We retrospectively evaluated elderly patients with advanced non-small cell lung cancer (NSCLC) treated with carboplatin (AUC 4-5) and gemcitabine (1,000-1,200 mg/m(2)). Thirty-six patients with Performance Status (PS) 0-1 and median age 73 (range 70-78 years) were considered. Histology was squamous cell carcinoma (8 patients), adenocarcinoma (22) and NSCLC not otherwise specified (6). 149 cycles of chemotherapy were administered with a median of 3 per patient (range 3-6). Grade 3 non-hematologic toxicities were dyspnea (1 patient) and fever (1). Grade 3/4 hematologic toxicities were anemia (6), neutropenia (6) and thrombocytopenia (10), with dose reduction required in 13 patients. The overall disease control rate was 44.4%. We recorded no complete response, 8 partial response, 8 stable disease and 20 progressive disease. After a medium follow-up of 11 months, median progression-free survival and median survival were 5 and 11 months, respectively. Carboplatin and gemcitabine is a safe and active regimen in elderly advanced NSCLC patients with good PS.

Ensuring that patients are aware of their situation and of their choices in oncology are concepts that have been asserted and accepted for quite some time and have become fundamental in the doctor–patient relationship. Oncologists have developed an approach towards cancer patients that is characterised by a global vision of patients’ needs: besides identifying the purely clinical necessities, more and more attention (even though it is not yet adequate) is given to communication; to relationships; to the social, ethical and spiritual aspects; and to what can be defined as the ‘patient's biography’. Each and every stage of the illness is critical for patients due to the extremely negative impact the communication of a diagnosis or a relapse or progression of the illness can have on their lives in both physical and psychological terms. It is, however, also a critical situation for the doctor particularly if he or she understands fully the importance and delicacy of the moment when communicating bad news [1.Buckman R. Breaking bad news: why is it still so difficult?.Br Med J. 1984; 288: 1597-1599Crossref PubMed Scopus (364) Google Scholar, 2.Maguire P. Pitceathly C. Key communication skills and how to acquire them.Br Med J. 2002; 325: 697-700Crossref PubMed Scopus (606) Google Scholar, 3.Fallowfield L. Jenkins V. Communicating sad, bad, and difficult news in medicine.Lancet. 2004; 363: 312-319Abstract Full Text Full Text PDF PubMed Scopus (730) Google Scholar]. It is almost always difficult for the doctor to understand what truth the patient wants: full disclosure, nondisclosure or individualised disclosure? For instance, the patients who say ‘I want the whole truth’ do they really want full disclosure or are they placing the responsibility of how much to disclose on the doctor's judgement to recognise how much of the truth they can take? [4.Aitini E. Aleotti P. Breaking bad news in oncology: like a walk in the twilight?.Ann Oncol. 2006; 17: 359-360Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. In Western countries, doctors are obliged to move within a world that presents dangerous fluctuations between an absolute faith, sometimes blind faith, in science and the ancestral fear of an incurable illness and consequently death. To understand and accept that we are mortal, that our lives end, to come to terms with death as part of life and see it not just as a biological event but as an existential happening can be a way to help and support terminal cancer patients to maintain their dignity. It seems that our society has lost the ability to understand and accept death, preferring instead to keep it hidden from our everyday lives [5.Royal College of Physicians Doctors in society. Medical professionalism in a changing world.Clin Med. 2005; 5: S5-S40PubMed Google Scholar]. Doctors, therefore, must be aware that removing the inevitability of death from our consciousness makes it impossible to restore dignity to an event that was perceived in ancient times as a natural part of life. At this point, the most important role of the doctor is to accompany terminal cancer patients along this difficult path, helping them not to be overwhelmed by the fears and anxieties generated by the perception that life is about to end. However, to do this the doctor must first face and control his or her own fears and anxieties: it is an extremely difficult task but if done properly it leads to the construction of a therapeutic alliance allowing the patient to listen to bad news without being overcome by it and to hear a possible truth, said with delicacy, without being dismissive or brutal and without shame. In general, when doctors communicate bad news, they try to involve the patient emotionally in a more active, expectant, future dimension and to take the dialogue forward by suggesting and offering therapies and alternative solutions which, at least, allow patients to cohabit with the illness, even though at times with great difficulty, and to give patients an element of hope. However, we must honestly admit that all too often doctors demonstrate serious difficulty and an evident reluctance to talk to their patients about the final stage of life. Generally, patients perceive the distinction between anticancer treatments and palliative care (which are lived as a whole for a long time) and their hopes often crumble when they are informed that the former will be suspended and only the latter will continue. It is as if the remainder of their lives has taken an irrevocable and irrecoverable direction. Making this situation even more dramatic is the fact that, usually, the doctors who have attended the patients during their often-long illness and know their medical history are no longer part of the patients’ lives: they will not be the doctors who will treat them during this final stage of life. Patients and family members come to the conclusion that this is an abandonment of treatment and their reaction is often one of refusing to be placed in a palliative care programme. As long as anticancer treatment continues, even in the most serious phase of the illness, patients have no precise perception of whatever time they have left but with the withdrawal of treatment they see their lives as finished and it is seen as a sentence of imminent death. Faced with the resistance of the patient and family members, who express the reaction of society when confronted by limits, by suffering and by death, doctors are placed in a very difficult position and are often unable to manage the emotional complexities. The irrational expectations of patients and family members tempt doctors to abandon a dialogue, which seems unsustainable and to propose further line of treatment, which, in many cases, the doctor knows will be totally futile. For the same reasons, doctors tend not to be completely clear and honest regarding the realistic possibilities the new treatment can offer, leaving patients the possibility to hope in unrealistic results. On the other hand, in this final stage of the disease, it is even more difficult to understand what the patient really wants to know or to what extent they are capable of supporting devastating news [6.Aitini E. Cetto G.L. A good death for cancer patients: still a dream?.Ann Oncol. 2006; 17: 733-734Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 7.Matsuyama R. Reddy S. Smith T.J. Why do patients choose chemotherapy near the end of life? A review of the perspective of those facing death from cancer [review].J Clin Oncol. 2006; 24: 3490-3496Crossref PubMed Scopus (302) Google Scholar]. In Europe, in the Esmo Moses Project and in North America the need to develop training programmes regarding palliative care and the transition from anticancer treatment to palliative care is beginning to receive the attention it deserves. The current lack of definition and of best practices could explain the difficulties facing the attending oncologist and consequently, at least in part, the high number of patients who choose or request further therapy in the final stage of the illness even though the advantages in terms of survival or in the improvement of their quality of life will most probably be minimal or totally absent: they continue to cling to this illusion [8.Snow A. Warner J. Zilberfein F. The increase of treatment options at the end of life: impact on the social work role in an inpatient hospital setting.Soc Work Health Care. 2008; 47: 376-391Crossref PubMed Scopus (13) Google Scholar, 9.Harrington S.E. Smith T.J. The role of chemotherapy at the end of life: “when is enough, enough?”.JAMA. 2008; 299: 2667-2678Crossref PubMed Scopus (231) Google Scholar, 10.Rayson D. McIntyre P. Transitions to palliation: two solitudes or inevitable integration?.Curr Oncol Rep. 2007; 9: 285-289Crossref PubMed Scopus (8) Google Scholar]. All this brings us to an ethical evaluation not only concerning the patient and family members but also regarding society in general, since prolonging futile therapies, which are sometimes very expensive, means an improper use of resources that could be used to help patients who could gain a real advantage from them. However, inevitably we must ask ourselves who has the absolute right to deprive someone of an irrational hope. Patients have the right to accept or reject therapy and more often than not continue to hope even though the situation may be hopeless. The role of the doctor is not to offer hope, which is but only an illusion, and this is probably the most crucial point in the doctor–patient relationship, the doctor must help patients reduce their expectations while, at the same time, heighten the patient's trust in the doctor and to comfort patients in the knowledge that they are not alone, and that their physical and psychological suffering will be the doctor's only concern [11.Whitney S.N. McCullough L.B. Frugé E. et al.Beyond breaking bad news: the roles of hope and hopefulness.Cancer. 2008; 113: 442-445Crossref PubMed Scopus (36) Google Scholar, 12.Chochinov H.M. Dignity and the eye of the beholder.J Clin Oncol. 2004; 22: 1336-1340Crossref PubMed Scopus (84) Google Scholar, 13.Giorgi F. Bascioni R. Another infusion of hope.J Clin Oncol. 2009; 27: 1722-1723Crossref PubMed Scopus (11) Google Scholar]. Accepting the prospect of death is very difficult, not only in cancer patients, and for doctors, talking to terminal patients about death is just as difficult. At the beginning of the twentieth century, Franz Kafka frequently said: ‘It's easy to write a prescription for medicine but talking to people who are suffering is more, much more difficult.’

1130 Background: Obesity and HER2 overexpression are associated with poor prognosis in breast cancer (BC). Recent studies suggest the existence of functional crosstalk between leptin, a hormone correlated with adiposity, and HER2. Specifically, stimulation with leptin can transactivate HER2 and activate its downstream signaling, while chronic exposure to leptin increases HER2 stability in presence or absence of Herceptin. In our study we evaluated if excess adipocity (associated with leptin overexpression) can impact the clinical outcome in HER2-positive patients treated with Herceptin. Methods: We analyzed retrospectively 155 patients with HER2-positive BC treated with Herceptin for early stage or metastatic disease in the period 2003-2008. The patients were grouped into normal, overweight, and obese categories according to Body Mass Index (BMI) following WHO guidelines. Overall survival (OS) and time to progression (TTP) were calculated by the Kaplan-Meier method and comparisons were made using the log-rank test. Results: 103 patients were treated with adjuvant Herceptin. 12.5% of the population relapsed; of these, 31% and 23% were overweight and obese, respectively. Inrelapsed patients, OS and TTP decreased with increased BMI: the median OS for normal, overweight and obese patients was 40, 36.5, and 31 months, respectively (p=ns); median TTP was 11, 8, and 5 months, respectively (p=0.0351). 52 patients received Herceptin for metastatic disease in association with chemotherapy. In this population, 33% and 15% patients were overweight and obese, respectively; median OS was 65 months and TTP 10.5 months. Decreased OS and TTP were associated with increased BMI: median OS for normal weight, overweight and obese patients was 67, 54, and 39 months, respectively (p=0.0010); median TTP was 12, 7.5, and 7 months, respectively (p=0.0442). The negative impact of increasing BMI was confirmed in subgroups differentiated by hormone receptor and menopausal status. Conclusions: The results suggest that obesity is not only a risk factor and an indicator of poor prognosis in BC patients, but also a negative predictive parameter in HER2-positive subjects. Our in vivo data validate in vitro observation that leptin can impair response to Herceptin in BC cells. No significant financial relationships to disclose.

BACKGROUND:Bisphosphonates (BPs) are the mainstay of bone-directed therapy for bone metastases from multiple myelomas and a wide range of solid tumours, but some patients experience renal toxicity or osteonecrosis of the jaw (ONJ).PATIENTS AND METHODS:We reviewed data relating to 398 patients treated with intravenous BP for bone metastases, checking their serum creatinine levels throughout the treatment period in order to assess renal function, and seeking any signs and symptoms of ONJ recorded in their medical records. We also analysed other risk factors for renal toxicity and ONJ in patients who developed them.RESULTS:The median treatment period was 14 months (range 1-119); 108 patients received BP for more than 1 year, and 112 for more than 2 years. Sixteen patients (4%) developed renal toxicity after a median of 24 months of BP treatment, eight of them had been treated for more than 2 years. Ten patients (2.5%) were diagnosed as having ONJ after a median of 39 months on BP, only three of them had been treated for less than 2 years. Two patients experienced both ONJ and renal toxicity.CONCLUSIONS:The low incidence of ONJ and renal toxicity indicates the safety of BP. However, prevention and early detection are still the "first-line therapy" for decreasing their occurrence further.

e21511 Background: SS is an aggressive soft tissue sarcoma (STS) characterized by a constitutive overexpression of the bcl-2 proteins and high proliferation rate (Ki67). The aim of the study was to evaluate prognostic value of proliferative activity and apoptosis in SS. Methods: A retrospective analysis of 32 patients treated at three oncology centers between January 2000 and August 2008 was conducted. Histologic diagnosis of SS was confirmed by FISH analysis of t(X;18). Bcl-2 and Ki67 were determined by immunohistochemistry at baseline and after neoadjuvant chemotherapy (CT). A cut-off value of 20% was established for Ki67. The bcl-2 gene status was evaluated by FISH in neoadjuvant subgroup. Treatment-induced pathological response (pCR) was defined as tumor necrosis of 100%. Endpoints were recurrence rate (RR), disease-free survival (DFS) and overall survival (OS). Clinical and pathological variables were considered in uni- and multivariate analysis. Results: 13/32 patients received an anthracycline/ifosfamide-based chemotherapy (CT) before surgery. 8 pts received concomitant radiotherapy. A median number of 3 cycles of neoadjuvant CT was administered. All patients underwent surgical resection and pathologic assessment of the coexpression of bcl-2 and Ki67 was evaluated in the resected specimens. At baseline, all samples showed immunoexpression of bcl-2 and 9/13 had Ki67 more than 20%. After neoadjuvant CT, Ki67 was downregulated <20% in 11/13 samples and bcl-2 was negative in 4/13 pts. At FISH analysis, bcl-2 gene was neither rearranged nor amplified. After a median follow-up of 21 months (range 13–64 months), 9/13 pts without pCR experienced progression disease and 5 of them were dead of SS. At uni- and multivariate analysis, both pCR and downregulation of bcl-2 and Ki67 activity had a significant impact on DFS and OS (p=0.03). Conclusions: 1. Downregulation of bcl-2 and Ki67 index after treatment could be a predictor of recurrence and overall survival. 2. SS is characterized by cellular heterogeneity in which a high proliferative compartment coexists with low proliferative/anti-apoptotic compartment with different response to treatment. No significant financial relationships to disclose.

10622 Background: Complete axillary lymph node dissection (ALND) is still the standard of care for breast cancer (BC) patients with sentinel node (SLN) metastases. The aim of this study was to identify the clinical, biological and pathological features that may predict NSLN status. Methods: The study involved 200 patients with a diagnosis of operable invasive BC and a positive SLN who underwent surgery with ALND at the University and Civic Hospitals of Verona between 2001 and 2008. The clinical features considered were age at the time of surgery and the symptomatic/asymptomatic presentation of disease, and the pathological and biological features were TNM stage, grading, histological type, the presence/absence of lymph vascular invasion, the presence/absence of multifocal disease, ER and PgR status, the Ki-67 proliferative index, HER2 overexpression, the number of SLNs analysed, the number of metastatic SLNs, the size of the SLN metastasis (macro, micro, isolated cancer cells), and type of surgery (conservative surgery or mastectomy). The data were statistically analysed using chi-squared test and multivariate logistic regression. Results: The variables predicting NSLN metastasis were an older age (p=0.008), symptomatic disease at diagnosis (p=0.007), size >15 mm (p=0.03), T >1 vs T1 (p=0.002), lower ER (p=0.04) and PgR levels (p=0.02), larger SLN metastasis (p=0.002), mastectomy vs conservative surgery (p=0.01). These variables were analysed using multivariate logistic regression, which showed that the probability of NSLN status increased with increasing age, symptomatic disease, and the increasing size of the SLN metastasis. Conclusions: The study findings demonstrate the existence of clinical, biological and pathological features that can predict NSLN status. Further studies are necessary, but they seem to identify a subgroup of patients at low risk of NSLN metastasis after showing a positive SLN who could avoid ALND.

BACKGROUND This clinical trial assessed the efficacy of pemetrexed combined with oxaliplatin (PEMOX) in patients with advanced gastric cancer (AGC). PATIENTS AND METHODS Forty-four patients with untreated AGC were enrolled to evaluate response rate (RR). Patients received pemetrexed (500 mg/m(2)) with vitamin supplementation and oxaliplatin (120 mg/m(2)) every 21 days for six cycles or until disease progression occurred. RESULTS Median age was 62 years (range 26-76). The majority of patients (93%) had metastatic disease. Sixteen of the 44 patients achieved confirmed response [RR 36%; 95% confidence interval (CI) 22% to 52%]; four complete responses and 12 partial responses (complete and partial responses according to the RECIST guidelines are the confirmed-responses observed in the study population). Median time to tumor progression (TTP) was 6.2 months (95% CI 4.3-7.5) and median survival was 10.8 months (95% CI 7.7-17.2). A total of 220 cycles were administered, with a median of six cycles. Most common grade 3/4 toxic effects were neutropenia in 41% of patients (19% of cycles) and thrombocytopenia in 11% of patients (4% of cycles). Treatment delays or dose reductions for toxicity occurred in 10% and 5% of cycles, respectively. CONCLUSIONS PEMOX is active and well tolerated in AGC. RR, TTP, and survival were comparable to those achieved in studies using different 5-fluorouracil (5-FU)-oxaliplatin combinations, without the inconvenience of prolonged 5-FU schedules.

Skeletal metastases represent a major complication of advanced hormone-refractory prostate cancer (HRPC). These lesions affect around 85% of patients and provide a poor quality of life due to associated pathological fractures, spinal compression and pain. Metastatic HRPC is incurable and typically fatal within 2 years of diagnosis. At present, there is no effective treatment for delaying disease progression. Current treatment options based on chemotherapy, radiotherapy and bisphosphonates are essentially palliative and do not appear to prolong survival. HRPC, therefore, represents a considerable unmet clinical need, and new therapies are required to alter the course of the disease process beyond providing palliation.Many factors are involved in bone remodelling, and a substantial body of evidence suggests a major role for endothelin-1 (ET-1) in the pathophysiology of bone lesions in metastatic HRPC. In HRPC, the binding of ET-1 to a specific receptor (ETA) not only enhances osteoblastic activity and promotes the development of metastatic bone lesions, but also generates a mitogenic and anti-apoptotic milieu. In vivo and in vitro studies show that ET-1-stimulated bone growth is inhibited when the ET-1 receptor (ETA) is blocked. Highly potent and specific ETA-receptor antagonists, therefore, represent an exciting development in the management of HRPC, providing a potentially effective therapeutic target for the delay or prevention of skeletal metastatic progression.

Estramustine and etoposide have been shown to inhibit the growth of prostate cancer cells in experimental models. An in vivo synergism of the two agents, when administered to patients with metastatic prostate cancer refractory to hormone therapy, has been reported. To confirm these results, we administered this combination to a large number of patients with hormone-refractory prostate cancer (HRPC).Fifty-six patients with metastatic HRPC were treated with oral estramustine 140 mg three times a day and oral etoposide 50 mg/m2/day for 21 days. Therapy was discontinued for 7 days and the cycle was then repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression.Forty-five percent of 33 patients with measurable soft tissue disease demonstrated an objective response, which included five complete and ten partial responses. Among 52 patients with osseous disease, 17% showed improvement and 50% showed stability of bone scan. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment prostate-specific antigen (PSA) levels. The median survival of all patients was 13 months. Good pretreatment performance status, measurable disease response, improvement or stability of bone scan, and PSA response were important predictors of longer survival.We conclude that the combination of estramustine and etoposide is an active and welltolerated oral regimen in HRPC.

This review discusses the role of molecular analysis in the diagnosis and treatment of gastrointestinal (GI) neoplasms. It is divided into 3 sections. The first section describes clinical applications of 11 immunohistochemical stains (p53, HER2, KIT, SDHB, SMAD4, beta-catenin, L-FABP, MLH1, PMS2, MSH2, and MSH6), the results of which directly reflect underlying genetic or epigenetic events. These applications are mainly diagnostic but in a few instances are predictive. Germline mutation testing is a diagnostic cornerstone in the hereditary cancer predisposition syndromes (HCPSs). Section two will describe the genotype and phenotype of 8 HCPSs presenting in the GI tract. Where available, guidelines based on evidence and/or expert opinion as to whom to test are presented. With our ever-expanding knowledge of the molecular genetic basis of cancer and an increasingly “biologic-oriented” therapeutic armamentarium, pathologists play a vital role in directing molecular-based predictive testing. The final section will discuss the 4 most mature examples in the GI tract: (1) HER2 testing to select patients with advanced gastroesophageal adenocarcinoma for anti-HER2 therapy, (2) KIT and PDGFRA mutation analysis to direct tyrosine kinase inhibitor therapy in gastrointestinal stromal tumor, (3) DNA mismatch repair function testing to determine the applicability of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC), and (4) KRAS mutation analysis and related testing to determine the appropriateness of anti-EGFR monoclonal antibody therapy in patients with metastatic CRC.

Recent research has shown that emotion influences postural control. The objective of the present study was to establish whether or not postural threat influences postural and physiological responses to aversive visual stimuli. In order to investigate the coupling between emotional reactions, motivated behavior and postural responses, we studied the displacement of the subject's center of pressure (COP) and the changes in electrodermal activity (EDA), heart rate (HR) and postural muscle activation. Thirty-two participants (15 males, 17 females; mean ± SD age: 21.4 ± 2.3) viewed affective and neutral pictures while standing still on a force platform in the presence or absence of postural threat. The HR and EDA data revealed that the emotional state varied as a function of the postural condition. The mean displacement in the anteroposterior (AP) axis was more rearwards in response to aversive stimuli that in response to neutral stimuli, in both the absence of postural threat (−0.65 mm and +0.90 mm for aversive and neutral stimuli, respectively) and the presence of postural threat (−0.00 mm vs. +0.89 mm, respectively). An aversive stimulus was associated with a shorter AP COP sway path than a neutral stimulus in the presence of a postural threat (167.26 mm vs. 174.66 mm for aversive and neutral stimuli, respectively) but not in the latter's absence (155.85 mm vs. 154.48 mm, respectively). Our results evidenced withdrawal behavior in response to an aversive stimulus (relative to a neutral stimulus) in the absence of postural threat. Withdrawal behavior was attenuated (but nevertheless active) in the presence of a postural threat.