To the Editor: Thymoma-associated multiorgan autoimmunity (TAMA) is a rare paraneoplastic syndrome described in patients with thymoma and characterized by multiorgan failure and graft-versus-host dis- ease (GVHD) like pathology affecting the skin, the gastrointestinal tract, and the liver. To date, only 21 cases are reported in liter- ature [1] , with some patients presenting gastrointestinal and hep- atic manifestations, mainly colitis, diarrhea, and abnormal liver en- zymes, but the hepatic involvement has not been histologically characterized yet. In the present study, we describe for the first time that liver involvement in a patient affected by TAMA resem- bles GVHD.

Bisphosphonates (BPs) are approved as standard therapy in breast cancer for the treatment of bone metastases, since they were demonstrated to reduce the prevalence of skeletal-related events including fractures and hypercalcemia. In the adjuvant setting, BPs can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone turnover, have also been evaluated for prevention of bone metastases occurrence. In this article we will review the mechanisms through which BPs have been demonstrated to prevent premetastatic niche formation and cell proliferation in bone lesions. Moreover, preclinical evidence of antitumoral effects of BPs will be presented and results from the most important clinical trials will be described critically. BPs may clearly play a clinically important role in early breast cancer in a postmenopausal adjuvant setting.

Bisphosphonates (Bps) are a class of drugs approved for treatment of bone metastases. There are two classes, the Nitrogenous-containing and non-Nitrogenous-containing Bps. They act on osteoclasts, inhibiting malignant osteolysis which causes skeletal-related events. These events are defined as pathological fractures, spinal cord compression, bone pain requiring palliative radiotherapy, orthopaedic surgery (such as vertebroplasty, kyphoplasty, and cementoplasty) and malignant hypercalcemia (HCM). In this chapter we will describe the mechanism of action of Bps and the major preclinical and clinical studies which evaluated the efficacy of these agents for the treatment of bone metastases from solid tumors. We will also describe the clinical data on the adjuvant role of Bps in breast and prostate cancer.

BACKGROUND:Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in RCC.PATIENTS AND METHODS:Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed.RESULTS:Median time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL), median time to first SRE was significantly prolonged versus control (n = 186) (3 months vs 1 month for control; P<0.05).CONCLUSIONS:RCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.

Background: This phase II trial was conducted to determine the activity and safety of the combination of fixed-dose rate (FDR) gemcitabine and capecitabine in metastatic biliary tract cancer (BTC) patients. Methods: Patients with unresectable BTC who had pathologically confirmed adenocarcinoma, no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and measurable disease were enrolled. Treatment consisted of FDR gemcitabine at 800 mg/m2 on days 1 and 8 every 21 days with capecitabine administered orally b.i.d. in equal doses (650 mg/m2 b.i.d.) for 14 days (28 doses). Results: Between May 2005 and February 2009, 30 patients were enrolled. The median age was 67 years (45–76) and there were 14 males. Thirty patients were evaluable for response and toxicity. A total of 221 cycles were administered (median 7, range 2–16). One patient achieved complete response and 7 patients achieved partial response, giving an overall response rate of 26.7% in the intention-to-treat population. Twelve patients (40.0%) had stable disease. The median progression-free survival was 6.33 months. The median overall survival was 10.8 months. Grade 3/4 neutropenia and thrombocytopenia were noted in 13 and 7% of the patients, respectively. Grade 2/3 nonhematologic toxicities were asthenia (54% of patients), diarrhea (17%), stomatitis (23%) and hand-foot syndrome (7%). There was no treatment-related death. The drugs taken were skipped at least once in 45% of the patients and the dose was reduced in 26% of them. Conclusions: The combination of FDR gemcitabine and capecitabine in this 3-week cycle is safe and seems to have a good activity in advanced biliary cancer.

Purpose: To evaluate bone density changes at the level of normal bone and bone metastases after zoledronic acid (ZA) treatment in oncologic patients.Materials and methods: We retrospectively evaluated 72 consecutive adult patients with histologically confirmed solid tumors with at least 1 newly diagnosed bone metastatic lesion. Bone metastases were diagnosed by bone scans and confirmed with computed tomography (CT). Patients received intravenous ZA, 4 mg, by 15-min infusion every 28 day through a peripheral or a central venous access and were monitored for at least 3 months and a maximum of 24 months. Bone density was determined at the level of bone metastases and at the level of normal trabecular and cortical bone using a ROI-based approach.Results: A significant increase was demonstrated at the level of normal trabecular bone of the calvarium and the femoral neck. No significant increase of density was observed at the level of the normal cortical bone. Bone metastases showed a significant increase in CT density as compared to baseline up to 24 months after zoledronic acid.Conclusion: We have found that long term treatment with ZA increases trabecular bone density in oncologic patients whereas normal cortical bone changes are not detectable. (C) 2012 Elsevier GmbH. All rights reserved.

BACKGROUNDData are limited regarding bone metastases from colorectal cancer (CRC). The objective of this study was to survey the natural history of bone metastasis in CRC.PATIENTS AND METHODSThis retrospective, multicenter, observational study of 264 patients with CRC involving bone examined cancer treatments, bone metastases characteristics, skeletal-related event (SRE) type and frequency, zoledronic acid therapy, and disease outcomes.RESULTSMost patients with bone metastases had pathologic T3/4 disease at CRC diagnosis. The spine was the most common site involved (65%), followed by hip/pelvis (34%), long bones (26%), and other sites (17%). Median time from CRC diagnosis to bone metastases was 11.00 months; median time to first SRE thereafter was 2.00 months. Radiation and pathologic fractures affected 45% and 10% of patients, respectively; 32% of patients had no reported SREs. Patients survived for a median of 7.00 months after bone metastases diagnosis; SREs did not significantly affect survival. Subgroup analyses revealed that zoledronic acid significantly prolonged median time to first SRE (2.00 months versus 1.00 month, respectively, P=0.009) and produced a trend toward improved overall survival versus no zoledronic acid.CONCLUSIONThis study illustrates the burden of bone metastases from CRC and supports the use of zoledronic acid in this setting.

4627 Background: bone metastases (mts) are an emerging clinical problem in renal cancer patients related to survival increase. We report the final data of largest survey never published in literature. Methods: 398 renal cancer patients (pts) with evidence of bone mts, all died at the moment of study inclusion, have been included. Clinico-pathological data, data on survival and Skeletal Related Events (SRE) data and skeletal related therapies have been collected and statistically analyzed. Results: 286 males/112 females; median age: 63 (16-87); pts with bone mts at the moment of renal cancer diagnosis: 31.4%; pts with single bone mts: 31.1%. Type: lytic 77%, mixed: 14.6%, blastic: 7.6 %. Sites: spine (65.8%), pelvis (38.4%), long bones (31.6%), other (18.8%). Median time to bone mts: 8 months (0-288) (all patients); 24 months (1-288) (pts without bone mts at diagnosis). Pts with at least 1 SRE: 71.1%. Types of SREs: pathologic fracture (12.6%), radiotherapy (61.8%), spinal compression (7.6%), bone surgery (14.8%), hypercalcaemia (3.2%). Median number of SRE for patient: 1 (0-4). Median time to first SRE: 2 (0-72), to second SRE: 4 (0-113), to third SRE: 11 (1-108). Median survival after bone mts diagnosis: 12 (1-178). Median survival after first SRE: 10 (0-144). Median survival in pts with at least one SRE: 14 (1-178); median survival in pts without SREs: 9 (0-62). In according with MKSCC criteria median time to skeletal disease was in patients with good prognosis was 24 (0-288), intermediate was 5 (0-180) and poor prognosis was 0 (0-77). A total of 168 pts received zoledronic acid until performance status worsening or death. 162 pts have been analysed as control group. The median time to first SRE in the zoledronic treated pts was 3 mths (0-101) compared with 1 mth (0 - 25) in the control group (p< 0.05). 5 cases of ONJ have been diagnosed. Conclusions: The present survey is the largest descriptive study concerning the natural history of bone disease in renal cancer patients. The effects of biological therpies on bone met will be presented during the meeting.

New emerging data suggest that bisphosphonates may exert antitumor properties. Preclinical studies have demonstrated that zoledronic acid (ZA) can induce direct and indirect antitumor activities such as inhibition of angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, stimulation of adoptive and innate immunity and emerging evidence suggests that the use of these agents may prevent the development of skeletal and extra skeletal metastases. This review will critically describe the new growing evidence of antitumor activity exerted by bisphosphonates in cancer patients, both in metastatic disease and in the adjuvant setting. The effects of bisphosphonates on survival in metastatic cancer patients will be described and evidence from retrospective analyses and prospective studies will be critically reported. The early evidence from prospective analyses of survival impact by ZA in the adjuvant setting in breast cancer will be discussed together with the recently published results of the ABCSG-12 study. A new "era" for bisphosphonates in the oncological setting is opening. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of adjuvant and metastatic cancer therapies.

Single-incision laparoscopic surgery (SILS) as a surgical approach in treatment of pancreatic disease has recently been reported in adults. However, its application in pancreatic surgery in children is limited. In this article, we report our preliminary experience of SILS in children with pancreatic disease.Three children with pancreatic tumor underwent single-incision laparoscopic partial pancreatectomy between July 2011 and August 2013. Two of three children were girls, and one was a boy. The ages ranged from 2 to 10 months, with an average age of 6.7 months.All operations were successfully performed. There was no conversion to the conventional multi-incision surgery. The mean operation time of the 3 cases was 153.3 minutes (range 120–200 minutes). The postoperative hospital stay was 7 days. The drainage tubes were kept for 3 to 4 days after surgery. There was no pancreatic juice leak in this case series. All patients were followed up and there was no recurrence.Single-incision laparoscopic partial pancreatectomy for children with pancreatic tumor is feasible.

Pamidronate is a potent aminobisphosphonate used in the treatment of osteolytic lesions and bone pain in bone metastases associated with cancer of the breast or with multiple myeloma, in Paget's disease of the bone and in hypercalcemia of malignancy. The drug is administered intravenously. Like other aminobisphosphonates, pamidronate selectively inhibits the mevalonate pathway by inhibition of farnesyl diphosphate synthase, inhibiting the conversion of geranylpyrophosphate to farnesylpyrophosphate, with a resultant depletion of geranylgeranylpyrophosphate and the inhibition of protein prenylation, including the prenylation of small GTPases. This results in osteoclast apoptosis and inhibition of bone resorption.

Context. Existing studies on breakthrough pain (BP) have reported different prevalence rates because of different settings, populations, and assessment methods. These studies have used cross-sectional designs, and the relationship of BP with analgesic treatment has not been evaluated.Objectives. The aim of this study was to longitudinally assess BP in cancer patients admitted to oncology units.Methods. A consecutive sample of patients admitted to oncology centers was selected. At admission (T0), three months after admission (T3), and six months after admission (T6), data on background pain and BP were recorded. BP was assessed in terms of its intensity, duration, number of episodes, onset with movement, spontaneous relief after stopping activity, limitation of physical activity, and effectiveness of analgesics.Results. Three hundred two patients completed the study. At T0, T3, and T6, 39%, 38%, and 33% patients, respectively, had continuous pain (P=0.294). Pain intensity significantly decreased (P=0.004 and 0.027 at T3 and T6, respectively). Most patients had BP at T0 (87.1%), T3 (80.9%), and T6 (73.2%), and there was a significant decrease in the prevalence of BP over time (P=0.016). Of 149 patients with BP, pain on movement was recorded in 43.6%, 43.4%, and 32.4% at T0, T3, and T6, respectively (P=0.228). Pain spontaneously decreased or ceased when stopping physical activity in 66%, 56%, and 62% at T0, T3, and T6, respectively (P=0.537). Pain on movement strongly limited physical activity in most patients.Conclusion. These data expand current information about BP and underline the need for a longitudinal assessment of a phenomenon that is invariably dependent on stage of disease, patient, and therapeutic factors. J Pain Symptom Manage 2010;40:183-190. (C) 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

e15530 Background: The aims of this phase II trial are to determine the activity and the safety of the new combination modality with Gemcitabine fixed dose rate (FDR) infusion and Capecitabine in patients with advanced pancreatic cancer. Methods: Patients with unresectable pancreatic cancer who had pathologically confirmed adenocarcinoma, no prior chemotherapy, ECOG PS < 2 and measurable disease were enrolled. Gemcitabine (800 mg/mq IV infused in 80 minutes on days 1 and 8) and Capecitabine (650 mg/mq orally twice daily for 14 days) were administered and repeated every 21 days. Results: 47 patients were enrolled between January 2004 and October 2008. Median age was 66 (range: 37–79), 18 female and 29 male. A total of 299 cycles were administered, median cycles for patient were 6 (range: 1–17). CR was observed in one patient (2.1 %) and 10 patients achieved PR (21.3 %) giving an overall response rate of 23.4 % in intention-to-treat population. 22 pts (46.8 %) had stable disease obtaining an overall tumour control of 70.2 %. The median time to progression was 5.2 months (95 % CI, 2.4–7.6); the median overall survival was 8.4 months (95 % CI, 5.5–20). Grade 3–4 neutropenia was observed in 29.8 % of subjects, thrombocytopenia in 6.4 %. Grade 1–2 non-hematological toxicities were asthenia (61.7 %), diarrhea (29.8%), stomatitis (29.8 %) and hand foot syndrome (2.1 %). There were no treatment-related deaths. Gemcitabine was skipped at least once/reduced in 51/10.6 % of the patients, respectively. Capecitabine was skipped at least once/reduced in 16/8 % of the patients, respectively. Conclusions: The combination of FDR Gemcitabine and Capecitabine with this modality of infusion is feaseble, safe and seems to be active. No significant financial relationships to disclose.

Biliary tract cancers (BTCs) include cholangiocarcinoma (intrahepatic, perihilar and extrahepatic), carcinoma of the gall bladder and ampullary carcinoma. In patients with advanced disease the prognosis is poor. There is not a consensus regarding treatment strategy. Chemotherapy has only limited efficacy. This review summarizes the new approaches for BTC patients and the rationale for targeted therapies. The prognostic factors and the molecular features of BTC are analyzed. The clinical trials evaluating the targeted agents are accurately described, especially those assessing the role of anti-EGFR and antiangiogenic drugs. The ongoing trials are also analyzed. In fact, only the results of these trials will establish which is the most effective agent or combination for this setting.

e15510 Background: The combination of fixed dose rate (FDR) gemcitabine (C) and capecitabine (G) has been demonstrated to be well tolerated in patients with advanced cancers. To determine the activity and safety of this combination in metastatic metastatic biliary tract cancer patients, a phase II trial was conducted. Methods: Patients with unresectable BTC who had pathologically confirmed adenocarcinoma, no prior chemotherapy, ECOG PS < 2 and measurable disease were enrolled. Treatment consisted of FDR G at 800 mg/m(2) infused in 80 minutes on days 1 and 8 every 21 days with C administered orally bid in equal doses (650 mg/m2 bid) for 14 days (28 doses). Results: Between Feb 2005 and Sept 2008, 30 pts were enrolled. Median age was 67 (45–86) with 14 males. 30 pts were evaluable for response and toxicity. A total of 219 cycles were administered (median, 8; range, 2–16). One patient achieved CR and 8 pts achieved PR giving an overall response rate of 30.0% in intention-to-treat population (95% CI, 19.2–42.6%). And 11 pts (36.6%) had stable disease. The median time to progression of all patients was 7.4 months (mo) (95% CI, 3.2–19.5). The median overall survival was 15.3 mo (95% CI, 4.6–27.9). Grade 3/4 neutropenia and thrombocytopenia were noted in 13.3% and 6.6% of the pts, respectively. Grade 2/3 non-hematologic toxicities were asthenia (50.0 % of pts), diarrhea (16.6%), stomatitis (23.3%) and hand-foot syndrome (6.6%). There was no treatment-related death. Gemcitabine was skipped at least once/reduced in 20%/15% of the patients, respectively. Capecitabine was skipped at least once/reduced in 20%/25% of the patients, respectively. Conclusions: The combination of FDR gemcitabine and capecitabine in this three week cycle is safe and seems to have advantages in activity over other regimens in advanced biliary cancer. No significant financial relationships to disclose.