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Aim To determine the differential effect of the treatment periods on the survival of patients with stage IV serous papillary peritoneal carcinoma (SPPC), fallopian tube cancers, and epithelial ovarian cancers (EOC). Methods This was an exploratory, population-based observational study of all patients with stage IV SPPC, fallopian tube cancers, and EOC collected from the SEER Research Data 1973–2017. The study period was divided into three time-periods: platinum combinations before the taxane era (1990–1995), platinum plus taxane chemotherapy era (1996–2013), and bevacizumab era (2014–2017). Results A total of 9828 patients were eligible for analyses: SPPC (3898 patients; 39.7%), fallopian tube cancers (1290 patients; 13.1%) and EOC (4640 patients, 47.2%). In the 1990–1995 era, the 3-year cause-specific survival was 40% for SPPC, 53% for fallopian tube cancers, and 40% for POC. In the following era 1993–2013, the 3-year cause-specific survival increased to 55% for SPPC, 74% for fallopian tube cancers, and 45% for POC. The last era 2014–2017 showed a 3-year cause-specific survival of 64%, 67%, and 45% for patients with SPPC, fallopian tube cancers, and POC, respectively. The differences in cause-specific survival were statistically significant for patients with SPPC (p=0.004). Multivariable analysis showed that the treatment eras and age at diagnosis were associated with cause-specific survival. Conclusion The results of this study are hypothesis-generating and cannot be considered conclusive given the inherent limitations of registry analysis. Subgroup analyses of the phase III randomized controlled trials, by tumor subset (EOC, fallopian tube cancer, and SPPC) would shed more light on the differential effects of novel therapies.

Purpose: Cancer is a leading cause of mortality worldwide. Its incidence is still increasing, particularly in developing countries. Recent progresses further strengthen the differences between low/middle and high-income countries. This situation calls for joint action to reduce inequities in cancer outcomes among the patients. The Association of Radiotherapy and Oncology of the Mediterranean Area (AROME) and the European School of Oncology (ESO), have initiated joint conferences devoted to access to innovations in oncology in the Mediterranean area. The heterogeneity of the economic, political and cultural situations of the different participating countries, offers the opportunity to develop consensus conference. Methods: Cancer prevention and treatment strategies were discussed according to existing international guidelines. The Scientific committee prepared 111 questions with an objective to prioritize the access to treatments and innovations in low/middle-income Mediterranean countries. The results from the votes of 65 oncology experts, coming from 16 countries and 33 institutions have been analysed and access priorities classified accordingly. Results: Ninety six percent of the proposed general recommendations concerning national health care strategies, oncology education, and treatment organization were considered to be high priorities. Regarding access to systemic treatments, 41% of the drugs without validated predictive markers and 53% of those with validated predictive markers were considered to be 1st level priority. Only 4 biological tests were considered to be 1st level priority to access to innovation. Conclusions: AROME-ESO consensus offers to cancer specialists from developing countries a basis for discussion with health authorities and payers on the prioritization of access to innovations in cancer care., AROME and ESO Oncology Consensus Conference

Epithelial ovarian cancer (EOC) accounts for nearly 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery and neo (adjuvant) platinum-based chemotherapy. Relapse of advanced high grade serous ovarian cancer (HGSOC) is related to the development of drug resistance. A defective DNA damage response is a defining hallmark of HGSOC. Poly (ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in breast cancer gene (BRCA1 or BRCA2) mutation carriers. Apart from inducing synthetic lethality, PARP inhibitors have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. This “PARP trapping” potentiates synergism between PARP inhibition and both alkylating agents and platinum-based chemotherapy. However, there are remarkable differences in the ability of PARP inhibitors to trap PARP, based on the size and structure of each separate molecule. Since monotherapy with PARP inhibitors is unlikely to induce cancer cell death in BRCA-proficient tumors, the efficacy of PARP inhibitors could be potentially optimized when combined with DNA-damaging agents, or with molecular targeted agents that also impair mechanisms of DNA repair. Olaparib, rucaparib, and niraparib have all obtained US Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approval in ovarian cancer in different settings. Veliparib does not yet have an approved label; nevertheless, there are currently promising results available in preclinical and early clinical settings. This comprehensive review summarizes the mechanism of action of veliparib and provides an overview of its early and ongoing clinical investigations.

Cancer of unknown primary accounts for 3–5% of all cancers for which an adequate investigation does not identify the primary tumor. The particular subset of brain metastasis in cancer of unknown primary (BMCUP) is a clinical challenge that lacks standardized diagnostic and therapeutic options. It is diagnosed predominantly in male patients in the sixth decade of age with complaints of headache, neurological dysfunction, cognitive and behavioral disturbances and seizures. The therapeutic approach to patients with BMCUP relies on local control and systemic treatment. Surgery or stereotactic radiosurgery and/or whole brain radiation therapy seems to be the cornerstone of the treatment approach to BMCUP. Systemic therapy remains essential as cancers of unknown primary are conceptually metastatic tumors. The benefits of chemotherapy were disappointing whereas those of targeted therapies and immune checkpoint inhibitors remain to be evaluated. In this Review, we address the advances in the diagnosis and treatment of BMCUP.

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

Paraneoplastic syndromes are signs or symptoms that result from tissue damage at locations remote from tumour sites. Paraneoplastic syndromes associated with cancer of unknown primary (CUP) are not well recognized as they are rarely reported. These syndromes can impair various organ functions and include endocrine, neurologic, dermatologic, rheumatologic, hematologic and several other system alterations. To our knowledge, the association between the histological CUP type and the paraneoplastic syndrome has never been assessed. In some instances, paraneoplastic syndromes can become the major clinical problems determining survival. However, they can also herald earlier the occurrence of CUP in patients with asymptomatic tumors. In this article, we review the available literature of CUP patients presenting paraneoplastic syndromes by trying to collect all available published cases during the last three decades. One additional goal of this article is to make practicing oncologists aware of the coexistence of paraneoplastic syndromes in patients with CUP.

Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers for which a primary tumor cannot be identified after a standardized work-up. The biology of CUP has not been fully elucidated and epidemiologic data may be helpful in this regard. The variations in the incidence-rate over time and between countries reflect changes in the risk factors for CUP, incidence trends of the primary tumors that potentially contribute to the burden of CUP and changes in the diagnostic technologies and practice. CUP accounted for 3-5% of cancers in the historical series but its incidence seems to decline in the recent publications. This paper reviews the published cancer-registry studies in order to identify and understand the variations in the incidence-rates of CUP.

Aim: The literature lacks direct evidence comparing the different regimens evaluated in the second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Methods: We conducted a network meta-analysis (NMA) of the randomized controlled Phase III trials reporting on the second-line drug treatment options in R/M SCCHN. Results: The eligible trials included 11 regimens among which six targeted therapies, two immune checkpoint inhibitors and three chemotherapy regimens. Only nivolumab has shown statistically significant superiority over methotrexate in terms of overall survival (HR: 0.64; 95% CI: 0.43–0.96) and objective response rate (OR: 2.51; 95% CI: 1.07–5.86). Conclusion: Based on the efficacy and safety outcomes of this network meta-analysis, nivolumab seems the most favorable regimen inthe management of R/M SCCHN.

Cancer of unknown primary site (CUP) is a deadly disease diagnosed through metastases at various organs without primary tumor identification. Despite the major molecular and technological advances, the carcinogenesis of CUP remains enigmatic which hampers adequate study design of treatments leading to survival improvement. To date, the pathogenesis of CUP is still debatable with one hypothesis considering CUP simply a group of metastatic tumors with unidentified primaries and another considering it a distinct entity with specific genetic and phenotypic aberrations. Familial CUP seems to favor the first hypothesis due to common genetic predisposition factors between known primaries and CUP. Two clinical implications may be withdrawn from the pathogenesis of familial clustering of CUP. The detailed family history and environmental risk factors may orient towards the primary tumor identification. Smoking avoidance and adherence to general population guidelines for cancer screening would be strongly encouraged.

Vaccines, cytokines, and adoptive cellular therapies (ACT) represent immuno-therapeutic modalities with great development potential, and they are currently approved for the treatment of a limited number of advanced malignancies. The most up-to-date knowledge on the regulation of the anti-cancer immune response has recently led to the development and approval of inhibitors of immune checkpoints, which have produced unprecedented clinical activity in several hard to treat solid malignancies. However, severe adverse events (AEs) represent a limitation to the use of these drugs. Currently approved checkpoint inhibitors block cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand (PD-L1), resulted in increased survival of patients with several solid and hematologic malignancies. The most common treatment AEs associated with these drugs are fatigue, rash, and auto-immune/inflammatory reactions. Many of the immune-related AEs are reversible and the strategies for their management include supportive care either with or without treatment withdrawal; nevertheless, in severe cases, hospitalization and treatment with immune suppressants, and/or immunomodulators may be required. Steroid therapy is a critical component of the treatment algorithm; nevertheless, the associated immunosuppression may compromise the antitumor response. This article provides a comprehensive and narrative review of luminal gastrointestinal and hepatic complications, including recommendations for their investigation and management.

Melanoma of unknown primary site (MUP) comprises 3-4 % of all melanomas. It mostly presents in lymph nodes (LNs), followed by subcutaneous sites, and visceral organs; nevertheless, there is a trend of increase in the relative incidence of visceral counterpart in recent years. Spontaneous regression of the primary lesion is a well-established theory, based on the evidence that melanoma can undergo regression at the primary site. MUP and stage-matched melanoma of known primary site (MKP) share similar prognostic factors. The survival rate of patients with MUP has been compared to those with stage-matched MKP. Multiple studies conducted before the era of novel therapy with immune checkpoint or BRAF/MEK inhibitors found improved survival in favor of MUP, whereas others reported equivalent or poorer outcomes. Here, we discuss the genetic and molecular features, epidemiology, diagnosis, prognostic factors, survival, and treatment of MUP in comparison with MKP, in the pre- and post-novel therapy era.

Serous peritoneal papillary carcinoma (SPPC) represents a particular cancer of unknown primary (CUP) entity that arises in the peritoneal surface lining the abdomen and pelvis without a discriminative primary tumor site. In this review, we discuss the validity of SPPC as a distinct entity. Clinically, patients with SPPC are older, have higher parity and later menarche, are more often obese and probably have poorer survival compared to those with primary ovarian cancer. Pathologically, SPPC is more anaplastic and multifocal, unlike primary ovarian cancer which is commonly unifocal. Biologically, it presents a higher expression of proliferative signals and similar cell cycle and DNA repair protein expression. These differences hint towards SPPC and primary ovarian cancer being as a spectrum of disease. Patients with SPPC are traditionally managed similarly to stage III–IV ovarian cancer. The recommended approach integrates aggressive cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and systemic chemotherapy to remove the macroscopic tumor, eradicate the microscopic residual disease, and control the microscopic metastasis. However, the available evidence lacks proper randomized or prospective studies on SPPC and is limited to retrospective series. The diligent identification of SPPC is warranted to design specific clinical trials that eventually evaluate the impact of the new therapeutics on this distinct entity.

We investigated the impact of the European School of Oncology’s (ESO) Masterclass (MCO) in Clinical Oncology on the career development of young participants. MCO represents the flagship educational activity of ESO and is organized annually, mostly in collaboration with the European Society for Medical Oncology (ESMO) in five different geographical regions. A questionnaire consisting of 21 questions was sent to all doctors who attended the ESO MCOs from 2009 to 2016. The 228 responders were mostly from European countries and hold the specialty of Medical Oncology. Ninety-five percent of them evaluated ESO MCOs as “extremely useful” or “useful” for their professional career. Around 60% were trained at University Hospitals or Cancer Institutes and currently, one-third of them are employed in Academic Centers. Eighty percent have performed translational or clinical research and 77.5% were able to publish in pertinent international journals. The contribution of ESO MCOs to trainees’ career development in different oncology disciplines around the world is discussed.

Cancers of Unknown Primary Site (CUP) account for approximately 1-3 % of all malignant neoplasms. It represents a heterogeneous group of malignancies without a detectable primary and is characterized by aggressive clinical behavior. Patients with CUP are presumably categorized into prognostic subsets according to their clinical and pathological characteristics. The majority of these patients are chemoresistant and treated with empiric chemotherapy regimens which yield limited survival. Recent diagnostic advances have led to the identification of a higher percentage of culprit primaries among which colorectal, lung and renal tumors. The empiric CUP regimens may be suboptimal in these patients which explain in part their poor prognosis. In the absence of prospective randomized studies to prove the benefit of site-specific therapy in these subsets, we reviewed the literature to assess whether CUP with colorectal, lung and renal - profiles should be treated similarly to the correspondent primary tumors.

Non-Hodgkin lymphomas commonly show extranodal involvement (25-30%) but primary diffuse large B-cell lymphomas(DLBCL) with extranodal localization represent clinically and molecularly distinct entities. The present study involved retrospective analysis of case records of 4 patients who were diagnosed with extranodal DLBCL between 2010 and 2016 at the Medical Oncology and Hematology Departments of the Ioannina University Hospital, Greece. Median age of presentation was 69 years (range 60-77 years). There were 2 males and 2 females. The sites of DLBCL involvement included adrenal gland, mandible, cervix uteri, and ileum. Two patients had B symptoms while none had bone marrow involvement. After staging workup, all the patients fell into IE stage. The treatment approach included chemotherapy combined with rituximab (R), whereas one patient received additionally irradiation therapy. Post-treatment positron emission tomography-computed tomography scan was performed in 3 patients. In terms of the outcome, 3 patients are alive in complete response, whereas one was lost in follow-up. Further prospective data analyses are required so as to better elucidate the biology and course of extranodal DLBCL.

Objective: Treatment decisional preferences impact breast cancer patients? health-related quality oflife (HRQoL) and may relate to psychological variables, although many aspects of this relationshipremain unknown. This prospective study aimed to assess psychological correlates of treatmentdecisional preferences and predictors of HRQoL in women with early non-metastatic breast cancer.Methods: Of the 124 women initially assessed for anxiety (Spielberger?s State?Trait AnxietyInventory) and depressive (Center for Epidemiologic Studies-Depression (CES-D)) symptoms, HRQoL(WHOQOL-BREF), and defense mechanisms (Life Style Index), 82 (66.1%) completed the 1-year followup.Mean age was 54.6 years (SD= 9.76), andmean disease duration was 19.4months (SD= 25.55); 19.5%had stage I, 63.4% stage II and 17.1% stage III disease. The predictive power and moderator effects ofpsychological variables were tested using multiple and hierarchical regression models.Results: Depressive symptoms and physical HRQoL improved significantly, state anxiety and mentaland environment HRQoL remained stable, and social relations HRQoL deteriorated over the 1-yearperiod. Older age (p = 0.021) and higher scores in repression defense (p = 0.044) were independentlyassociated with passive decisional preferences. Earlier stage of cancer (p = 0.043), lower state anxiety(p = 0.039), lower repression scores (p = 0.021) and improvement in depressive symptoms (p

Objective Psychiatric manifestations and personality traits are known to influence cancer patients. We aimed to assess psychological distress symptoms, psychosocial factors and health-related quality of life (HRQoL) in cancer of unknown primary site (CUP) and to test whether these parameters differ between CUP and Metastatic (MKPC) or Non-Metastatic Known Primary Cancers (N-MKPC) after controlling for demographics and clinical variables. Methods In this cross-sectional study, we recruited 50 CUP, 264 N-MKPC and 52 MKPC participants. We assessed depressive symptoms (Center for Epidemiologic Studies-Depression [CES-D]), psychological distress symptoms (Symptom Distress Checklist-90 Revised), sense of coherence (SOC), ego defense mechanisms (Life Style Index) and HRQoL (World Health Organization Quality of Life Instrument, Short Form). Results The prevalence of clinically significant depressive symptoms (CES-D ≥ 23) was 40.0% in CUP, 28.8% in MKPC and 23.5% N-MKPC (p = 0.037). Multivariate logistic regression analysis showed that N-MKPC patients were 5 times less likely (p = 0.028) and MKPC patients 3.3 times less likely (p = 0.05) to be assessed with probable depression compared with CUP patients after controlling for the major demographic and clinical variables studied. CUP patients presented also higher levels of somatization, anxiety and depressive symptoms; they also had more impaired Physical (p = 0.005), Mental (p = 0.041) and Social Relations (p = 0.044) HRQoL, along with lower scores on SOC and intellectualization defense and higher scores on repression defense, compared with MKPC and N-MKPC patients. Conclusions These findings suggest that psychiatric manifestations are frequent in CUP, and the patients' resources to cope with the burden of their illness are limited. Attention to CUP patients' psychological distress and coping resources and capacities may enable oncologists to identify and manage modifiable aspects of HRQoL. Copyright © 2013 John Wiley & Sons, Ltd.

Thoracic tumors during pregnancy is a rare coexistence. Only 66 cases of lung cancer have been published during the last two decades. Gestational thymomas and mesotheliomas are even more infrequent gestational tumors.

This chapter covers cancer of unknown primary site (CUP), and includes information on epidemiology, molecular biology, pathology, and multidisciplinary management of clinicopathological subsets. Previously, these tumours were diagnosed and treated based on clinical presentation, light microscopy and clinical intuition. Today, the majority of cancers of unknown primary site are becoming less unknown, more accurately classified, and appropriately treated by the use of multiplex or genome-wide expression profiling platforms. These techniques allow for precise and correct knowledge of the true tumour origin, leading to more rational and effective treatment. However, there also may be genetic signatures that are primary-independent, pro-metastatic, and possibly CUP-specific.

Background Pregnancy-associated breast cancer (PABC), defined as breast cancer diagnosed during pregnancy or one year after is a relatively rare disease and hence considerable controversy exists regarding its prognosis compared to non-pregnancy-related breast cancer. Methods: Two of the authors independently performed a literature search on MEDLINE and Cochrane Library with no date or language restrictions. Eligible studies were control-matched, population-based and hospital-based studies that have addressed the outcome of patients diagnosed during pregnancy or one-year afterwards. The control group was defined as patients diagnosed with breast cancer not related to pregnancy. The primary and secondary end-points were overall and disease-free survival respectively. Pooling of data was done using the random effect model. To control for potential differences between the two groups in systemic treatment and clinico-pathological features (e.g. tumor size, nodal status, ER, etc …) that could affect prognosis, we performed a sensitivity analysis by pooling the hazard ratios (HRs) of the adjusted multivariate models within each study. We also analyzed differences according to time of diagnosis (during pregnancy or post-partum), type of study and year of reporting the study. Finally, we communicated with the authors of the eligible studies to collect unpublished statistics relevant to our analysis to further refine our findings. Results: 29 studies were included in this meta-analysis (2903 cases and 36, 512 controls). Women diagnosed with PABC had a significantly higher risk of death compared to those diagnosed with non-pregnancy-related breast cancer (pooled hazard ratio (pHR): 1.47 [95% CI: 1.30−1.65]). A sensitivity analysis including 11 studies (1222 PABC cases, 19231 controls) adjusted for differences in tumor size, nodal status and systemic treatment showed the same result (pHR: 1.44 [95% CI: 1.17−1.77]). These findings were consistent in patients diagnosed either during pregnancy (pHR: 1.30 [95% CI: 1.01−1.67]) or in the post-partum period (pHR: 1.56 [95% CI: 1.08−2.26]) with no heterogeneity observed (p=0.43). Sensitivity analyses according to the type and year of study showed the same findings. Regarding the secondary end-point, only ten studies (531 cases, 1842 controls) provided sufficient information to estimate disease-free survival, and indeed PABC patients had a higher risk of relapse compared to breast cancer controls [pHR: 1.59 (95%CI: 1.23−2.07)]. Collection of unpublished data is currently ongoing and further analyses will be presented at the meeting. Conclusion: To the best of our knowledge, this is the largest analysis addressing the prognosis of PABC. Our results confirm that PABC is independently associated with a worse prognosis whether diagnosis is made during pregnancy or in the post-partum period. This underscores the possible impact of pregnancy on breast cancer biology. In this regard, we are currently interrogating potential biological differences between PABC patients and matched breast cancer controls at the gene expression level to elucidate the biology of this relatively rare, yet very challenging disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-03.

Background: HER2 status (gene amplification, protein overexpression) is the hallmark for the selection of patients who will benefit from trastuzumab-based treatment. Except for HER2, however, the status of additional genes located at chromosome 17q seems to have an impact on disease biology and patients’ outcome. In this retrospective study, we investigated the impact of TOP2A (chr 17q21-q22, telomerically to ERBB2) and PPP1R1B (DARPP32, chr 17q12, centromerically to ERBB2) status on the outcome of patients with ABC treated with trastuzumab-based regimens. Materials and Methods: In a cohort of 199 patients with ABC treated with 1st or 2nd line trastuzumab-containing regimens, tumor tissues were assessed for HER2 and TOP2A gene amplification (by FISH), HER2, TOP2A and DARPP32 mRNA expression (by RTQ-PCR), and Her2 and TopoIIa protein expression (by IHC). Tumors were HER2 positive (FISH amplified and/or 3+ by IHC) (n= 137) or negative (n=62). Disease outcome was assessed as time to progression (TTP), survival from trastuzumab administration (survivalT) and survival from 1st metastasis (survivalM). Results: In comparison to patients with HER2-negative tumors, those with HER2-positive tumors exhibited a longer TTP (Median [95% CI] = 13.7 [10.7-16.7] vs 9.2 [7.5-10.9], p=0.037) and survivalT (Median [95% CI] = 47.4 [37.9-56.9] vs 34.8 [24.3-45.4], p=0.008), as expected. HER2 positivity was strongly associated with relatively high HER2 mRNA and protein expression (P1 equally distributed among HER2-positive and negative tumors. In patients with HER2-positive tumors, TOP2A gene amplification was associated with longer survival, irrespectively of the chemotherapy regimen administered in addition to trastuzumab (survivalT: p=0.004, survivalM: p=0.003). Interestingly, in patients with HER2-negative tumors, DARPP32/HER2 ratios of >1 were associated with a favorable outcome (survivalT: p=0.008 and survivalM: p=0.043). No association with disease outcome was observed for high DARPP32 expression or for DARPP32/HER2 ratios in HER2-positive tumors. Discussion: This study shows that genes located peripherally to HER2 on the same chromosome arm, such as TOP2A and DARPP32, may be concomitantly altered in the same breast tumor, but may have a different impact on the course of the disease. A favorable outcome may be predicted for HER2-positive tumors with amplified TOP2A and for HER2-negative tumors expressing higher DARPP32 mRNA in comparison to HER2. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-15.

Objective: The aim of the present study was to test whether psychological distress and personality variables are independently associated with health-related quality of life (HRQOL) in colorectal cancer patients, after adjusting for age, gender, education and disease severity.Methods: In a cross-sectional study of 162 colorectal cancer patients (response rate 65.6%), the following self-report instruments were administered: the Symptom Distress Checklist-90-R, the Sense of Coherence scale, the Life Style Index and the Hostility and Direction of Hostility Questionnaire. The outcome measures were the four components of the WHO Quality of Life Instrument, Short Form. We used hierarchical regressions to determine whether psychological distress mediates the relationship of personality and disease parameters with HRQOL.Results: The overall proportion of the variance in the four components of HRQOL explained by our regression models ranged from 28.1 to 44.4%. Psychological distress was an independent correlate of HRQOL, associated with physical (p

We report on a small-cell lung cancer case that was heralded by the presence of CENP-B specific anti-centromere autoantibodies (ACA) detected well before the diagnosis of cancer. The patient received chemotherapy plus radiotherapy, which resulted in complete remission of the tumor. Serum ACA levels were zeroed at the time of radiological documentation of tumor response and remained undetected at serial follow-up assessments until they rose again along with documentation of tumor recurrence which occurred 12 months later. We review in brief published research and discuss anti-centromere autoantibodies as potential biomarkers in small-cell lung cancer, a highly proliferative tumor which lacks sensitive serum markers.

Urine cytology has been a useful tool for the diagnosis of urinary tract malignancies. However, the presence of tumor cells in the urine sediment without an obvious urothelial metastatic deposit is a rare phenomenon and in patients with lung cancer has never been reported. We present five cases with metastatic lung cancer and positive urine cytology. The possible mechanisms underlining this phenomenon and its implications are discussed.

Cancer in pregnancy is a rare disease with breast cancer, cervical cancer, melanoma and Hodgkin's disease to be the most commonly diagnosed malignancies during gestation. Cancer of unknown primary (CUP) is a well-recognized clinical disorder where the primary site can not be identified after a standard diagnostic approach. CUP in pregnancy has rarely been described.We searched MEDLINE and contacted cancer Centers in Europe, United States and Australia where patients with CUP or pregnant patients with cancer were diagnosed and treated.Since 1976 we identified 18 pregnant women with CUP in a median gestational age of 34 weeks. Most of these patients were diagnosed with poorly-differentiated histology, had poor response to systemic treatment and a median maternal survival of 8 months. Seventy-two percent of mothers have died, while 80% of the newborns were alive and healthy. Almost one fourth of placentas examined showed metastatic disease.CUP during pregnancy is a very rare coexistence, usually has an aggressive disease with poor response to chemotherapy and a dismal prognosis. Both obstetricians and oncologists should be aware of this rare condition.

The purpose of this retrospective study, the largest unselected series in our country, was to illustrate the clinicopathological features of non-Hodgkin’s lymphoma (NHL) classified according to the World Health Organization (WHO) classification of lymphoid neoplasms. A retrospective analysis was conducted and clinical features of histological subtypes were established in 810 patients (age ≧15 years) with NHL who were treated at 8 major centers representative of Greece. There were 435 males and 375 females 95% of them aged >30 years. B symptoms were present in 34% of the patients, while 45.3% had stages I–II and 54.6% had stages III–IV. LDH was increased in 37% of the patients. B cell lymphomas formed 88% of the cases whereas T cell lymphomas formed 12% of the total. Indolent lymphomas accounted for 31.1%, aggressive ones for 66.7% and very aggressive ones for 2.4% of all NHLs. Among indolent lymphomas extranodal ones (MALT B cell lymphoma) were the most common subset while follicular lymphoma grade I and II and small lymphocytic ones presented with equal frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype; this entity along with large-cell immunoblastic lymphomas accounted for 45.2% of all B cell lymphomas. Among the T cell lymphomas, peripheral T cell lymphomas and anaplastic large cell lymphomas of the T/null-cell type were the most common subtypes. The most common extranodal presentation was the gastrointestinal tract (GI). Next in frequency were primary extranodal NHL of the head and neck region. MALT B cell lymphomas were found in almost half of the patients with GI tract NHL, whereas in all other extranodal places DLCL was the predominant histological subtype. The median survival for indolent and aggressive NHL was 123.5 and 55.5 months, respectively. This is the first report of a large series of malignant lymphomas in Greece using the WHO classification. It appears that there are no significant differences between NHL in Greece and other large series as far as clinical and extranodal presentation is concerned. The frequency of follicular lymphoma in the current study is comparable to that reported from Asian countries and mainland Europe, but lower than that of US and Northern European series. There were no important differences in the incidence of the remaining histological subtypes between Greece and other European countries.

Research on systemic interventions in patients with advanced stage malignancies should be systematised with an emphasis on the absolute gain in survival for the median patient. Such information is most meaningful with relatively large-scale evidence. Here, we summarise the survival impact of 36 interventions compared against other interventions or no treatment for advanced stage malignancies in meta-analyses of individual patient data or in selected recent (2000–2002) randomised trials with >300 randomised subjects. Although 16 interventions showed a formally statistically significant survival benefit against the comparator arm, this exceeded 3 months in only 7 cases. We propose a standardised categorisation of the median survival prolongation in trials and meta-analyses. Level 0: no proven survival benefit; level I: 0–3 months; level II: >3–6 months; level III: >6–24 months; and level IV: more than 24 months. These standardised levels may be incorporated into clinical practice guidelines for individual care and policy-making.

The deleted in colorectal cancer (DCC) gene is a candidate tumor suppressor gene that may be associated with differentiation and proliferation of normal cells. Loss of heterozygosity (LOH) of 18q, where the gene is located, and absence of DCC protein expression have been associated with worse prognosis in certain subgroups of patients with colorectal adenocarcinoma. We studied the prognostic significance of loss-of-protein expression in 66 patients with resected gastric cancer with a high probability of relapse (T3, T4, N+). The DCC protein was detected with immunohistochemistry using an anti-DCC monoclonal antibody on paraffin-embedded sections. The DCC protein expression was present in 51 cases (77.3%) and absent in 15 cases (22.7%). Poorly differentiated and signet ring carcinomas had significantly lower expression than more differentiated tumors (p < 0.05) as did diffuse-type tumors compared to intestinal and mixed (p < 0.01). There was no correlation with proliferation rate, estimated immunohistochemically using an anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody. Absence of DCC protein was an independent favorable prognostic factor (median survival 57 months vs. 18 months, p = 0.0176). The DCC protein expression was correlated with relapse site: all patients with distant metastases were positive for DCC staining, while one-third of patients with local/peritoneal relapse were negative (p < 0.01). In conclusion, DCC protein expression seems to be a significant prognostic factor in high-risk resected gastric cancer. Our results support previous data associating the DCC gene with differentiation and indicate that this gene may play a role in the metastatic potential of these tumors. These findings need to be confirmed by future larger studies.

Cancer complicating pregnancy is a rare coexistence. The incidence is approximately 1 in 1,000 pregnancies. The most common cancers are those more frequently seen during the reproductive age of a woman. Breast cancer, cervical cancer, Hodgkin's disease, malignant melanoma, and leukemias are the most frequently diagnosed malignancies during gestation. The diagnostic and therapeutic management of the pregnant patient with cancer is especially difficult because it involves two persons, the mother and the fetus. In this paper we review: A) the therapeutic and diagnostic management of these patients; B) the safety of diagnostic and therapeutic procedures; C) the metastatic pattern of the maternal tumors to the placenta and fetus, and D) the potential recommendations for therapeutic abortion.

No consensus on clinicopathologic prognostic factors that predict the outcome of patients with newly diagnosed glioblastoma multiforme (GBM) managed with resection, postoperative radiotherapy (RT) and adjuvant temozolomide (TMZ) exists today. The purpose of this study was to assess the outcome, compliance and toxicity in GBM patients treated with TMZ at our Center, as well as to evaluate factors with prognostic significance.91 GBM patients were enrolled in this retrospective study (2004-2012). 3D-conformal RT was given to a median total dose of 60Gy (daily dose 2Gy). Eighty nine (98%) of the patients received concurrent TMZ (75mg/m²) and 74 (81%) received adjuvant TMZ (150-200mg/m² for 5 days every 28 days) up to 12 cycles.At a mean follow up of 18.6 months, the median overall survival (OS) was 15.1 months. Grade 3/4 haematologic toxicity was observed in 19.8% of the patients while 4 patients (4.4%) experienced grade 3/4 non haematologic toxicity. In univariate analysis, significant correlation was found between OS and no/minor neurologic deficit at diagnosis (p=0.02), acute onset of symptoms (p=0.04) and 6 cycles of adjuvant TMZ (p0.001). The addition of more than 6 cycles of TMZ did not offer any statistically significant survival benefit. In multivariate analysis, only the absence of major neurologic deficit remained associated with overall survival (p=0.016).3D conformal RT with TMZ achieved acceptable disease control with satisfactory compliance and toxicity. Intact neurologic function was associated with superior outcome, as a surrogate of low tumor burden, early treatment start and/or indolent tumor biology.

Comparative Observational Study of Two Ethnic Population Groups of Patients with Hepatocellular Carcinoma Background: In order to elucidate potential differences in the natural history, clinical presentation and prognosis of patients with hepatocellular carcinoma (HCC) from two different continents, we studied demographics, management and outcome data of two groups of patients from Egypt and Greece. To our knowledge this is the first study to do so. Patients and Methods: Record-based data from one hundred and five Egyptian and seventy eight Greek patients with HCC, were retrieved and analyzed for demographic, tumor and disease characteristics as well as for treatment and prognostic features. Results: Median age at HCC diagnosis was 61 years for Egyptians and 70.5 years for Greeks (p

BACKGROUND Cancer antigen 15-3 (CA 15-3), a circulating marker that determines secreted products of the polymorphic MUC1 gene, has been established as a convenient tool for monitoring breast carcinoma patients. METHODS The authors investigated alterations of soluble CA 15-3 in 57 postoperative breast carcinoma patients while they were receiving intensified adjuvant chemotherapy with granulocyte colony stimulating factor (G-CSF) support; 26 patients had American Joint Committee on Cancer (AJCC) Stage II, and 31 patients had AJCC Stage III breast carcinoma. Serial CA 15-3 values recorded thoughout the treatment were compared with baseline values, analyzed for correlation with hematologic and biochemical parameters, and compared with clinicopathologic characteristics and patient outcome. At a median follow-up time of 32 months, 47 of these patients remained relapse-free. RESULTS A twofold increase of CA 15-3 was detected at the end of the second week of treatment, remained significantly elevated in most patients at above the cutoff level of 30 U/mL throughout the treatment period (P < 0.0001), and subsided to pretreatment values 1–2 months after treatment cessation. CA 15-3 values were found to be associated strongly with absolute neutrophil count, serum lactate dehydrogenase, and alkaline phosphatase. The median values and the kinetics of tumor markers did not differ over time in regard to hormonal receptor status and disease recurrence. CONCLUSIONS These data provide strong evidence that G-CSF administration can induce elevation of CA 15-3 and indicate that false-positive results should be considered when evaluating CA 15-3 in patients who are receiving G-CSF. It is speculated that this phenomenon occurs through the induction of MUC1 antigen of unknown origin by G-CSF. Experimental investigation of this clinical observation is warranted. Cancer 2001;91:909–17. © 2001 American Cancer Society.

Aggressive non-Hodgkin’s lymphoma (NHL) is a biologically heterogeneous disease that can be cured with aggressive chemotherapy treatment. Different clinical, biological, cellular and molecular features have been identified as having prognostic significance on the outcome of NHL patients. The knowledge of these prognostic features can be used in everyday practice in order to predict the prognosis of every new NHL patient and tailor his or her treatment accordingly. The Oncologist 1998;3:189-197

The encouraging results that have been reported for cisplatin combination chemotherapy in a minority of patients with cancer of unknown primary (CUP) together with the previously shown equal activity of carboplatin in this setting, prompted us to investigate the effectiveness of a carboplatin-containing regimen in a phase II clinical trial.Sixty-two evaluable CUP patients entered the protocol. The chemotherapy regimen consisted of carboplatin 300 mg/m2 IV D1, epirubicin 45 mg/m2 IV D1 and etoposide 120 mg/m2 IV D1–3 (CEE regimen) administered every 3 weeks. The median age of the patients was 61 years and 36 were male. Thirty-one diagnosed as poorly differentiated carcinomas (pdc) and the rest as adenocarcinomas. By clinicopathological criteria, 14 patients had a predominately nodal disease with pdc or poorly differentiated adenocarcinomas (pda), 3 women peritoneal carcinomatosis, and the remaining 46 patients had a predominately splanchnic involvement (24 pdc, 22 pda). Twenty-three patients responded to chemotherapy with 4 (6.5%) complete and 19 (30.5%) partial responders (RR 37%, 95% CI 25–49%). An equal activity of the regimen was observed between the two major histopathological types, the pdc and the adenocarcinomas. Nevertheless, significant differences were seen when the CEE regimen was assessed for its activity in the distinct clinicopathological subsets of CUP. Patients with predominately nodal disease of midline distribution with pdc or pda, and women with peritoneal carcinomatosis, achieved a response rate of 64 and 62% respectively, as compared with a 26% response rate for those with predominately splanchnic involvement. Overall median survival was 10 months and for patients with midline distribution 15 months. The regimen was well tolerated. It is concluded that CEE is a relatively nontoxic chemotherapy regimen and easily administered on an outpatient basis. This prospective phase II study confirmed the activity of carboplatin in the chemosensitive subsets of the predominately nodal disease of midline distribution and peritoneal carcinomatosis in women in the CUP syndrome.

About 3% of all cancer patients suffer from cancer of unknown primary origin. These patients present with metastatic disease for which a primary site cannot be detected at the time of diagnosis. Sophisticated diagnostic techniques and operational procedures have failed to improve the diagnostic efficacy in this group of patients. Consequently, a limited diagnostic procedure with basic laboratory tests and imaging studies is sufficient for the diagnosis of this syndrome. The use of immunohistochemistry, as well as serum tumor markers of high specificity that may help to identify other tumors, is highly suggested. Although the prognosis for the majority of these patients still remains poor, several subsets of favorable outcome to treatment have been recognized. Nevertheless, promising in vitro data and new drugs on trials, paralleled with a better knowledge of the underlying pathogenetic molecular mechanisms, offer a more optimistic look to the future therapeutic management of these patients.

Treatment decisional preferences impact breast cancer patients' health-related quality of life (HRQoL) and may relate to psychological variables, although many aspects of this relationship remain unknown. This prospective study aimed to assess psychological correlates of treatment decisional preferences and predictors of HRQoL in women with early non-metastatic breast cancer.Of the 124 women initially assessed for anxiety (Spielberger's State-Trait Anxiety Inventory) and depressive (Center for Epidemiologic Studies-Depression (CES-D)) symptoms, HRQoL (WHOQOL-BREF), and defense mechanisms (Life Style Index), 82 (66.1%) completed the 1-year follow-up. Mean age was 54.6 years (SD = 9.76), and mean disease duration was 19.4 months (SD = 25.55); 19.5% had stage I, 63.4% stage II and 17.1% stage III disease. The predictive power and moderator effects of psychological variables were tested using multiple and hierarchical regression models.Depressive symptoms and physical HRQoL improved significantly, state anxiety and mental and environment HRQoL remained stable, and social relations HRQoL deteriorated over the 1-year period. Older age (p = 0.021) and higher scores in repression defense (p = 0.044) were independently associated with passive decisional preferences. Earlier stage of cancer (p = 0.043), lower state anxiety (p = 0.039), lower repression scores (p = 0.021) and improvement in depressive symptoms (p0.001) predicted physical HRQoL improvement. Moderation analysis showed that active decisional preferences predicted physical HRQoL improvement, but only in those women with lower repression levels.Defense mechanisms are associated with treatment decisional preferences and interact with factors predicting HRQoL in women with breast cancer. Clinicians should address the patients' anxiety and depressive symptoms and refer patients with high repression tendencies for psychological evaluation and management.

PURPOSE To investigate if double modulation of fluorouracil (5-FU) with leucovorin (folinic acid [FA]) and interferon alfa-2b (IFN 2b) improves responses and survival in comparison to single modulation of 5-FU with FA. PATIENTS AND METHODS One hundred six patients with histologically confirmed advanced colorectal cancer, measurable disease, and without previous chemotherapy were prospectively randomized into two groups. Patients in group A received 5-FU 450 mg/m2 as an intravenous bolus in the midinfusion of FA weekly. FA was given at a dose of 200 mg/m2 in 500 mL 0.9% normal saline solution in 2-hour infusion. Patients in group B received exactly the same regimen plus IFN 2b 5 million units subcutaneously three times weekly. RESULTS All patients were well balanced in both groups regarding age, sex, performance status, number, and site of metastasis. One hundred two patients were assessable. All patients have died. There was no difference in response between the two groups (7.8% v 9.8%). Median survival was 10.1 months in group A, and 7.2 months in group B (P = .00189). Median time to progression was 8.4 and 5.2 months, respectively (P = .00196). Overall, better performance status and older age had a positive impact on survival. Toxicity was the most important and catastrophic aspect of this study. Patients who received IFN 2b had significantly worse anemia, neutropenia, diarrhea, anorexia, weight loss, flu-like syndrome, and psychological reactions. CONCLUSION Based on this final analysis, the addition of IFN 2b to the combination of 5-FU and FA enhances toxicity and contributes to decreased survival.

Possible prognostic variables for tumor response, time to progression (TTP), and survival in 141 patients with advanced colorectal cancer treated with fluorouracil and leucovorin-based chemotherapy were analyzed. None of the variables examined for their possible influence on tumor response attained significance in the stepwise logistic regression. In the univariate analysis, variables found to be strongly associated with TTP were performance status (PS) (P = 0.0301), liver involvement (P = 0.030), and the initial values of WBC (P = 0.0319), lactic dehydrogenase (LDH; P = 0.0053), gamma-glutamyl-transpeptidase (gamma-GT; P = 0.0013), alkaline phosphatase (ALP; P = 0.0186), albumin (P = 0.0004), and carcinoembryonic antigen (CEA; P = 0.0014). In the Cox analysis, liver involvement (P = 0.0553), albumin (P = 0.0181), PS (P = 0.484), and ALP (P = 0.0553) were retained as independently significant variables. When only patients with liver metastases were included in the analysis, then only albumin (P < 0.001) demonstrated a prognostic significance. Also, in the univariate analysis, variables predicting survival were PS (P = 0.0230), grade (P = 0.00600), liver involvement (P = 0.0002), LDH (P = 0.0001), gamma-GT (P < 0.001), ALP (P = 0.0006), albumin (P = 0.0309), and CEA (P = 0.005). With the multivariate analysis, gamma-GT (P = 0.0004), albumin (P = 0.0634), and CEA (P = 0.0804) were selected as significant. In those patients who presented with liver involvement, variables predicted survival were gamma-GT (P = 0.0041), albumin (P = 0.0442), and the percentage of involved liver parenchyma (P = 0.0690). These results could be helpful for the stratification of future trials in advanced colorectal cancer. Med Pediatr Oncol

Rhizoxin is a macrocyclic lactone compound that binds to tubulin and inhibits microtubule assembly. Rhizoxin demonstrated preclinical anti-tumour activity against a variety of human tumour cell lines and xenograft models. Phase I evaluation found a maximum tolerated rhizoxin dose of 2.6 mg m-2, with reversible, but dose-limiting, mucositis, leucopenia and diarrhoea. Clinical trials were then initiated by the EORTC ECSG in melanoma, breast, head and neck, and non-small-cell lung cancers with the recommended phase II rhizoxin dose of 2 mg m-2. Pharmacological studies were instituted with the phase II trials to complement the limited pharmacokinetic data available from the phase I trial. Blood samples were obtained from 69 of 103 eligible patients enrolled in phase II rhizoxin studies, and these were evaluable for pharmacokinetic analysis in 36 patients. Plasma rhizoxin concentrations were determined by high-performance liquid chromatography (HPLC), and post-distribution pharmacokinetic parameters were estimated by a one-compartment model. Rhizoxin was rapidly eliminated from plasma, with a median systemic clearance of 8.41 min-1 m-2 and an elimination half-life of 10.4 min. Rhizoxin area under the concentration-time curve (AUC) was higher in patients obtaining a partial response or stable disease than in those with progressive disease (median 314 vs 222 ng ml-1 min; P = 0.03). As predicted from previous studies, haematological and gastrointestinal toxicity was observed, but could not be shown to be related to rhizoxin AUC. This study demonstrated the rapid and variable elimination of rhizoxin from the systemic circulation. The presence of pharmacodynamic relationships and the low level of systemic toxicity suggest that future trials of rhizoxin with alternative dosage or treatment schedules are warranted.

Aims and Background To improve local control in patients with locally advanced inoperable head and neck cancer we administered carboplatin concurrently with radiation. Methods Thirty-nine patients entered the study. There were 35 men and 4 women with a median age of 58 years (range, 24-74) and a median performance status of 90 (range, 60-100) of the Karnofsky scale. The primary site included nasopharynx (5 patients), oropharynx (n=10), hypopharynx (n=5), larynx (n=12), oral cavity (n=2), paranasal sinuses (n=3), salivary glands (n=1) and unknown (n=1). Histology was squamous cell carcinoma in all cases. All patients were irradiated with a 60Co unit. According to the protocol, they should receive 66-70 Gy to the tumor area and 45 Gy to the tumor-free area of the neck. Carboplatin was administered at a dose of 400 mg/m2 on days 2, 22 and 42. Results Totally, 112 cycles of carboplatin were administered, of which 106 (95%) were at full dose. Median dose intensity of carboplatin actually delivered was 170 mg/m2/week (range, 57-200). All patients were irradiated, although only 30 (77%) received >66 Gy. After the completion of combined treatment, 23 (59%, 95% C.I. 42-74%) achieved a CR and 10 (26%, 95% C.I. 13-42%) a PR. Grade 3-4 myelotoxicity was noticed in 60% of the patients. Other grade 3-4 toxicities included stomatitis (13%), dysphagia (5%) and weight loss (3%). Median time to progression was 18 months (range, 2-25). Conclusions Radiation and concurrent administration of carboplatin determined a high CR rate in patients with HNC, although the superiority of this combined modality approach over radiation alone has to be proven in phase III trials.

Psychiatric manifestations and personality traits are known to influence cancer patients. We aimed to assess psychological distress symptoms, psychosocial factors and health-related quality of life (HRQoL) in cancer of unknown primary site (CUP) and to test whether these parameters differ between CUP and Metastatic (MKPC) or Non-Metastatic Known Primary Cancers (N-MKPC) after controlling for demographics and clinical variables.In this cross-sectional study, we recruited 50 CUP, 264 N-MKPC and 52 MKPC participants. We assessed depressive symptoms (Center for Epidemiologic Studies-Depression [CES-D]), psychological distress symptoms (Symptom Distress Checklist-90 Revised), sense of coherence (SOC), ego defense mechanisms (Life Style Index) and HRQoL (World Health Organization Quality of Life Instrument, Short Form).The prevalence of clinically significant depressive symptoms (CES-D ≥ 23) was 40.0% in CUP, 28.8% in MKPC and 23.5% N-MKPC (p=0.037). Multivariate logistic regression analysis showed that N-MKPC patients were 5 times less likely (p=0.028) and MKPC patients 3.3 times less likely (p=0.05) to be assessed with probable depression compared with CUP patients after controlling for the major demographic and clinical variables studied. CUP patients presented also higher levels of somatization, anxiety and depressive symptoms; they also had more impaired Physical (p=0.005), Mental (p=0.041) and Social Relations (p=0.044) HRQoL, along with lower scores on SOC and intellectualization defense and higher scores on repression defense, compared with MKPC and N-MKPC patients.These findings suggest that psychiatric manifestations are frequent in CUP, and the patients' resources to cope with the burden of their illness are limited. Attention to CUP patients' psychological distress and coping resources and capacities may enable oncologists to identify and manage modifiable aspects of HRQoL.

The epithelial to mesenchymal transition (EMT) has been associated with metastatic dissemination and poor outcome in several solid tumour types. Our aim was to study its incidence and its prognostic significance in cancer of unknown primary (CUP).One hundred tumour samples of CUP were loaded in tissue microarrays and were studied for immunohistochemical (IHC) expression of E-cadherin, N-cadherin, vimentin, the EMT transcription factor (SNAIL) and the stem cell marker octamer-binding transcription marker 4(OCT4). An EMT phenotype was defined as low expression of E-cadherin, expression of N-cadherin with/without vimentin with concomitant expression of SNAIL, as assessed by percentage of tumour cell staining.Among 100 CUP cases, the histological diagnosis was adenocarcinoma in 55, squamous carcinoma in 20 and undifferentiated carcinoma in 15, with a high grade seen in 46. Therapy consisted of palliative chemotherapy, mostly platinum based. The median progression-free survival and overall survival (OS) were 7 and 12 months respectively. Distributional studies resulted in selection of IHC cut-offs for E-cadherin (negative when expressed in60% of tumour cells), N-cadherin, vimentin (positive when expressed in ≥40% of tumour cells), SNAIL (positive when stained in ≥80% of tumour cells). An EMT phenotype was observed in 8 cases (8.1%) and was strongly associated with poor OS (median OS EMT(-)=13 months vs. median OS EMT(+)=8 months, p=0.023). When we used staining intensity (H-Score), an EMT phenotype was observed in 16 patients and carried borderline adverse prognostic utility for outcome (median OS 9 vs. 14 months, p=0.07). The presence of the EMT phenotype correlated significantly with male gender, high grade and presence of visceral metastases (χ(2) p0.05), while EMT mediator expression was correlated to high NOTCH 2/3 expression. Other factors, prognostic for poor survival, were male gender, PS≥2, non-platinum therapy (χ(2) p0.05).EMT is infrequently seen in tumours of CUP. However, an adverse prognostic significance for patient outcome has been identified and may warrant studies of therapeutic targeting.

The toxicity of cancer chemotherapy is among the most important factors limiting its use. Clear delineation and communication of benefits and risks is an essential component of treatment decisions. Gastrointestinal toxicity during chemotherapy is frequent and contributes to dose reductions, delays and cessation of cancer treatment. The development of intervention strategies that could eliminate an expected side effect of chemotherapy is vital. Physiologic changes that can increase the toxicity of chemotherapy are decreased stem cell reserves, decreased ability to repair cell damage, progressive loss of body protein, and accumulation of body fat. Symptoms only arise when physiological functions are altered. The gastrointestinal symptoms arising during cancer chemotherapy can often be cured if newly acquired, and if gastrointestinal physiological deficits are identified. Developing new chemotherapy regimens with similar efficacy but less toxicity should be a priority for future research.