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Abstract Background BRCA1 (B), ERCC1 (E), RRM1 (R) and TYMS (T) mRNA expression has been extensively studied with respect to NSCLC patient outcome upon various chemotherapy agents. However, these markers have not been introduced into clinical practice yet. One of the reasons seems to be lack of a standard approach for the classification of the reported high/low mRNA expression. The aim of this study was to determine the prognostic/predictive impact of B, E, R, T in routinely-treated NSCLC patients by taking into account the expression of these genes in the normal lung parenchyma. Methods B, E, R, T mRNA expression was examined in 276 NSCLC samples (real-time PCR). The normal range of B, E, R, T transcript levels was first determined in matched tumor – normal pairs and then applied to the entire tumor series. Four main chemotherapy categories were examined: taxanes-without-platinum (Tax); platinum-without-taxanes (Plat); taxanes/platinum doublets (Tax/Plat); and, all-other combinations. Results In comparison to remotely located normal lung parenchyma, B, E, R, T mRNA expression was generally increased in matched tumors, as well as in the entire tumor series. Therefore, tumors were classified as expressing normal or aberrant B, E, R, T mRNA. In general, no marker was associated with overall and progression free survival (OS, PFS). Upon multivariate analysis, aberrant intratumoral TYMS predicted for shorter PFS than normal TYMS in 1st line chemo-naïve treated patients (p = 0.012). In the same setting, specific interactions were observed for aberrant TYMS with Plat and Tax/Plat (p = 0.003 and p = 0.006, respectively). Corresponding patients had longer PFS in comparison to those treated with Tax (Plat: HR = 0.234, 95% CI:0.108-0.506, Wald’s p Conclusion Classifying intratumoral B, E, R, T mRNA expression in comparison to normal lung may facilitate standardization of these parameters for prospective studies. With this approach, NSCLC patients with aberrant intratumoral TYMS expression will probably fare better with platinum-based treatments.

Abstract Background Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer. Methods The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2 intravenously (IV), LV 200 mg/m2 and 5FU 450 mg/m2 bolus (Arm A) versus LV 200 mg/m2 and 5FU 500 mg/m2 IV bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years. Results The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms. Conclusions Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12610000148077

Abstract Background Metastatic involvement of the ovary from malignant melanoma is uncommon and presents a diagnostic challenge. Most cases are associated with disseminated disease and carry a dismal prognosis. Delayed ovarian recurrences from melanoma may mimic primary ovarian cancer and lead to aggressive cytoreductive procedures. Case presentation A case of malignant melanoma in a premenopausal patient is presented with late abdominal and ovarian metastatic spread, where ascitic fluid cytology led to an accurate preoperative diagnosis and the avoidance of unnecessary surgical procedures. Conclusion Secondary ovarian involvement is associated with a poor prognosis and efforts should be made for adequate palliation. Pathologic diagnosis with non-invasive procedures is crucial in order to avoid unnecessary surgery. Surgical interventions may be undertaken only in selected cases of limited metastatic disease, where complete resection is expected

What Is This Summary About?: This is a summary of a phase 2 clinical study called DeLLphi-301. The study looked at how effective and safe a medicine called tarlatamab was in participants with small cell lung cancer (SCLC). Participants previously received at least two other treatments for their SCLC. Tarlatamab is a new medicine that locates a protein called DLL3 on the cancer, which allows T cells to attack the cancer. T cells belong to the body's natural defense system known as the immune system. The DeLLphi-301 study separated participants into two groups to receive tarlatamab 10 mg or 100 mg to determine which dose best shrank SCLC with minimal side effects. All participants received a small first dose (1 mg tarlatamab) to decrease the risk of an immune system reaction called cytokine release syndrome (CRS). Tarlatamab was given through the participant's vein once every 2 weeks. This method of administration is known as intravenous (IV) infusion., What Were the Results of the Dellphi-301 Study?: In the group given 10 mg tarlatamab, 40% of participants responded to treatment (cancer shrank). In the group given 100 mg tarlatamab, 32% of participants responded to treatment (cancer shrank). After taking tarlatamab at either dose, 59% of participants lived for at least 6 months without their cancer growing or getting worse.The most common side effect was CRS, which occurred in 51% of participants in the group given 10 mg tarlatamab and 61% of participants in the group given 100 mg tarlatamab. Other common side effects were decreased appetite, fever, constipation, and anemia. Some participants had a type of immune reaction called immune effector cell-associated neurotoxicity syndrome (ICANS). A small number of participants (3%) stopped taking tarlatamab because of side effects related to tarlatamab., What Do the Results From the Dellphi-301 Study Mean?: The study found that tarlatamab given every 2 weeks shrank SCLC in participants with SCLC who received previous treatments. Participants given the 10 mg tarlatamab dose had fewer side effects than those given the 100 mg tarlatamab dose. Clinical Trial Registration: NCT05740566 (DeLLphi-304) (ClinicalTrials.gov).

Background: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer., Methods: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1., Results: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events., Conclusions: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.)., (Copyright © 2023 Massachusetts Medical Society.)

Background/aim: Real-world data on the EGFR mutational profile upon progression after first/second-generation EGFR-TKI treatment in patients with advanced non-small-cell lung cancer (NSCLC) and treatment strategies employed thereon are needed., Patients and Methods: This observational study was conducted in 23 hospital-based lung cancer Centers in Greece (protocol code: D133FR00126). Ninety-six eligible patients were consecutively enrolled between July-2017 and September-2019. Re-biopsy was performed in 18 of 79 patients who tested T790M-negative in liquid biopsy after progression in the first-line (1L) setting., Results: Of the study population, 21.9% tested T790M-positive, while 72.9% proceeded to 2L treatment, mainly comprising of a third-generation EGFR-TKI (48.6%), a switch to chemotherapy (30.0%), or chemo-immunotherapy (17.1%). The objective response rate (ORR) in 2L was 27.9% in T790M-negative and 50.0% in T790M-positive patients. Of evaluable patients, 67.2% experienced disease progression; median progression-free survival (PFS) was 5.7 and 10.0 months among T790M-negative and positive patients, respectively. Among T790M-negative patients, longer median PFS and post-progression survival were observed with third-generation EGFR-TKI treatment., Conclusion: Mutational status and treatment strategy were identified as critical determinants of clinical outcomes in the 2L-setting of EGFR-mutated NSCLC patients in real-world settings in Greece, with early diagnosis, appropriate molecular testing and high-efficacy treatments at first lines positively affecting ORR and PFS., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking., Methods: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models., Results: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%-95%) and mean tumor mutational burden was 7.06 (range: 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival ( p  = 0.051) and overall survival ( p  = 0.03)., Conclusions: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO., (© 2022 The Authors.)

Background/aim: Low expression of HER2 has defined a new "HER2-low" subgroup of breast cancer with distinct clinicopathological characteristics and both prognostic and predictive implications. The impact of low HER2 expression in metastatic hormone receptor-positive HER2-negative breast cancer treated with first-line CDK4/6 inhibitors has not been studied. Using real-world patient data, we aimed to identify prognostic differences in this patient population according to HER2 expression with immunohistochemistry., Patients and Methods: We retrospectively analyzed 191 patients from 5 Oncology Department databases in Thessaloniki, Greece, with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors in the first line, for whom detailed immunohistochemical HER2 data could be retrieved., Results: Median progression-free survival was numerically different among the different HER2 subgroups (3.35 years for HER2 0 tumors, 2.18 years for HER2 +1 tumors, 1.74 years for HER2 +2/ISH-negative tumors), but this difference was not statistically significant (p=0.477). Median PFS was statistically significantly longer in patients without visceral metastases (5.45 years) compared to patients with visceral metastases (1.61 years) (p=0.017). Median PFS was also statistically significantly longer in patients taking an aromatase inhibitor (2.99 years) compared to patients taking fulvestrant (1.33 years) (p<0.0001). There were no statistically significant differences in the other subgroups examined., Conclusion: CDK4/6 inhibitors are equally effective as first-line treatment agents, regardless of the exact level of HER2 expression. Numerical differences, however, do exist among the different HER2 subgroups, and merit further evaluation in future studies to better study this phenomenon., Competing Interests: GD declares no relevant conflict of interest. GK has received honoraria and consultancy fees from Amgen, Avaviosis, Astellas, AstraZeneca, Boehringer, BMS, Demo, Galenica, Ipsen, LEO Pharma, Merck, MSD, Novartis, Pfizer, Roche, and Sanofi. EL has received honoraria and consultancy fees from AstraZeneca, Genesis Pharma, Novartis, Pfizer, Roche, and Amgen. IK has received honoraria and consultancy fees from Boehringer, Sandoz, Amgen, Roche, AstraZeneca, Pfizer, Novartis, Sanofi, MSD, Merck and BMS. IB has received honoraria and consultancy fees from Sandoz, Amgen, Roche, AstraZeneca, Ipsen, Pfizer, Novartis, Sanofi, Genesis Pharma, MSD, LEO pharma, Merck, Servier and BMS and Research Funding from Boehringer, Regeneron, Eli Lilly, Pfizer, Novartis, BMS, MSD and Roche. KP has received honoraria and consultancy fees from MSD, Gilead, AstraZeneca, Novartis, Eli Lilly, Roche and GSK and Research Funding from Roche, Novartis, Daiichi Sankyo, Eli Lilly, AstraZeneca, BMS, Boehringer and EISAI., (Copyright 2022, International Institute of Anticancer Research.)

Background: During the last decade, significant improvement was made in systemic therapy of pancreatic adenocarcinoma (PAC). The impact of this progress in everyday clinical practice has not been fully described yet. The aim of the study was to investigate the pattern followed by Greek Medical Oncologists regarding the treatment of patients with PAC., Methods: This observational, noninterventional multicenter study recorded clinical data from the files of 200 active patients (alive and under treatment or follow-up) for a two-year period (November 2015 until November 2017) from 20 oncology centers around Greece., Results: In total, 51 (25.5%) patients underwent radical surgical resection of PAC, and 40 (78.4%) of them received adjuvant and 1 (2.0%) neoadjuvant chemotherapy. The median time to recurrence was 7.9 months, and median overall survival (OS), 20.2 months. First-line chemotherapy was administered to 193 (96.5%) patients. The majority of patients were treated with the combination of nab-paclitaxel-gemcitabine (NPG), 5-fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), or gemcitabine monotherapy. Of them, 39.5% responded to the treatment. Median OS and PFS were 14.1 months and 7.0 months, respectively. Second-line treatment was administered to 112 patients. The majority received NPG, FOLFIRINOX/capecitabine, oxaliplatin, irinotecan (CAPOXIRI), or 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (CAPOX). Median OS with second-line treatment was 8.6 months, and median PFS, 5.5 months. The most common chemotherapy sequences were NPG as first-line followed by FOLFIRINOX/CAPOXIRI as second-line, NPG followed by FOLFOX/CAPOX, NPG followed by other regimens, and FOLFIRINOX/CAPOXIRI followed by NPG., Conclusion: This study described the significant improvement in prognosis of PAC patients receiving palliative chemotherapy and the relatively high rate of receipt of second-line chemotherapy, according to real-world data. However, due to the nonrandomized nature of the study, any comparison between different chemotherapy regimens should be regarded with caution., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 George Papaxoinis et al.)

Objective: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but data on its use in the elderly are inconclusive., Methods: All consecutive HCC patients who were treated in our institution with sorafenib since its licensing were included in the analysis. Patients were divided into two groups: (A) up to 75 and (B) older than 75 years old. Our endpoints were overall survival (OS) and time to treatment failure (TTF) because of disease progression or toxicity. Safety parameters and the prognostic effect of HCC characteristics were also investigated., Results: Data from 190 patients (157 men), median age 66 (26-87) years, were studied (A=151 and B=39). No significant difference in OS and TTF was detected between the two groups [7.1 (5.5-8.7) vs. 10.4 (6.5-14.3) months, P=0.360 and 4.2 (2.3-6.2) vs. 5.6 (3.1-8.1) months, P=0.369, respectively]. Incidence of toxicities at all grades and dose reductions were comparable between groups A and B. In a multivariate setting, patients with Child-Pugh B score at baseline were associated with a higher risk of death (adjusted hazard ratio=2.17, 95% confidence interval:1.24-3.79, P=0.007) and treatment failure (adjusted hazard ratio=4.64, 95% confidence interval: 2.55-8.42, P=0.001) and had shorter OS and TTF compared with patients with a Child-Pugh A (P=0.004 and P<0.001, respectively)., Conclusion: Elderly patients with advanced HCC, when treated with sorafenib, have an equivalent clinical outcome with similar toxicity rates as their younger counterparts. Age alone should not be a discriminating factor for the management of advanced HCC with sorafenib.

Video-assisted thoracoscopic surgery (VATS) is a type of thoracic surgery performed using a small video camera that is introduced into the patient's chest via a scope. It is considered a minimally invasive technique where the surgeon is able to view the instruments that are being used along with the anatomy on which the surgeon is operating. The camera and instruments are inserted through separate holes in the chest wall also known as "ports", depending on the patient and problem there are surgeries with one port "uniport", two or three ports. These small ports have the advantage that fewer infections are observed. This allows for a faster recovery. Traditionally, thoracic surgery performed for diagnosis or treatment of chest conditions has required access to the chest through thoracotomy or sternotomy incisions. Vats minimally invasive technique has replaced in many cases thoracotomy or sternotomy. In our current review we will present this technique in detail.

Barotrauma is physical damage to body tissues caused by a difference in pressure between a gas space inside, or in contact with the body, and the surrounding fluid. This situation typically occurs when the organism is exposed to a significant change in ambient pressure, such as when a scuba diver, a free-diver or an airplane passenger ascends or descends, or during uncontrolled decompression of a pressure vessel, but it can also happen by a shock wave. Whales and dolphins are also vulnerable to barotrauma if exposed to rapid and excessive changes in diving pressures. In the current review we will focus on barotraumas from definition to treatment.

Lung cancer can be diagnosed with minimal interventional procedures such as: bronchoscopy, endobronchial ultrasound (EBUS), fine needle aspiration under CT guidance and esophageal ultrasound. In our current editorial we will provide a definition and current up to date information regarding fine needle aspiration under CT guidance. We will focus on pneumothorax and treatment methods.

The pleural cavity is the potential space between the two pleurae (visceral and parietal) of the lungs. The pleurae are serous membranes which fold back onto themselves to form a two-layered membranous structure. The thin space between the two pleural layers is known as the pleural cavity and normally contains a small amount of pleural fluid. There are two layers; the outer pleura (parietal pleura) is attached to the chest wall and the inner pleura (visceral pleura) covers the lungs and adjoining structures, via blood vessels, bronchi and nerves. The parietal pleurae are highly sensitive to pain, while the visceral pleura are not, due to its lack of sensory innervation. In the current review we will present the anatomy of the pleural space.

The pleural cavity is created between the 4(th) and 7(th) week of embryologic development. These embryonic components of visceral and parietal pleurae develop different anatomic characteristics with regard to vascular, lymphatic, and nervous supply. There are two layers: a superficial mesothelial cell layer facing the pleural space and an underlying connective tissue layer. The pleura might present inflammatory response and maintenance of the pleural fluid is observed. The latter function is especially important in the mechanical coupling of the lung and chest wall. Fluid is filtered into the pleural space according to the net hydrostatic oncotic pressure gradient. It flows downward along a vertical pressure gradient, presumably determined by hydrostatic pressure and resistance to viscous flow. There also may be a net movement of fluid from the costal pleura to the mediastinal and interlobar regions. In these areas, pleural fluid is resorbed primarily through lymphatic stomata on the parietal pleural surface. In the current review we will present the physiology of the pleural space in a step by step manner.

Summary: Improved diagnostic methods and medical therapies are necessary for early detection and treatment and an improved prognosis. It is thus vital to both examine and evaluate the role of the various existing proteins as biomarkers in carcinogenesis and to assess the contribution of these proteins in anti-cancer activity, for consideration in therapeutic strategies. It is essential to both examine and evaluate the role of the various existing proteins as biomarkers in carcinogenesis and to assess the contribution of these proteins in anti-cancer activity, for consideration in therapeutic strategies. The purpose of this review is twofold. Firstly, it is to evaluate recent data about which proteins can be utilized as biomarkers in carcinogenesis. The proteins reviewed include: CPTP, IL-6, CCN, and S100. Secondly, it is to evaluate the contribution of dietary proteins in cancer activity. Specifically, how whey protein, soy proteins and lectin, a phytochemical could be useful in cancer prevention and treatment., Recent Findings: Whey protein, present in dairy products, is an excellent source of the sulphur amino acid cysteine, the rate limiting substrate in glutathione synthesis. Notably, this protein survives digestion and has been shown to have anti-carcinogenic properties in animal studies. Lectins are phytochemicals present in plant foods, and have active components which alters cancer initiation, promotion and progression. Lectins have been characterized as a useful tool in biochemistry, cell biology, immunology and in diagnostic and therapeutic purposes in cancer research. Soy proteins contain various compounds, including isoflavones, protease inhibitors and protein kinase inhibitors, which have been proven effective in tumor growth inhibition. They have therefore, been greatly emphasized in cancer prevention and treatment. It has been proved that soy food consumption was associated with decreased risk of death and recurrence of breast cancer. CPTP is a recently discovered protein whose main role is to transport C1P, a pro-inflammatory molecule. The discovery of CPTP may shine a light on the mechanism of inflammatory diseases, and hopefully offer a potential target for therapeutic purposes in cancer research. Interleukin-6 is a multifunctional cytokine that affects the activity of cancer cells. It is involved in tumor growth, and elevated levels is associated with an increased risk of cancer. S100B is a well-established biomarker for malignant melanoma, and useful in assessing tumor load, stage and prognosis for patients with this disease. Other members of this family of proteins include S100A4, which has been associated with several malignancies and S100A2, which has been found to be decreased in some cancers. CCN are a group of regulatory proteins, located in the extracellular matrix (maricellular). They are involved in cellular adhesion, mitogenesis, chemotaxis, cell survival, and wound healing. CCN proteins are also able to modulate the signals of several proteins, which may also influence skeletal development and angiogenesis. Many of the functions of these proteins are thus also related to tumor growth. Furthermore, CCN interacts with estrogen in the development of cancer, and is implicated in some breast and ovarian cancers.

Background: Metronomic chemotherapy targets the inhibition of tumor growth primarily through antiangiogenic mechanisms. The aim of the present study was to investigate the antiangiogenic properties of weekly metronomic docetaxel administration in patients with metastatic breast cancer., Patients and Methods: In total, 157 patients with metastatic breast cancer received docetaxel at 35 mg/m(2) on a weekly basis as first-line treatment. Blood samples were collected before and during treatment. Plasma protein levels and peripheral blood mRNA expression of human epidermal growth factor-2 (HER2), interleukin-8 (IL8) and transforming growth factor beta-1 (TGF-β1) were measured by enzyme-linked immunosorbent assays (ELISA) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively in 127 patients and 39 healthy controls., Results: Sixty-one patients (38%) achieved an objective response (4% complete and 33% partial responses), 52 (33%) had stable disease, and in 27 patients (17%) the disease progressed. At a median follow-up of 33.5 months, 118 patients (74%) demonstrated disease progression and 94 (59%) had died. The median overall survival (OS) was 27.7 months, while the median progression-free survival (PFS) was 8.8 months. Median baseline plasma HER2 protein levels were significantly higher in patients than in controls (Mann-Whitney test, p=0.033). In addition, the median relative quantification (RQ) values for blood IL8 mRNA were significantly lower in patients (p<0.001) compared to healthy controls, while the median RQ values for TGF-β1 mRNA were significantly higher (p<0.001). Furthermore, plasma HER2 protein levels (Wilcoxon signed ranked test, p<0.001), as well as blood IL8 mRNA (p=0.026) and TGF-β1 mRNA levels (p=0.016) decreased significantly upon treatment. Univariate Cox regression analysis showed that high baseline plasma protein levels of IL8 were of adverse prognostic significance for OS (Wald's p=0.031), while high blood HER2 mRNA levels were marginally associated with longer OS (p=0.060). In multivariate analysis, plasma IL8 protein lost its prognostic significance, while high blood HER2 mRNA levels were associated with significantly improved OS (Wald's p=0.022)., Conclusion: Our study demonstrated a potential in vivo antiangiogenic activity of weekly docetaxel. Some interesting observations were made regarding the prognostic role of baseline plasma IL8 protein levels and blood HER2 mRNA levels, however, further research is required in order to validate these findings in larger cohorts, and to fully understand the angiogenic processes and optimize treatment strategies.

Primary cutaneous plasmacytoma is defined as monoclonal proliferation of plasma cells that arises primarily in the skin without evidence of systemic disease. We present an extremely rare case of a young adult diagnosed with solitary plasmacytoma. A 20-year-old woman presented with a pruritic erythematosquamous indurated plaque on the inner aspect of her right thigh. She had undergone a biopsy 5 years ago, and under the diagnosis of Nekam disease, she was treated with topical steroids followed by intralesional injections of triamcinolone acetonide. A new skin biopsy revealed infiltration of the epidermis by small T lymphocytes while plasma cell accumulations were found in the dermis. Immunostains for light and heavy chains [kappa, lambda, immunoglobulin (Ig) G, IgA, and IgM] demonstrated IgG/κ monoclonality of the plasma cells. On molecular analysis, T-cell receptor and immunoglobulin heavy chain rearrangements were polyclonal. Serum protein electrophoresis, immunofixation, and quantitative assessment of serum Igs were normal. Bone marrow biopsy, skeletal survey, and body computed tomography scan were unremarkable. A diagnosis of primary solitary cutaneous plasmacytoma was made. The lesion was removed surgically, and the patient remains in remission up to now. Primary cutaneous plasmacytoma represents only 2%-4% of extramedullary plasmacytomas. The rarity and the nonspecific presentation of cutaneous plasmacytomas does not allow a definite clinical diagnosis. Only histopathology reveals the typical pattern of a dense monomorphic dermal plasmacytic infiltrate, whereas immunohistochemistry shows monoclonality of the neoplastic cells.

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.

Unlabelled: Obesity in childhood increases the risk for early adult cardiovascular disease. However, the underlying mechanism is not fully known. The aims of this study were to measure levels of prothrombotic factors and examine their possible association with obesity and insulin resistance in obese children and adolescents. A total of 313 obese children and adolescents were recruited. In a cross-sectional design, we measured anthropometric parameters, plasminogen activator inhibitor-1-antigen (PAI-1-Ag), von Willebrand factor-antigen (vWF-Ag), fibrinogen (FB), lipids, fasting glucose, and insulin (FI) levels. Insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA-IR) index. Boys presented significantly higher PAI-1-Ag levels than girls (82.6 vs. 71.3 ng/ml, p = 0.01). Higher levels of PAI-1-Ag (96.8 vs. 69 ng/ml, p < 0.001), vWF-Ag (123.5 vs. 107.6%, p = 0.004) but not FB (353.1 vs. 337.6 mg/dl, p = 0.137) were found in insulin-resistant (IR) participants after adjusted for age, gender, and pubertal stage. IR patients were at 2.98 (CI: 1.084-8.193) and 4.86 (CI: 1.119-15.606) times greater risk for high PAI-1-Ag and vWF-Ag levels, respectively. All three prothrombotic factors were positively correlated with body mass index (BMI) and FI levels (p < 0.05), but only PAI-1-Ag and vWF-Ag were significantly correlated with HOMA-IR index (p ≤ 0.001). After adjustment for confounding factors, both BMI and HOMA-IR indices remained significantly associated with PAI-1-Ag (r₂ = 0.225, p < 0.001) and vWF-Ag levels (r₂ =0.077, p = 0.003)., Conclusion: This study shows that obesity in youngsters, when accompanied with insulin resistance, is associated with at least threefold increased risk for elevated levels of prothrombotic factors, contributing to the early development of atherothrombosis. This impaired prothrombotic state may partially explain the increased risk for developing cardiovascular disease later in adulthood.

Background: Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer., Methods: The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2 intravenously (i.v.), LV 200 mg/m2 and 5FU 450 mg/m2 bolus (Arm A) versus LV 200 mg/m2 and 5FU 500 mg/m2 i.v. bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years., Results: The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms., Conclusions: Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12610000148077.

Deletions of the long arm of chromosome 5 [del(5q)] are frequent chromosome aberrations with known prognosis in myelodysplastic syndromes and acute myeloid leukemia (AML). However, in chronic lymphocytic leukemia (CLL), they are rare and have been reported only as karyotypic results without known prognosis. In the present study, we report a novel conventional and molecular cytogenetic study of two CLL patients carrying interstitial del(5q) in order to contribute to the identification of rare recurrent aberrations and their prognostic impact in CLL. Karyotypic and fluorescence in situ hybridization analysis that used probes for the most common aberrations of CLL demonstrated that del(5q) was the sole chromosome abnormality in both patients at the time of diagnosis. None of these patients had a history of exposure to chemotherapy or radiotherapy. Both patients had disease that was still staged as Binet A at 28 and 18 months after diagnosis, respectively, without receiving any therapy because of their good clinical condition. Therefore, it could be suggested that del(5q) may not be associated with an adverse prognosis in CLL and is not related with therapy-induced chromosome changes. Further studies are required to elucidate the prognostic value of these deletions in more CLL patients, which could be advisable for prognostic and therapeutic purposes, as well as to identify candidate genes that may potentially play a role in the pathogenesis of CLL., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Introduction: The present case-control study was designed in order to investigate the association between plasma protein Z (PZ) levels, the intron F G79A polymorphism and unexplained pregnancy loss., Materials and Methods: 51 women with at least two consecutive or three non-consecutive fetal losses between the 8th and 12th week of gestation and 47 apparently healthy parous women of reproductive age with no history of pregnancy loss (controls) were enrolled. Allele frequencies of the PZ intron F G79A polymorphism and PZ levels were measured., Results: PZ levels (mg/L) were significantly lower in cases (mean +/- S.D. 1.28 +/- 0.56) than controls (1.97 +/- 0.76, p < 0.001) and in carriers of the A allele (1.46 +/- 0.62), compared to GG homozygous subjects (1.72 +/- 0.81, p = 0.044). A higher proportion of cases (41.2%) were PZ-deficient (<1 mg/L), compared to controls (10.6%, p = 0.001). No significant difference in the frequency of at least one A allele carriers was observed between cases (39.2%) and controls (40.4%)., Conclusion(s): It is possible that low PZ levels are a novel risk factor for unexplained recurrent miscarriage or fetal death. The presence of the F 79A allele is associated with significantly lower PZ levels, but, in the present study, was unrelated to unexplained early pregnancy loss.

Background: Metastatic involvement of the ovary from malignant melanoma is uncommon and presents a diagnostic challenge. Most cases are associated with disseminated disease and carry a dismal prognosis. Delayed ovarian recurrences from melanoma may mimic primary ovarian cancer and lead to aggressive cytoreductive procedures., Case Presentation: A case of malignant melanoma in a premenopausal patient is presented with late abdominal and ovarian metastatic spread, where ascitic fluid cytology led to an accurate preoperative diagnosis and the avoidance of unnecessary surgical procedures., Conclusion: Secondary ovarian involvement is associated with a poor prognosis and efforts should be made for adequate palliation. Pathologic diagnosis with non-invasive procedures is crucial in order to avoid unnecessary surgery. Surgical interventions may be undertaken only in selected cases of limited metastatic disease, where complete resection is expected.

In this report we describe a patient suffering from chronic myeloid leukemia (CML), who was treated for 4.5 years with imatinib and developed pneumonia caused by two Candida species, i.e., C. krusei and C. glabrata. The patient was in complete hematologic remission and molecular analyses did not display the presence of TLR2-R752Q, TLR4-D299G and TLR4-T399I polymorphisms that may predispose individuals to fungal infections. This case report indicates that in some patients, as previously observed, the long-term administration of targeted therapy might affect immunity and predispose patients to opportunistic and life-threatening fungal infections.

Recently, the acquired mutation JAK2-V617F has been described in the majority of patients with myeloproliferative disorders (MPDs). In this study we evaluated its clinical and laboratory correlates in 166 patients with MPDs. The mutation was detected by allele-specific PCR in 119 patients: 81.4% (35/43) of those with polycythemia vera, 69.1% (77/111) of those with essential thrombocythemia and 58.1% (7/12) of those with idiopathic myelofibrosis. The patients carrying the mutation were older (p=0.02) and displayed higher levels of Ht (p<0.01) and Hb (<0.01) and lower erythropoietin levels (p<0.01). Moreover, mutation-positive patients displayed a higher probability of having leucocytosis, splenomegaly and thrombotic events (three-fold, two-fold and two-fold, respectively) than mutation-negative patients. These correlations imply that the JAK2-V617F mutation may be useful for the classification and the management of patients with MPDs.