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Objective: Lung cancer is an uncommon diagnosis during pregnancy. The combination of smoking in young women, increased maternal age during pregnancy, and increasing incidence of lung cancer worldwide may cause an increase of pregnancy associated lung cancer. The aim of this study was to describe all cases of lung cancer during pregnancy, registered in the international Cancer in Pregnancy registration study (CIP study; www.cancerinpregnancy.org). Materials and methods: We present nine cases, all advanced lung cancer during the course of pregnancy. Collected data included demographic features of the study patients, cancer treatment, pregnancy outcome as well as maternal and fetal outcomes. Results and conclusion: Nine pregnant patients from 4 European centres with a median age of 33 years old (range, 26-42) were included. The median gestational age at diagnosis was 17 weeks (range, 6-28). All patients presented with metastatic disease including bone, lung, brain, spinal cord, pleura, lymph nodes, adrenal and liver. Histopathology was compatible with adenocarcinoma in 4 patients, non-small cell lung cancer with unidentified subtype in 2 patients and squamous-cell, large-cell and a poorly differentiated carcinoma in 3 patients, respectively. Eight patients were treated with systemic therapy, five of them during gestation. No responses were seen. The maternal postpartum outcome was poor with less than one year survival following delivery. One patient experienced a spontaneous abortion and three pregnancies were terminated. Five infants were all born premature due to poor maternal status by cesarean section, with a median gestational age of 30 weeks (range 26-33). To summarize, lung cancer in pregnancy has a dismal maternal outcome in our series. We add nine new cases and discuss both therapeutic and prognostic results. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Background: Therapeutic approach for patients with metastatic breast cancer (MBC) is still controversial. This study was conducted to assess the efficacy and safety of bevacizumab in combination with docetaxel plus capecitabine as first-line treatment for MBC. The feasibility of bevacizumab maintenance therapy in this setting was also evaluated. Patients and methods: In this single-arm, multicenter phase II study, patients received bevacizumab 15 mg/kg and docetaxel 60 mg/m2 on day 1, plus capecitabine 900 mg/m2 twice daily on days 1-14 every 21 days. Treatment was administered for up to 6 cycles, then bevacizumab continued until progressive disease. The primary end point was progression-free survival (PFS); secondary end points were tumor response rate, overall survival, and toxicity. Results: Seventy-nine eligible patients were treated with bevacizumab in combination with docetaxel plus capecitabine. The overall response rate was 61 %, with a complete response rate of 8 % and a median duration of response of 10 months. At a median follow-up of 28 months, the median PFS was 11 months. Fifty-two (65 %) patients received bevacizumab maintenance therapy for a median duration of 7 months (range 1 to 33+). Neutropenia was the most common grade 3-4 toxicity (28.1 % of patients), and two fatal adverse events occurred (septic shock and gastrointestinal perforation). Conclusions: Bevacizumab in combination with docetaxel and capecitabine demonstrates significant activity and quite acceptable toxicity profile as first-line treatment of MBC. Subsequent maintenance therapy with bevacizumab is feasible for a long period of stable disease. Results deserve confirmation. © 2013 Springer-Verlag Berlin Heidelberg.

The prognosis of patients affected by metastatic renal cell carcinoma (mRCC) has improved markedly with targeted therapies. Unfortunately, 20-25% of the patients are refractory to treatment at the first response assessment and most patients will acquire drug resistance during the treatment. Moreover, current data on the clinical activity of targeted agents in poor risk or non-clear-cell mRCC patients are inconclusive because of the absence of prospective trials. Therefore, there are still several patients in need of new therapeutic approaches to improve clinical outcomes. Kidney cancer is historically considered resistant to chemotherapy on the basis that the results of phase II trials have not always been promising. We carried out a systematic review of both monochemotherapy and polychemotherapy alone or combined with immunotherapy or targeted agents in mRCC to define the state of the art and to evaluate further clinical research fields. All retrospectives, phase I/dose finding, phase II and phase III studies on chemotherapy in mRCC, published in the literature from January 2003 to November 2012, with at least 20 patients enrolled, were evaluated. Although the results of clinical trials have often been disappointing, in selected cases of mRCC, chemotherapy may have a promising antitumor activity, particularly when there are sarcomatoid differentiation features, or in highly progressive disease where the combination of doxorubicine plus gemcitabine or capecitabine has yielded interesting results. Chemotherapy may play a role in mRCC, whereas targeted agents and immunotherapy have not yielded durable and satisfactory results; further studies are needed. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

SummaryCancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6− progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target.

e14086 Background: Other than the well-known EGFR pathway activation via the Ras-Raf-MAP-kinase, a possible role of other potential biomarkers could be relevant in determining resistance to anti-EGFR treatment, such as the protein-serine/threonine kinase Akt. We tried to assess the role of Akt and MAPK expression in metastatic colorectal cancer patients and their relationship with outcome for patients receiving Irinotecan-Cetuximab. Methods: Eligible patients were metastatic colorectal cancer patients treated in 2nd or 3rd line setting with a irinotecan-cetuximab based regimen. Patients were tested for K-ras status and subsequently assessed by immunoistochemistry for pAkt and MAPK expression, both in primary tumours and metastases whenever sufficient tissue was available. The role of pAkt and MAPK expression was evaluated for K-ras wild type patients for different likelihood of response, overall survival and progression free survival. Response was evaluated by RECIST criteria. Survival analysis was performed via Kaplan-Meier method. Results: In metastases pAkt correlated with RR (9% vs. 58%, p=0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001) and pMAPK correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p=0.0004). At multivariate analysis pAkt and pMAPK in metastases were able to independently predict PFS. pAkt in metastases independently correlated with RR as well. Conclusions: pAkt and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAkt and pMAPK metastases expression targeting these factors may be crucial.

Background: Epidermal growth factor receptor (EGFR) promoter methylation may be responsible for the loss of EGFR expression in neoplastic cells. The primary aim of our study was to verify a possible correlation between EGFR gene promoter methylation and clinical outcome in metastatic colorectal cancer patients receiving chemotherapy with irinotecan and cetuximab. Methods: Colorectal samples from patients treated with irinotecan–cetuximab were analysed for EGFR promoter methylation and EGFR immunohistochemistry. Results: Fifty-two patients were analysed. Thirty patients (58%) showed EGFR promoter hypermethylation. In EGFR promoter methylated and EGFR promoter unmethylated patients, we observed a partial response in 3 (10%) and 13 (59%) patients, respectively (P=0.03), progressive disease was obtained in 19 (63%) and 2 (9%) patients, respectively, with EGFR promoter methylated and EGFR promoter unmethylated tumours (P=0.0001). Median progression-free survival was 2.4 months in patients showing EGFR promoter methylated tumours and 7.4 months for those who had EGFR promoter unmethylated tumours (P

Aims: Patients with metastatic colorectal carcinoma (mCRC) carrying activating mutations of the KRAS gene do not benefit from treatment with anti-EGF receptor monoclonal antibodies. Therefore, KRAS mutation testing of mCRC patients is mandatory in the clinical setting to aid in the choice of appropriate therapy. Materials & methods: We developed a cost-effective approach for the determination of KRAS mutations in codons 12 and 13 in clinical practice based on a sensitive PCR/sequencing technique and the commercially available real-time PCR-based Therascreen® kit (DxS Ltd). Results & conclusion: The PCR/sequencing test was able to detect 10% mutant DNA in a background of wild-type DNA. By using this assay, we determined the mutational status of KRAS in 527 out of 540 (97.6%) formalin-fixed paraffin-embedded tissues from mCRC patients. PCR/sequencing was not conclusive in 13 cases, in which low-intensity peaks suggestive of potential mutations were identified. The DxS assay, which showed a sensitivity of 1%, identified mutations in 11 out of 13 inconclusive cases. Interestingly, five of these 11 cases showed high levels of DNA fragmentation. No significant difference was found in the ability of PCR/sequencing and DxS to identify KRAS mutations within 160 cases with more than 30% tumor cells. However, in 24 samples with less than 30% tumor cells, DxS showed an higher sensitivity. In conclusion, our findings suggest that PCR/sequencing can be used for mutational analysis of the majority of tumor samples that have more than 30% tumor cell content, whereas more sensitive and expensive tests should be reserved for inconclusive cases and for samples with a low amount of tumor cells.

Purpose The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. Patients and Methods Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. Results The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. Conclusion The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

The skeleton is the most common organ for metastasis from solid tumours. Bone metastases pose significant diagnostic and clinical challenges and represent an important cause of cancer-related morbidity. Without appropriate bone-directed therapy, many patients will be at high risk for potentially debilitating skeletal-related events (SREs), such as pain, bone fractures, neurologic deficits and hypercalcemia, severely impacting on the patient's quality of life. Because of their high incidence, bone metastases impose significant demands on health care resources. The optimal management of skeletal metastases depends on the underlying biology of the disease, the extent of bone involvement, the presence and severity of symptoms, the availability of effective systemic therapies and life expectancy of the patient. This article discusses clinical issues concerning diagnosis and available treatment approaches based on the presentation of skeletal involvement. Emphasis is placed on the role of external beam-radiotherapy as a local mode of treatment for palliation of bone pain, decompression of epidural compression and as potential ablative approach through high-dose image-guided irradiation (IGRT) in patients presenting with oligometastatic disease.

Purpose: The purpose of our study was to retrospectively evaluate the feasibility, toxicity and impact on overall (OS) and disease-free (DFS) survival of intra-arterial liver perfusion with mitomycin-C (MMC) [hypoxic liver perfusion with MMC (HLPM)] in patients with multifocal liver metastases or with unresectable primary liver tumours. Materials and methods: Forty-two patients underwent 56 intra-arterial liver infusions with MMC between June 2001 and May 2009. The patients presented specific characteristics, i.e. they were all refractory to locoregional (LR) and/or systemic treatments. HLPM consists of selective catheterisation of the common hepatic artery, permanent occlusion of the gastroduodenal artery at its origin using metal coils, an inflated balloon catheter placement at the origin of the proper hepatic artery to block blood flow and induce hypoxia for around 10 min, MMC infusion and vascular-bed occlusion through injection of an absorbable haemostatic agent. During the procedure, the patients received anaesthesiological monitoring. Biochemical and morphological responses were evaluated, as were haematological, hepatic and systemic toxicity. Results: Patients were hospitalised for 10 days on average (range 7-15). Side effects were liver toxicity in all cases, acute pancreatitis in one case and liver failure in one case. Computed tomography performed at 30 days documented a partial response (PR) in 29%, stable disease (SD) in 45% and progressive disease (PD) in 26% of patients. The response lasted 4 months on average (range 3-6). Mean overall survival (OS) was 20 months for all patients, reaching 30 months in those with colorectal carcinoma. Conclusions: The procedure is feasible, and treatmentrelated toxicity and mortality rates are acceptable. It may be considered a palliative treatment option in patients with advanced liver disease in centres with adequately experienced medical teams. © 2011 Springer-Verlag Italia.

Background: Psychological studies have documented the presence of a self-punishment profile in cancer patients. Recent immuno-oncological studies have shown that within the group of CD4+ cells, which play a fundamental role in the generation of anticancer immunity, there is a subtype of cells that in contrast mediates the suppression of the anticancer immunity, the so-called T-regulatory cells (T-reg), which may be identified as CD4 +CD25+ cells. Patients and Methods: On this basis, we performed a psychoncological study to evaluate CD4+CD25+ cell numbers in relation to the response to Rorschach's test in a group of 30 cancer patients suffering from the most frequent tumor histotypes. Results: Normal values obtained in our laboratory (95% confidence limits) of T-reg lymphocytes and CD4+/CD4+CD25+ were 4mm3, respectively. The psychological profile of self-punishment was found in 18/30 patients (60%). The percentage of patients with abnormally high CD4+CD25+ values observed in the group with self-punishment was significantly higher than that found in patients without self punishment (11/18 vs. 3/12 (25%), p

Lung cancer is the leading cause of cancer-related mortality. It is categorized into two histological groups that have distinct clinical behaviors, the nonsmall cell lung cancers (NSCLC) and the small cell lung cancer (SCLC). When identified at an early stage, NSCLC is treated by surgical resection. However, patients who undergo surgical resection still have a relative low survival rate, primarily for tumor recurrence. Unfortunately, advances in cytotoxic therapy have reached a plateau and new approaches to treatment are needed together with new and better parameters for more accurate prediction of the outcome and more precise indication of the efficacy of the treatment. Several in vitro studies have examined the role of Clusterin (CLU) in carcinogenesis, lung cancer progression, and response to chemo- and radiotherapy. Studies performed in lung cancer cell lines and animal models showed that CLU is upregulated after exposure to chemo- and radiotherapy. A potential role proposed for the protein is cytoprotective. In vitro, CLU silencing by antisense oligonucleotides (ASO) and small-interfering RNAs (siRNA) directed against CLU mRNA in CLU-rich lung cancer cell lines sensitized cells to chemotherapy and radiotherapy and decreased their metastatic potential. In vivo, a recent work analyzed the prognostic role of CLU in NSCLC, showing that CLU-positive patients with lung cancer had a better overall survival and disease-free survival than those with CLU-negative tumors. These data are contradictory to the promising in vitro results. From the results of these studies we may hypothesize that in early-stage lung cancers CLU represents a positive biomarker correlating with better overall survival. In advanced patients, already treated with chemo- and radiotherapy, the induction of CLU may confer resistance to the treatments. However, many studies are needed to better understand the role of CLU in early-stage and advanced lung cancers with the aim to discriminate patients and specific local conditions that could benefit for a CLU knocking down treatment.

The urokinase-type plasminogen activator receptor (uPAR) plays a central role in sustaining the malignant phenotype and promoting tumor metastasis. The Ser88-Arg-Ser-Arg-Tyr92 is the minimum chemotactic sequence of uPAR required to induce the same intracellular signaling as its ligand uPA. Here, we describe the generation of new peptide inhibitors of cell migration and invasion derived from SRSRY by a drug design approach. Ac-Arg-Glu-Arg-Phe-NH2 (i.e., RERF), which adopts a turned structure in solution, was selected for its ability to potently prevent SRSRY-directed cell migration. Fluorescein-RERF associates with very high affinity to RBL-2H3 rat basophilic leukemia cells expressing the human formyl peptide receptor (FPR). Accordingly, femtomolar concentrations of RERF prevent agonist-dependent internalization of FPR and inhibit N-formyl-Met-Leu-Phe–dependent migration in a dose-dependent manner. In the absence of FPR, fluorescein-RERF binds to cell surface at picomolar concentrations in an αv integrin–dependent manner. The involvement of vitronectin receptor is further supported by the findings that 100 pmol/L RERF selectively inhibits vitronectin-dependent RBL-2H3 cell migration and prevents SRSRY-triggered uPAR/αv association. Furthermore, RERF reduces the speed of wound closure and the extent of Matrigel invasion by human fibrosarcoma HT1080 cells without affecting cell proliferation. Finally, a 3- to 5-fold reduction of lung metastasis number and size in nude mice following i.v. injection of green fluorescent protein–expressing HT1080 cells in the presence of 3.32 mg/kg RERF is observed. Our findings indicate that RERF effectively prevents malignant cell invasion in vivo with no signs of toxicity and may represent a promising prototype drug for anticancer therapy. [Mol Cancer Ther 2009;8(9):2708–17]

Background: A retrospective analysis of the results and relapse pattern was evaluated in 34 patients with Ewing's family bone tumors (EFBT) treated at Rizzoli Institute with neoadjuvant chemotherapy between 1983 and 2003. Objectives: The aim of the study was to evaluate treatment strategy and compare our results with those obtained in other studies. Methods: Local treatment in these patients was radiotherapy alone in 4 cases, surgery alone in 13 and surgery followed by radiotherapy in 17. Results: Five-year event-free survival (EFS) was 44%, no different from that observed in another 558 patients with EFBT located in other sites treated in the same period with neoadjuvant chemotherapy protocols. Eighteen patients had a systemic relapse, followed by local relapse in two and one patient had a local relapse alone. EFS was significantly correlated to the time interval between onset symptoms and beginning of treatment and, in operated patients to histologic response to preoperative treatment. Conclusions: We conclude that EFBT of the ribs, when treated with neoadjuvant chemotherapy, have an outcome similar to that of patients with EFBT located in other sites. © 2009 Wiley-Liss, Inc.

BACKGROUND: The optimal treatment for synovial sarcoma remains controversial. Treatment, outcome, and prognostic factors in patients treated in a single institution were examined. METHODS: Synovial sarcoma patients who underwent surgery at the Rizzoli Institute between 1976 and 2006 were identified and analyzed. RESULTS: Characteristics of the 250 patients (128 female; 122 male) included: median age, 37 years (range, 7-83 years); 177 (71%) with tumors in the lower extremity, 40 (16%) with tumors in the upper extremity, and 33 with tumors in the trunk (13%); primary lesion size >5 cm in 121 patients (55%); and 204 (82%) patients with localized disease and 46 (18%) with metastatic disease at the time of presentation. All patients with localized disease underwent surgery. Twenty-four percent of patients underwent amputation. Adequate surgical margins were achieved in 88% patients. In patients with localized disease, radiotherapy was administered to 103 (50%) patients, and chemotherapy to 98 (48%). With a median follow-up of 5.5 years (range, 1-30 years), the 5-year overall survival rate was 10% for patients with metastatic disease and 76% for patients with localized disease (P = .0001). The 5-year event-free survival was 58% in patients with localized disease. Multivariate analysis indicated that size, age, histologic subtype, and the use of radiotherapy were independent factors for event-free survival. CONCLUSIONS: In those patients with localized disease, a good rate of cure can be achieved. Age, size, histology, and use of radiotherapy influence prognosis, whereas to the authors' knowledge, the role of adjuvant chemotherapy remains unproven. © 2009 American Cancer Society.

Background: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. Patients and methods: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. Results: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. Conclusion: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Canine mammary tumours are generally treated with surgery alone, despite the fact that 50% of them are malignant and many will eventually lead to recurrence or metastases. A prospective clinical trial in which dogs with aggressive mammary carcinoma of clinical stages IV and V were treated with surgical excision (n = 9) or with surgery and adjuvant weekly gemcitabine (n = 10) for at least four cycles was conducted. Gemcitabine was given as an intravenous infusion at the dose of 800 mg m(-2). Aim of the study was to explore potential beneficial effects of gemcitabine on time to local recurrence (TTR), time to distant metastases (TTM) and overall survival (OS) in canine patients with operated mammary tumours bearing high risk for locoregional failure and distant metastases. Also, factors associated with OS, including neutering status, body weight, age, clinical stage at presentation, tumour size, histological grade and, in dogs receiving chemotherapy, the number of gemcitabine treatments, were investigated. Finally, acute toxicities related to chemotherapy and quality of life were assessed in dogs receiving gemcitabine. Dogs treated with surgery alone or surgery followed by gemcitabine had no difference in TTR, TTM or OS (P > 0.05). In the group of dogs receiving adjuvant chemotherapy, the number of gemcitabine treatments was positively correlated with OS (P = 0.017). Gemcitabine treatment was well tolerated, with no dogs experiencing clinically relevant haematological or gastrointestinal toxicity. Despite being safe at the present dose, gemcitabine chemotherapy as an adjunct treatment to surgical excision may not be recommended in dogs with aggressive mammary carcinoma.

OBJECTIVES: To evaluate the frequency of distant metastases (DM) and to determine the ability of certain clinical and pathologic factors to predict the development of distant metastases. DESIGN: Retrospective analysis. SETTING: University hospital. PATIENTS: A total of 1972 patients with oral, oropharyngeal, hypopharyngeal, and laryngeal squamous cell carcinomas who were treated from 1981 to 1998 and who were not diagnosed as having DM at the time of initial treatment. MAIN OUTCOME MEASURES: We evaluated the frequency of DM and the influence of different variables in their appearance. RESULTS: A total of 181 patients (9.2%) (95% confidence interval, 7.9%-10.5%) developed DM. Younger age (

Tumor-suppressors have commanded attention due to the selection for their inactivating mutations in human tumors. However, relatively little is understood about the inverse, namely, that tumors do not select for a large proportion of seemingly favorable mutations in tumor-suppressor genes. This could be explained by a detrimental phenotype accruing in a cell type–specific manner to most cells experiencing a biallelic loss. For example, MKK4, a tumor suppressor gene distinguished by a remarkably consistent mutational rate across diverse tumor types and an unusually high rate of loss of heterozygosity, has the surprisingly low rate of genetic inactivation of only ∼5%. To explore this incongruity, we engineered a somatic gene knockout of MKK4 in human cancer cells. Although the null cells resembled the wild-type cells regarding in vitro viability and proliferation in plastic dishes, there was a marked difference in a more relevant in vivo model of experimental metastasis and tumorigenesis. MKK4−/− clones injected i.v. produced fewer lung metastases than syngeneic MKK4-competent cells (P = 0.0034). These findings show how cell type-specific detrimental phenotypes can offer a paradoxical and yet key counterweight to the selective advantage attained by cells as they experiment with genetic null states during tumorigenesis, the resultant balance then determining the observed biallelic mutation rate for a given tumor-suppressor gene. (Cancer Res 2006; 66(11): 5560-4)

Endocrine pancreatic tumors are rare and their surgical treatment is often debated. This review analyzes the management and the different indications in functioning and non-functioning neoplasms. The choice among different procedures is described as well as the role of intra operative ultrasound. Moreover, the different patterns of tumor spread are considered (local, loco-regional and metastatic) along with the indications according to the main controversies relating to cytoreductive surgery, transplantation and multiple endocrine neoplasia type 1 patients.

BACKGROUND Investigation of the relation between primary tumor and metastatic disease is necessary for the identification of predictive factors for postrecurrence survival (PRS) in patients with recurrent osteosarcoma. METHODS Cellular levels of P-glycoprotein, ErbB-2, p53, and Bcl-2 expression were evaluated in primary tumor biopsy and metachronous pulmonary metastasis specimens from 19 patients with high-grade osteosarcoma. Results were analyzed for differences between primary tumor and pulmonary metastases and for correlations between expression patterns and survival. RESULTS Positive staining in lung metastases was noted in 68%, 53%, 32%, and 84% of patients for P-glycoprotein, ErbB-2, p53, and Bcl-2, respectively. These percentages were higher than those observed in primary tumor specimens for all genetic markers evaluated, with a significant difference in the percentage of patients with positive staining for P-glycoprotein (68% vs. 32%; P = 0.05) and a near-significant difference in the percentage of patients with positive staining for Bcl-2 (84% vs. 53%; P = 0.08). Patients with ErbB-2 expression in the primary tumor were more likely to have multiple metastases and shorter recurrence-free intervals compared with patients in whom ErbB-2 expression was not observed, whereas differences in P-glycoprotein, p53, and Bcl-2 expression were not related to differences in metastatic pattern. PRS was influenced by p53 expression levels in pulmonary metastases, with patients who had negative staining for p53 having a significantly better PRS rate relative to patients with positive staining for p53 (3-year PRS rate: p53-negative, 64%; p53-positive, 17%; P = 0.008). CONCLUSIONS In the current study of patients with high-grade osteosarcoma, most patients exhibited increased cellular expression of P-glycoprotein, ErbB-2, and Bcl-2 in recurrent pulmonary metastases compared with primary tumor. Further studies aimed at investigating the relation between altered p53 expression in lung metastases and postrecurrence survival are recommended. Cancer 2004. © 2004 American Cancer Society.

Background: Effective adjuvant or neoadjuvant regimens of chemotherapy have dramatically improved the prognosis of patients with high-grade osteosarcoma of the extremity, localized at diagnosis. Currently, little is known about patients with metastatic disease at presentation. Patients and methods: From May 1995 to May 2000, 57 patients with osteosarcoma of the extremity, metastatic at presentation, were treated according to the following scheme: primary chemotherapy, restaging, simultaneous resection of primary tumor and metastatic lesions, and maintenance chemotherapy. Results: Thirty-five patients achieved remission. At a follow-up ranging from 2 to 7 years, seven remained continuously free of disease, one died of chemotherapy-related toxicity and 27 patients relapsed. Twenty-one of the 22 patients who never achieved remission died as a result of the tumor, as well as 20 of the 27 who achieved remission but then relapsed. Of the remaining seven relapsing patients, six are alive with uncontrolled disease, while one is alive and free of disease 24 months after the last post-relapse treatment. Two-year event-free survival (EFS) and overall survival (OS) were 21% and 55%, respectively. These results are significantly poorer than those achieved in 128 contemporary patients with non-metastatic disease at presentation, treated with the same chemotherapy protocol (2-year EFS and OS of 75% and 94%, respectively). Conclusions: The results of our study confirm that the prognosis of patients with osteosarcoma of the extremity, metastatic at presentation, remains poor, despite the use of aggressive treatments.

In metastatic renal cell carcinoma (mRCC), the transition to the targeted therapy era has made available a variety of effective new agents, including vascular endothelial growth factor tyrosine kinase receptor (VEGF-TKR) inhibitors, such as sunitinib, pazopanib, sorafenib; anti-VEGF monoclonal antibody bevacizumab; and mTOR (mammalian target of rapamycin) inhibitors, everolimus and temsirolimus. A statistically significant improvement in progression-free survival (PFS) was obtained with each of these six biological drugs in well-conducted phase III trials, in comparison with either interferon alone (in the first-line setting) or placebo (in the second-line setting). As a consequence, all of these drugs have received regulatory approval in specific subsets of mRCC patients both in the US and in Europe (Gore and Larkin, 2011). Recently, VEGF-TKR inhibitor axitinib has proved to be a valuable second-line option in patients who have received targeted agents (Rini et al, 2011). With the rapidly growing number of biological drugs active in mRCC, the need to establish the optimal sequence of administration is becoming more and more compelling. In the first-line setting, no comparative phase III trial of targeted agents has been carried out (Gore and Larkin, 2011), although a number of indirect comparisons and economic evaluations involving sunitinib and bevacizumab are available. Sunitinib was associated to a prolonged PFS with respect to bevacizumab plus interferon in an indirect comparison analysis (Thompson Coon et al, 2009), but bevacizumab was more cost-effective than sunitinib in one study (Ravasio et al, 2011), although this finding was not replicated in another study (Benedict et al, 2011). Pazopanib has also recently emerged as an effective first-line treatment option (Gore and Larkin, 2011). Although cross-trial comparison is always challenging, pazopanib may be better tolerated than sunitinib, with a minor incidence of cardiovascular, endocrinologic and dermatologic adverse events, and it could be employed in selected patients (e.g., those with cardiovascular co-morbidities) (Di Lorenzo et al, 2011). Results from an ongoing head-to-head comparative phase III trial of first-line pazopanib vs sunitinib are eagerly awaited (COMPARZ trial, NCT 00720941). In the second-line setting, the only FDA- and EMA-approved drug after progression on VEGF-TK inhibitors is currently everolimus, which yielded a statistically meaningful PFS advantage (4.9 vs 1.9 months), with no difference in overall survival (OS), with respect to placebo, in a large phase III trial (Motzer et al, 2010). Progression-free survival obtained with everolimus was numerically superior to that obtained with second-line sorafenib in 52 patients with sunitinib-refractory mRCC by Di Lorenzo et al (2009). Importantly, although all of the patients enrolled in the Di Lorenzo trial had received a single agent for metastatic disease, 79% of patients in the RECORD-1 trial had received more than one medication for systemic disease at enrollement, including sunitinib, sorafenib or interferon. An indirect comparison analysis was performed by matching patients enrolled in these two trials for histology, prior treatment, and MSKCC risk score showed that everolimus was associated with a statistically significant improved median PFS (40.8 vs 17.7 weeks) and improved median OS (78 vs 32 weeks) with respect to sorafenib (Di Lorenzo et al, 2011). Interestingly, these data seem to be confirmed by another retrospective review of 108 mRCC patients treated with either the TKR inhibitor –TKR inhibitor sequence (46 patients), or with the TKI-EV sequence (62 patients). Although there was no difference in PFS, the estimated OS was statistically meaningfully longer for the rTKI-EV group (43 mo; 95% CI, 33.9–52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6–39.5; p=0.03), but was only numerically longer at multivariable analysis (Busch et al, 2011). All of these data taken together support the notion that everolimus may be a better second-line choice than sorafenib. Furthermore, everolimus has been shown to preserve its efficacy in individuals who were intolerant to first-line TKR inhibitor, and may be particularly suitable for these patients (Bracarda et al, 2011). Treatment in the second-line setting has been further complicated by the recently published results obtained in the AXIS trial in patients pre-treated with one prior line of therapy, including interferon, bevacizumab or sunitinib, and randomized to either axitinib or sorafenib (Rini et al, 2011). Median PFS was 6.7 months with axitinib compared with 4.7 months with sorafenib (hazard ratio 0.665; 95% CI 0.544–0.812) in the whole sample population, but the PFS advantage was smaller in patients previously treated with sunitinib (4.8 vs 3.4 months; hazard ratio 0.741; 95% CI 0.573–0.958), which underlines the critical importance of previous therapy with targeted agents. Axitinib is likely to be soon approved for second-line use in mRCC and become an alternative to everolimus. The third-line setting remains largely unexplored, and all of the available evidence is provided by small, retrospective studies. In a recent case study published on this Journal, Grunwald et al (2011) presented retrospective data regarding treatment of 40 patients with mRCC, who received VEGF-directed targeted agents before and after the use of everolimus. Sunitinib, sorafenib and combination of bevacizumab and interferon were administered to 75%, 23% and 3% of patients, respectively, as a first-line treatment. All patients of the study sample received either second- or third-line everolimus and were subsequently treated with a VEGF-directed targeted drug, that is to say sunitinib, sorafenib, bevacizumab/interferon and dovitinib in 48%, 20%, 8% and 25% of patients, respectively. Collected data seemed to provide some evidence in favor of the efficacy of retreatment with a VEGF-directed targeted drug following everolimus, considering that median PFS with either a third- or forth-line VEGF-directed targeted agent was overall 5.5 months. Differently from the study by Grunwald et al, we conducted a retrospective study of patients with mRCC, who had undergone the exact sequence sunitinib-mTOR inhibitor-sorafenib (Di Lorenzo et al, 2010). Importantly, of 150 medical records considered, a substantial proportion (about 25%) received third-line treatment with sorafenib, which was associated to a median PFS of 4 months and an OS of 7 months. A possible biological explanation for this finding, which can be considered satisfactory in the third-line setting, is based on the existence of two mTOR complexes: mTORC1, which is formed by mTOR binding to the FK-binding protein and is targeted by everolimus, and mTORC2, which is not inhibited by everolimus and can be responsible for a compensatory increase of the hypoxia-inducible factor (Rini, 2010). Activation of the VEGF pathway can be consequently targeted by third-line use of TKr inhibitors. Resistance to VEGF-directed targeted agents has been simplified into two main mechanisms: one involving the potentiation of the VEGF axis and the other based on the activation of alternative pathways and growth factors (Powles et al, 2011). Interestingly, the former model can be employed to explain the second-line activity of axitinib, a potent and selective (unlike sunitinib, pazopanib and sorafenib) inhibitor of VEGF-r. In fact, VEGFr may still be activated during VEGF-directed therapies via a number of mechanisms, such as increased VEGF production or receptor gene mutation, and the use of a more potent VEGFr inhibitor can be clinically meaningful. On the other hand, a number of separate pathways have been identified as possibly mediating acquired resistance to VEGF-directed biological agents. Activation of these pathways can stimulate angiogenesis both directly and indirectly via a number of proteins, such as fibroblast growth factor, ephrin and angiopoietin family proteins, interleukin-8 and PlGF. In this regard, it must be noted that activity of combination of synergism of bevacizumab and interferon may be explained by the bFGF-inhibiting activity of interferon. Furthermore, preliminary evidence suggests efficacy of an angiopoietin-2 inhibitor, AMG386, which is currently being investigated in two ongoing phase II trials in combination with either sunitinib or sorafenib (Rini et al, 2011). In conclusion, in patients at good- and intermediate-prognosis with clear cell mRCC sunitinib presently appears the best first-line choice, with pazopanib as a valuable alternative in selected populations. In this regard, it must be kept in mind that most of the available evidence in the second-line setting was obtained in sunitinib-pretreated patients, so efficacy data in patients treated with first-line pazopanib are lacking. Both axitinib and everolimus may be employed interchangeably as second- and third-line therapies. Everolimus may be used after axitinib, in view of the fact that the RECORD-1 trial also enrolled patients who had received two targeted therapies, and that the number of prior agents employed was not predictive of PFS. On the other hand, axitinib effectiveness may be enhanced after use of everolimus, for the reasons explained before. Temsirolimus is the only recommended treatment for patients with non-clear cell histology and those at poor prognosis, for whom a TKI-based second-line treatment is a reasonable option. Additional trials are eagerly awaited, in order to provide evidence regarding the best choice and sequence of administration of targeted agents in mRCC.

BACKGROUND Invasive vulvar carcinoma is a rare disease with an incidence rate of 3–5% of all female genital neoplasms. The current study discusses the limited number of articles in the literature regarding the patterns of recurrence as well as the clinical outcome of patients with recurrent disease based on a consistent and consecutive series of cases. METHODS A common clinical chart focusing on the study of patterns of recurrence was used in five Italian gynecologic institutions with uniform criteria of surgical nomenclature, pathologic variables, and sites of recurrence. Between 1980–1994, 502 cases of primary invasive squamous carcinoma of the vulva were registered consecutively, treated, and considered for this multicentered study. RESULTS Of 502 patients, 187 (37.3%) developed a recurrence. Distribution of the recurrences by site was as follows: perineal, 53.4%; inguinal, 18.7%; pelvic, 5.7%; distant, 7.9%; and multiple, 14.2%. In a multivariate analysis, 3 characteristics appeared to be statistically correlated with the risk of recurrence: International Federation of Gynecology and Obstetrics Stage > II (P = 0.029), positive lymph nodes (P = 0.009), and vascular space invasion (P = 0.004). The 5-year survival rate was 60% for perineal recurrences, 27% for inguinal and pelvic recurrences, 15% for distant recurrences, and 14% for multiple recurrences. CONCLUSIONS In the current study the prognostic factors found to have statistical significance as prognostic factors for risk of recurrence were tumor dimension, lymph node involvement, and stromal and vascular space invasion. The presence of inguinal lymph node metastases was predictive of multiple and distant recurrences with a low rate of incidence of isolated perineal recurrence (27%) compared with negative lymph node cases (57.5%). Survival analysis of recurrent disease showed that the surgical resection of local recurrences may provide acceptable results (51% at 5 years). This observation may justify a follow-up program aimed at identifying those patients with early local recurrence suitable for radical resection. Cancer 2000;89:116–22. © 2000 American Cancer Society.

to assess the results of bladder preservation in infiltrating bladder cancer. The potential for neoadjuvant chemotherapy followed by extensive TUR and radiotherapy was investigated in 40 patients with T2-T4a G2-G3 bladder carcinoma.from 1983 to 1995, 40 patients were submitted to bladder-sparing treatment consisting of neoadjuvant chemotherapy, extensive, TUR and radiotherapy. Most patients had T3G3 cancer. Cystectomy was not performed due to patient" choice in 29 cases (72.5%), for severe pulmonary or cardiovascular disease in disease in 9 patients (22.5) and age over 80 in 2 (5%) patients. A deep TUR-biopsy was performed before and after chemotherapy and an extensive TUR was repeated at the end of radiotherapy. In the first 30 patients chemotherapy consisted of 2-4 cycles of 70 mg/m2 cisplatin on fay 1, and 40 mg/m2 methotrexate on days 8 and 15. In the last 10 patients chemotherapy consisted of 3 cycles of CMV (100 mg/m2 cisplatin on day 2, 30 mg/m2 of vinblastine on days 1 and 8). Total dose of radiotherapy was 60-65 Gy. Recurrent superficial tumors were treated transurethrally. Radical cystectomy, when feasible, was considered for persistent or recurrent invasive disease.after chemotherapy, a clinical objective response was obtained in 27 patients (67.5%), 19 (47.5%) of whom showed a complete response. Thirteen (32.5%) patients showed no response and 5 (12.5%) progressed during chemotherapy. After extensive TUR of any residual mass and radiotherapy, a complete response was achieved in 6 patients who initially showed a partial response and in other 2 patients and stable disease after chemotherapy. Altogether, 27 patients (67.5%) presented had local recurrences, 3 patients underwent cystectomy. Fourteen patients (35%) are alive and 13 NED (65 months mean survival). Five patients died of unrelated disease. Twenty-one patients (52.5%) died of distant metastases (mean survival 28 months). Four patients presented distant metastases after vesical infiltrating recurrence and 4 patients had distant metastases in the absence of loco-regional recurrence. Twenty-two patients (55%) maintained an intact bladder. Patients with complete response to chemotherapy showed a low risk for developing recurrent infiltrating tumors and metastases.A complete tumor was maintained at 5 years in over 50% of the patients conservatively treated. Bladder salvage is feasible in selected patients.

Follicular carcinoma, in association with other prognostic factors, identifies a class of "high-risk" patients in which a more aggressive treatment is indicated. In fact, in patients operated on for follicular carcinoma bone metastases, also many years after primary surgery, are reported. A case of skull metastases in a young women occurred 3 years after a near total lobectomy for follicular thyroid carcinoma is described. After six years the patient underwent total thyroidectomy, resection of skull metastases, radiometabolic therapy with I131 180 m Ci; now she is disease free at three years of follow-up. The biology of metastases in thyroid follicular carcinoma, risk factors and diagnostic and therapeutic controversies are analyzed. Good prognostic factors are considered age < 45 years, good degree of differentiation of primary tumor, small size of bone metastases and early appearance after primary diagnosis. The conclusions is drawn that bone metastases are the worst prognostic factors. In case of single lesion, surgical treatment allows good results. Follicular carcinoma, in association with other prognostic factors, identifies a class of 'high risk' patients in which a more aggressive treatment is indicated. In fact, in patients operated on for follicular carcinoma bone metastases, also many years after primary surgery, are reported. A case of skull metastases in a young women occurred 3 years after a near total lobectomy for follicular thyroid carcinoma is described. After six years the patient underwent total thyroidectomy, resection of skull metastases, radiometabolic therapy with I131 180 m Ci; now she is disease free at three years of follow-up. The biology of metastases in thyroid follicular carcinoma, risk factors and diagnostic and therapeutic controversies are analyzed. Good prognostic factors are considered age < 45 years, good degree of differentiation of primary tumor, small size of bone metastases and early appearance after primary diagnosis. The conclusions is drawn that bone metastases are the worst prognostic factors. In case of single lesion, surgical treatment allows good results.

The purpose of this paper is to retrospectively analyze the clinical and pathological data of 118 cases of uterine carcinosarcoma. Prognostic factors and management were evaluated. chi 2 and log-rank tests were performed. Surgical stage at time of surgery was the most important prognostic factor (P < 0.0001); in stage I-II disease depth of myometrial invasion and lymphatic/vascular space involvement were significantly related to outcome, whereas other factors were not useful. In stage I-II patients postoperative radiation did not improve 5-year disease-free survival. Survival curves in patients with advanced disease treated with cisplatin-containing regimens or with doxorubicin (without cisplatin)-containing regimens were overlapping.

Experimental studies have showed that hepatocellular carcinoma (HCC) cells are susceptible to cytolysis of interleukin (IL)-2-activated lymphocytes. Moreover, our previous studies demonstrated that the pineal neurohormone melatonin (MLT) may enhance IL-2 efficacy. On this basis, a study was started with low-dose IL-2 (3 million U/day subcutaneously for 6 days/week for 4 weeks) plus MLT (50 mg/day orally every day given in the evening) as a first-line therapy of unresectable HCC. The study included 14 patients. Objective tumour regressions were obtained in 5/14 (36%) patients (one complete response, four partial responses), with a median duration of 7+ months. 6 patients had stable disease, while the other 3 progressed. Toxicity was low in all cases. This study shows that the neuroimmunotherapy with low-dose IL-2 plus MLT is a new well-tolerated and effective therapy of advanced HCC.

Summary The effects of the ortho and para isomers of aryldimethyltriazeno carboxylic and benzensulfonic acids and amides have been examined in mice bearing subcutaneous Lewis lung carcinoma. The toxicity of these compounds varies widely and does not correlate with the effects on tumor progression. The growth of subcutaneous primary tumor is unaffected or only marginally inhibited by all the tested compounds, while a marked depression in the formation of spontaneous lung metastasis is observed, with the exception of the sodium salt of the ortho benzensulfonic acid. The compounds showing the greatest activity on metastasis are the hydrosoluble salts of the ortho and para carboxylic acid and the para sulfonamido derivative, indicating that, in addition to the activity reported for the potassium salt of the para carboxylic acid, also its ortho isomer and the para sulfonamido derivative possess selective and pronounced antimetastatic effects. No correlation can be found between the reported effects on tumor progression and physicochemical parameters of the triazenes tested.

Two lines of Lewis lung carcinoma with a different potential to metastasize spontaneously to the lungs have been examined for their cytological and histological characteristics. Metastatic potential appears to be related with parenchymal organization of the primary tumours, since large haemorrhagic areas containing detached tumour cells and the absence of endothelialized capillaries are observed only in the line with high metastatic potential. At the same time, the cytological characteristics of the cells of the two tumour lines are similar, and do not seem to be related with metastatic potential. After treatment with the selective antimetastatic drugs ICRF-159 and DM-COOK, and with DTIC, the histological appearance of the line with high metastatic potential becomes similar to that of the line with low metastatic potential. These data seem to indicate that the early phases of tumour spread occurring in the primary tumour are of relevance for metastatic potential and control by antimetastatic drugs, and suggest that for DTIC such antimetastatic action may participate to its clinical antitumour effects.

Eleven previously untreated women with recurrent and/or metastatic granulosa cell tumor of the ovary were treated with cisplatin, vinblastine, and bleomycin in combination. All the six pathological complete responders but one are alive and free of disease at a median follow-up time of 14 months from the start of treatment. Of three partial responders, two died of drug-related toxicity while one, with only microscopic disease at second-look laparotomy, is alive and without evidence of disease at 34 months. Hematologic and nonhematologic toxicity were severe. These promising results require further examination of the activity and the best schedule of treatment with this combination.