received and the presence of metastases, clinical signs and symptoms, predisposing factors for PE development, laboratory data, radiological findings, electrocardiography findings, and the type of therapy received for PE and outcomes in a follow-up period of 6 months. In total, 60 cancer patients were enrolled. The majority of the cancer patients were males. The most common type of cancer observed was lung cancer. The majority of cases of PE occurred within the first year from the time of cancer diagnosis, while the majority of patients had already developed metastases. In addition, the majority of cancer patients had received chemotherapy over the past month, while they were not receiving anticoagulants and had central obstruction. A large proportion of patients had asymptomatic PE. The in-hospital mortality rate was 13.3% and no relapse or mortality were observed during the follow-up period. The present study demonstrates that elevated levels of lactic acid and an increased platelet count, as well as low serum levels of carcinoembryonic antigen, albumin and D-dimer, may be potential biomarkers for asymptomatic PE among cancer patients.

mRNA expression of specific HER ligands and their association with clinical outcome in patients with metastatic breast cancer treated with trastuzumab.

Prognostic and predictive biomarkers are being studied for the diagnosis and treatment of breast cancer. The present study retrospectively assessed the mRNA expression of HER family receptor ligands and of other potential prognostic biomarkers and their association with time to progression (TTP), survival and clinicopathological characteristics in patients with metastatic breast cancer (MBC) treated with trastuzumab. A total of 145 tumour tissue samples were analysed. mRNA expression analysis of the transcripts of interest was performed and the association of these markers with selected clinicopathological parameters was examined. HER2 status was centrally re-evaluated. Only 67.6% of patients were truly HER2-positive according to the central HER2 re-evaluation. Heparin binding epidermal growth factor (EGF)-like growth factor, transforming growth factor ß1 (TGFB1) and thyroid hormone receptor α (THRA) mRNA expression was higher in HER2-positive patients (P=0.026, P<0.001 and P<0.001). Insulin-like growth factor binding protein 4 was correlated with retinoic acid receptor α, TGFB1 and THRA (rho=0.45, rho=0.60 and rho=0.45). In HER2-positive patients, high neuregulin 1 and high betacellulin were unfavourable factors for TTP [hazard ratio (HR) = 1.78, P=0.040 and HR=2.00, P=0.043, respectively]. In patients with de novo MBC, high EGF expression was associated with a non-significant prolongation of TTP (HR=0.52, P=0.080) and significantly longer survival (HR=0.40, P=0.020). The present study examined clinical and biological implications of specific genes and it was concluded that their expression has an impact on the outcome of trastuzumab-treated patients with MBC.

Melanoma and Sarcoidosis in Patients Receiving or Not Antineoplastic Therapy.

Sarcoidosis and sarcoid-like reactions have been associated with many solid tumors including malignant melanoma. There are reports of melanoma patients who develop sarcoidosis without having received any antineoplastic treatment, but there are also melanoma patients who have received immunotherapy or targeted therapy and, therefore, develop drug-associated sarcoidosis. Herein, we describe 2 cases of thoracic sarcoidosis which occurred in asymptomatic patients with known malignant melanoma. The first patient had metastatic disease, and she was under melanoma treatment with BRAF/MEK inhibitors at the time of sarcoidosis diagnosis. The second case involves a patient with early stage melanoma who had received no antineoplastic treatment. In both cases, the thoracic lesions were suspicious for metastatic involvement, and it was the biopsy which gave the diagnosis of granulomatous disease. Sarcoidosis induced by immune checkpoint or BRAF/MEK inhibitors seems to be more frequent in real-world studies than in large phase 3 melanoma trials. Sarcoidosis can mimic metastasis, predominately in mediastinum, representing a diagnostic pitfall. Therefore, biopsies must always be performed to exclude the metastatic spread before initiation of any antineoplastic treatment.

AGAPP: efficacy of first-line cisplatin, 5-fluorouracil with afatinib in inoperable gastric and gastroesophageal junction carcinomas. A Hellenic Cooperative Oncology Group study.

PURPOSE: Gastric cancer is the fifth most common neoplasm worldwide with high rates of mortality. Afatinib, a low molecular, irreversible potent inhibitor of ErbB trans-membrane receptor family, has shown promising results according to preclinical and phase I clinical trial data when combined with chemotherapy. We aimed at evaluating the safety and efficacy of the combination of cisplatin, 5FU with afatinib in molecularly unselected patients with advanced gastric cancer. METHODS: Patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma received first line combination therapy of cisplatin, 5FU and afatinib every 21 days, followed by afatinib maintenance monotherapy. The primary endpoint was the Objective Response Rate (ORR); secondary endpoints included Overall Survival (OS), Progression Free Survival (PFS) and the safety profile. Unplanned exploratory analysis of HER2 and tumor mutational profile was performed. RESULTS: Among 55 patients (ITT population) enrolled, 19 (34.5%) achieved an objective tumor response; stable disease was observed in 16 patients (29.1%) and progressive disease in 10 patients (18.2%). The ORR in the per protocol population (PP) was 42.9%. Within a median follow-up of 56 months, the median PFS and OS in the ITT population was 5.0 and 8.7 months, respectively. Seven of the 47 HER2 informative cases carried HER2 positive tumors while TP53, BRCA2 and SMAD4 were the most frequently mutated genes. The most common toxicities were neutrophil count and white blood cell decrease occurring in 56.4% of patients, followed by anemia (50.9%), hyperglycemia (40%), and diarrhea (38.2%). CONCLUSIONS: The combination of cisplatin/5FU with afatinib did not surpass the benchmarks of efficacy of the contemporary therapeutic regimens that are being applied for the treatment of patients with advanced gastric cancer. However, the observed efficacy and the improved safety profile support that our administration schedule may be further investigated to overcome toxicity problems when integrating afatinib to cytotoxic chemotherapy. CLINICAL TRIAL REGISTRATION: NCT01743365.

Real-world clinical outcome and toxicity data and economic aspects in patients with advanced breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy: the experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: We evaluated real-world clinical outcomes and toxicity data and assessed treatment-related costs in patients with advanced breast cancer who received treatment with cyclin-dependent kinase inhibitors (CDKi). PATIENTS AND METHODS: We conducted a prospective-retrospective analysis of patients with advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who received a CDKi, in combination with endocrine therapy, at any line of treatment. The primary endpoint was progression-free survival (PFS). Cost analysis was conducted from a public third-payer (National Organization for Healthcare Services Provision (EOPYY)) perspective, assessing only costs related to direct medical care, including drug therapy costs and adverse drug reaction (ADR)-related costs. RESULTS: From July 2015 to October 2019, 365 women received endocrine therapy combined with CDKi; median age was 61 years, postmenopausal 290 (80.6%) patients. CDKi were administered as first-line treatment in 149 (40.9%) patients, second-line treatment in 96 (26.4%) and third-line treatment and beyond in 119 (32.7%) patients. The most common adverse events were neutropenia, anaemia, thrombocytopenia and fatigue. Grade 3-4 adverse events occurred in 86 (23.6%) patients, whereas 8 (2.2%) patients permanently discontinued treatment due to toxicity. The median PFS for patients who received CDKi as first-line, second-line and third-line treatment and beyond was 18.7, 12 and 7.4 months, respectively. The median overall survival since the initiation of CDKi treatment was 29.9 months (95% CI: 23.0-not yet reached (NR)). The mean pharmaceutical therapy cost estimated per cycle was 2 724.12 € for each patient, whereas the main driver of the ADR-related costs was haematological adverse events. CONCLUSIONS: Treatment with CDKi was well tolerated, with a low drug discontinuation rate. Patients who received CDKi as first-line treatment had improved PFS and OS compared with second-line treatment and beyond. The main component of direct medical costs assessed in the cost analysis comprises CDKi pharmaceutical therapy costs. TRIAL REGISTRATION NUMBER: NCT04133207.

Phase 2 study of cabazitaxel as second-line treatment in patients with HER2-negative metastatic breast cancer previously treated with taxanes-a Hellenic Cooperative Oncology Group (HeCOG) Trial.

BACKGROUND: Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes. METHODS: The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR). RESULTS: Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2-4.4) and 15.2 months (95% CI 11.3-19.4), respectively. Regarding toxicity, grade 3-4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment. CONCLUSIONS: This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity.

Pathology of BRCA1- and BRCA2-associated Breast Cancers: Known and Less Known Connections.

INTRODUCTION: BRCA1/BRCA2 mutation carriers indefinitely comprise a distinct group of patients with breast cancer (BC), with their tumors displaying specific pathologic characteristics. Although these connections are known, they are not fully elucidated. We therefore sought to investigate the clinicopathologic characteristics and overall survival of Greek patients with BC carrying BRCA1/BRCA2 mutations. PATIENTS AND METHODS: Greek patients with BC diagnosed between 1999 and 2016, fulfilling the National Comprehensive Cancer Network criteria for genetic testing, were analyzed for BRCA1/BRCA2 mutations by Sanger sequencing or by a 94-gene panel. Medical records and pathology reports were retrospectively reviewed to retrieve patient and tumor baseline characteristics. Potential associations with mutation status were assessed using the Fisher exact, Pearson χ2, and Mann-Whitney tests. RESULTS: Of 2096 selected patients with BC, we identified 297 (14.2%) BRCA1 and 88 (4.2%) BRCA2 carriers. The mean age at BC diagnosis was 40 and 42.6 years, respectively (P = .02). Tumor histologic subtypes in BRCA1 and BRCA2 carriers were predominantly ductal (79%) followed by medullary (10%), and ductal (72%) followed by lobular (15%), respectively. A significantly higher percentage of BRCA2 tumors were human epidermal growth factor receptor 2-positive, compared with BRCA1 tumors (21.7% vs. 5.8%; P < .001). Second primary cancer diagnosis was more frequent in BRCA1 compared with BRCA2 mutation carriers (36.2% vs. 10.7%; P < .001), whereas there was no difference in 15-year overall survival (hazard ratio, 0.92; 95% confidence interval, 0.48-1.83; P = .804) between the 2 groups. CONCLUSIONS: These data confirm established observations in the pathology of BRCA-related tumors and provide further insight on the association of rare histologic entities with mutations in these genes, which can be clinically beneficial.

One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene.

BACKGROUND: Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations. METHODS: To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case-control analysis. RESULTS: Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively. CONCLUSION: Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial.

BACKGROUND: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients. METHODS: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF). RESULTS: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients versus 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity. CONCLUSIONS: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00911716.

Estrogen receptor beta increases sensitivity to enzalutamide in androgen receptor-positive triple-negative breast cancer.

PURPOSE: Androgen receptor (AR) is playing an important role in the progression of a subset of TNBC. We evaluated the impact of ERß expression along with anti-AR drugs in AR-positive TNBC. METHODS: ERß expression was examined in AR-positive TNBC cell line using MTT assay, scratch and Annexin V-FITC assay in the presence or absence of anti-androgens. Protein levels of involved molecules were assessed using Western blot. Receptors' localization was detected by immunofluorescence and their physical association was examined using proximity ligation assay (PLA), which enables the visualization of interacting proteins in fixed cells and tissues. RESULTS: Transient transfection of ERß in MDA-MB 453 AR-positive TNBC cell line significantly inhibited cell proliferation, metastatic potential and induced apoptosis. ERß expression reversed the aggravating role of AR in both indirect and direct ways. Indirectly, ERß decreased AR activation through the inhibition of PI3K/AKT signaling pathway. Directly, ERß formed heterodimers with AR in MDA-MB 453 cells and in human tissue samples impeding AR from forming homodimers. Enzalutamide is a more potent anti-androgen in AR + TNBC compared to bicalutamide. ERß expression increased the sensitivity of MDA-MB 453 cells to anti-androgens and especially to enzalutamide. The administration of enzalutamide enhanced AR:ERß heterodimers formation increasing the anti-tumor capacity of ERß. CONCLUSIONS: Collectively, our results provide evidence for a novel mechanism by which ERß exerts oncosuppressive effect in AR-positive TBNC through direct and indirect interactions with AR. Moreover, ERß expression may identify a new subset of TNBC that would respond more favorable to anti-androgens.

Aromatase Inhibitor-Associated Tendinopathy and Muscle Tendon Rupture: Report of Three Cases of This Exceedingly Rare Adverse Event.

Aromatase inhibitors (AIs) are a commonly used antihormonal therapy in the treatment of breast cancer in postmenopausal women, specifically in the treatment of hormone receptor-positive breast cancer. AI-associated tendinopathy and muscle tendon rupture is exceedingly rare. Until now, only one case with AI-associated severe tendinopathy has been reported in the medical literature, and there are no recorded cases of AI-associated muscle tendon rapture. We report three cases of postmenopausal women with hormone receptor-positive breast cancer, who experienced tendinopathy or muscle tendon rupture under antihormonal treatment with letrozole. All of the three women were in the adjuvant setting, and the treatment of tendinopathy or tendon rupture consisted of AI discontinuation, initiation of corticosteroids, or surgical treatment. Diagnosis was made via MRI. Furthermore, in our cases, there were no signs of underlying systemic disease, there was no abnormal physical activity preceding the complaints, and there was no use of other drugs beside letrozole. AIs are one of the most commonly used drugs in antihormonal therapy for hormone receptor-positive breast cancer. In every case of a female patient with hormone receptor-positive breast cancer under treatment with AIs and arthralgia, an MRI should be performed in order to exclude the presence of tendinopathy or muscle tendon rupture.

Impact of timing of trastuzumab initiation on long-term outcome of patients with early-stage HER2-positive breast cancer: the "one thousand HER2 patients" project.

BACKGROUND: The optimal timing of (neo)adjuvant trastuzumab initiation with respect to chemotherapy and surgery remains undefined. METHODS: Retrospective analysis of a large institutional database of HER2-positive patients who received anti-HER2 therapy. We included all Stage I to III patients treated with trastuzumab with a minimum follow up of 3 years. The date of first breast biopsy was recorded as initial diagnosis. RESULTS: A total of 506 patients [adjuvant: 386 (76%)-neo-adjuvant: 120 (24%)] were included. The median time-to-first-trastuzumab (TFT) from diagnosis was 12 weeks (range 1.9-122.3). Median follow-up is 73.3 months (range 1.4-176.3). TFT was significantly shorter in the neo-adjuvant than in the adjuvant cohort (median: 4.4 vs. 14 weeks, p < 0.00001). Despite the neo-adjuvant cohort having significantly more node-positive patients (75 vs. 53%, p < 0.0001), DFS rate (neo-adjuvant: 12.5 vs. adjuvant: 18%, p = 0.094) was numerically superior in neo-adjuvant patients. A TFT ≤ 12 weeks was associated with significantly superior DFS and OS over TFT > 12 weeks. Early concomitant regimens were associated with superior DFS over delayed-concomitant and sequential regimens. CONCLUSIONS: Initiating trastuzumab more than 12 weeks from diagnosis has a negative impact on clinical outcome. Neo-adjuvant anti-HER2 therapy could be the optimal strategy to treat early stage HER2-positive breast cancer.

Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer.

PURPOSE: Male breast cancer (MBC) is a rare cancer entity, with mutations in BRCA1 and BRCA2 genes accounting for ~ 10% of patients. Multiple-gene sequencing has already entered clinical practice for female breast cancer, whereas the performance of panel testing in MBC has not been studied extensively. Therefore, the aim of this study was to evaluate the clinical utility of panel testing for MBC, by the largest gene panel used so far, through investigation of patients deriving from a population with known founder effects. METHODS: Genomic DNA from one hundred and two Greek MBC patients, unselected for age and family history, was used to prepare libraries which capture the entire coding regions of 94 cancer genes. RESULTS: Loss-of-function (LoF) mutations were found in 12.7% of the cases, distributed in six genes: BRCA2, ATM, BRCA1, CHEK2, PMS2, and FANCL. BRCA2 mutations were the most frequent, followed by ATM mutations, accounting for 6.9 and 2%, respectively, while mutations in other genes were detected in single cases. Age at diagnosis or family history was not predictive of mutation status. Beyond mutations in established breast cancer predisposing genes, LoF mutations in PMS2 and FANCL among MBC patients are reported here for the first time. CONCLUSIONS: Our findings, using the largest gene panel for MBC patients so far, indicate that BRCA testing should be the primary concern for MBC patients. Until sufficient evidence arises from larger studies, multiple-gene panels may be of limited benefit for MBC and their families, at least for MBC patients of specific descent.

A collecting duct carcinoma producing carcinoembryonic antigen and Ca-125 in a 29-year-old woman.

Collecting duct carcinoma is a rare renal malignant neoplasm, arising from the medullary collecting duct and accounting for less than 1% of renal cell carcinomas. It is more common in middle-aged men and is usually presented with hematuria, abdominal mass and back or flank pain. Its immunohistochemical analysis detects the expression of various markers, such as low and high molecular weight keratins, Ulex europaeus agglutinin-1, epithelial membrane antigen and peanut lectin. Here, we present a case of a 29-year-old woman with CDC presented with back pain and supraclavicular lymphadenopathy that produced carcinoembryonic antigen and CA-125.

Predictive biomarkers for dasatinib treatment in melanoma.

Dasatinib has anti-proliferative and anti-invasive effects in melanoma cell lines. However clinical trials have shown modest activity for dasatinib in metastatic melanoma. Although dasatinib targets SRC kinase, neither expression nor phosphorylation of SRC appears to predict response to dasatinib. Identification of predictive biomarkers for dasatinib may facilitate selection of melanoma patients who are more likely to respond to dasatinib. We correlated the anti-proliferative effects of dasatinib in 8 melanoma cell lines with expression of a previously identified 6-gene biomarker panel. We examined the relationship between response to dasatinib and expression of each gene at both the mRNA and protein level. Dasatinib inhibited growth in 3 of the 8 cell lines tested. mRNA expression of the panel of 6 biomarkers did not correlate with response, whilst elevated protein expression of ANXA1, CAV-1 and EphA2 correlated significantly with response to dasatinib in the panel of cell lines. Expression of ANXA1, CAV-1 and EphA2 were analysed in 124 melanoma samples by immunohistochemistry. ANXA1 protein was detected in 81 % (97/120) of tumours, CAV-1 in 44 % (54/122) of tumours and EphA2 in 74 % (90/121) of tumours. Thirty one % (35/113) of tumours tested expressed all three markers and 19 % (21/112) had moderate or strong expression of ANXA1, CAV-1 and EphA2. Seventeen percent (19/112) of melanoma samples were positive for SRC kinase expression, combined with high expression of ANXA1, CAV-1 and EphA2. This subgroup may represent a population of melanoma patients who would be more likely to derive clinical benefit from dasatinib treatment.

Coexistence of intracranial germ cell tumor and craniopharyngioma in an adolescent: case report and review of the literature.

PURPOSE: We present the case of a patient treated for intracranial germ cell tumor in which elements of craniopharyngioma were found in the residual tumor mass. FINDINGS: A 17 year old patient presented with a history of secondary amenorrhea. She deteriorated with headache and left eyelid drop, paresis of the abducent nerve and convergent strabismus (Parinaud syndrome). ß-HCG was 722mIU/ml and pregnancy was excluded. AFP was 6322 ng/ml. Brain CT scan showed a large endosellar tumor to the hypersellar region. There was left papillary atrophy. MRI confirmed a tumor to dorsum sellae. Primary germ cell intracranial tumor was diagnosed. Severe clinically evident pituitary failure developed with signs of increased intracranial pressure and brain edema as well as diabetes insipidus, while AFP increased to 15786,3ng/ml. Urgent treatment with combination chemotherapy including cisplatin etoposide and bleomycin (ΡEB) was administered for 4 courses. As a result her clinical condition improved and tumor markers dropped but nevertheless did not become normal. In addition CT scans revealed a remaining endocranial mass and therefore the patient was subjected to high-dose chemotherapy followed by autologous stemcell rescue which resulted in complete clinical and biochemical remission. Due to the persisting mass in the area, it was delivered radiotherapy. CONCLUSIONS: The above case is extremely rare in worldwide literature. Dysgerminoma may coexist with craniopharyngioma which in fact may be part of a germ cell tumor in the context of dysembryogenesis and benign "teratoma".

A case of paraneoplastic autoimmune pancreatitis: mini-review of paraneoplastic syndromes in breast cancer.

Breast cancer (BC), the most common type of cancer in women of the Western world, is often associated with paraneoplastic syndromes (PNS). Autoimmune pancreatitis is a recently recognized entity belonging to the spectrum of IgG4-related systemic diseases, which are characterized by target-organ plasmacytic infiltration and fibrosis. In this report we review PNS associated with BC and we present the first case of BC-associated autoimmune pancreatitis as well as its successful management with steroids and immunosuppressive BC-tailored chemotherapy.

Salvage chemotherapy with cisplatin and 5-fluorouracil in metastatic breast cancer. Particular activity against liver metastases.

BACKGROUND: The prognosis of patients with metastatic breast cancer who have failed to respond to at least two different chemotherapy regimens is poor. Such patients with metastatic disease to the liver have even worse prognosis. Cisplatin and 5-fluorouracil (5-FU) can be given in patients with impaired hepatic function but their combination has not been extensively studied in this setting. PATIENTS AND METHODS: We retrospectively collected data from our registry on patients with advanced metastatic breast cancer who received combination of cisplatin/5-FU. We sought to determine the toxicity, the response rate, the disease control rate and the survival of this combination. RESULTS: We identified 25 heavily pre-treated patients, out of which 19 (76%) had liver metastases. They had been treated before with a median of three lines of cytotoxic chemotherapy. The majority of patients had also received hormonal manipulation or trastuzumab. The median number of cisplatin/5-FU administered cycles, without toxic deaths or unexpected toxicities was four. The partial response (PR) rate was 32% and the disease control rate (DCR) was 68%. The time to progression was five months and the median survival after starting on cisplatin/5-FU was six months. CONCLUSION: The combination of cisplatin/5-FU is active and safe in heavily pre-treated patients with metastatic breast cancer even in the presence of liver metastases and jaundice.