Search

Background Prostate-specific membrane antigen is overexpressed in prostate cancer and it is considered a good target for positron emission tomography/computed tomography imaging of primary cancer and recurrent/metastatic disease, as well as for radioligand therapy. Different PSMA-analogues labeled with [68Ga]gallium have been investigated, showing excellent imaging properties; however, only small amounts can be produced for each radiolabeling. Recently, a [18F]fluoride labeled PSMA-inhibitor, [18F]PSMA-1007, has been introduced, and it has ensured large-scale productions, overcoming this limitation of [68Ga]PSMAs. In this study, PSMA-1007 has been labeled with low (A), medium (B) and high (C) starting activities of [18F]fluoride, in order to verify if radiochemical yield, radiochemical purity and stability of [18F]PSMA-1007 were affected. These parameters have been measured in sixty-five consecutive batches. In addition, the estimation of [18F]PSMA-1007 production costs is provided. Results The radiochemical yield for low and medium activities of [18F]fluoride was 52%, while for the high one it decreased to 40%. The radiochemical purity was 99% for all three activities. [18F]PSMA-1007 did not show radiolysis up to 8 h after the end of synthesis, confirming that the radiopharmaceutical is stable and suitable to perform diagnostic studies in humans for a long period of time after the end of radiolabeling. Furthermore, radiochemical stability was demonstrated in fetal bovine serum at 4 °C and 37 °C for 120′. Conclusions A starting activity of [18F]fluoride of 90 GBq (B) seems to be the best option enabling a final amount of about of 50 GBq of [18F]PSMA-1007, which is promising as it allows to: (a) perform a large number of scans, and/or (b) supply the radiopharmaceutical to any peripheral diagnostic centers in need.

Background: Eighty percent of patients with pancreatic adenocarcinoma present a locally advanced or metastatic disease at diagnosis and are not eligible for surgery if not with palliative intent. In cases of locally advanced disease (LAPC), the combination of chemo and radiotherapy is the only therapeutic option and correlates with a median survival of 15 months (10 months without treatment), with partial remission of disease in 50% of cases. The feasibility and safety of Electrochemotherapy (ECT) have been demonstrated in the treatment of deep tumors. Aim: The aim of the study is to evaluate the efficacy of electrochemotherapy (ECT) followed by conventional systemic treatment compared to the only conventional systemic treatment in LAPC in terms of objective response and overall survival. Patients and Methods: This study is a phase IIb prospective multicenter randomized controlled trial with two arms. The study will include 90 patients: 45 in the control group and 45 in the experimental group. Patients with LAPC in the control arm will receive conventional chemotherapy (FOLFOXIRI). Patients with LAPC in the experimental arm will be subjected to Electrochemotherapy and subsequently to FOLFOXIRI. The objective response at 30, 90, and 180 days from treatment will be based on the computed tomography (CT), magnetic resonance (MR), and positron emission tomography/CT response (PET/CT). The objective long-term treatment response will be evaluated with the modified response evaluation criteria in solid tumors (m-RECIST) criteria, which will take into account the difference in vascularization, determined by the images obtained by CT and MR of the tumor treated before and after ECT. Conclusions: Not resectable liver metastasis, pancreatic tumors, and locally advanced renal carcinomas can be treated with laparoscopic electrodes. ECT could represent an effective therapeutic option for patients not eligible for surgery susceptible to be managed only with palliative therapies.

Objective. To assess local disease control rates (LDCR) and overall survival (OS) in locally advanced pancreatic cancer (LAPC) treated with electrochemotherapy (ECT). Methods. Electrochemotherapy with bleomycin was performed in 25 LAPC patients who underwent baseline Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and Position Emission Tomography (PET) scans before ECT and 1 and 6 months post ECT. LDCR were assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Choi criteria. Needle electrodes with fixed linear (N-30-4B) or fixed hexagonal configurations (N-30-HG or I-40-HG or H-30-ST) or variable geometry (VGD1230 or VGD1240) (IGEA S.p.A., Carpi, Italy) were used to apply electric pulses. Pain evaluation was performed pre-ECT, after 1 month and after 6 months with ECT. Overall survival estimates were calculated by means of a Kaplan-Meier analysis. Results. At 1 month after ECT, 76% of patients were in partial response (PR) and 20% in stable disease (SD). Six months after ECT, 44.0% patients were still in PR and 12.0% in SD. A LDCR of 56.0% was reached six months after ECT: 13 patients treated with fixed geometry had a LDCR of 46.1%, while for the 12 patients treated with variable geometry, the LDCR was 66.7%. The overall survival median value was 11.5 months: for patients treated with fixed geometry the OS was 6 months, while for patients treated with variable geometry it was 12 months. Electrochemotherapy was well-tolerated and abdominal pain was rapidly resolved. Conclusions. Electrochemotherapy obtained good results in terms of LDCR and OS in LAPC. Multiple needle insertion in a variable geometry configuration optimized by pre-treatment planning determined an increase in LDCR and OS compared to a fixed geometry configuration.

Importance Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. Objective To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. Design, Setting, and Participants This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line–treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020. Interventions Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo–folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm). Main Outcomes and Measures The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL). Results Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n = 115) or the experimental arm (n = 115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm;P = .89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm;P = .15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99;P = .04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%];P = .006) and nausea (2 [1.8%] vs 8 [7.0%];P = .05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs −7.41 [2.95] at 24 weeks;P= .02), and constipation scores (mean [SD] change from baseline, −17.2 [3.73] vs −0.62 [4.44];P= .003). Conclusions and Relevance In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives. Trial Registration EudraCT Identifier:2011-004997-27; ClinicalTrials.gov Identifier:NCT01718873

AIM To report early imaging assessment of ablated area post electrochemotherapy (ECT) in patients with locally advanced pancreatic cancer (LAPC). METHODS ECT was performed in 19 LAPC patients enrolled in an approved ongoing clinical phase I/II study. Before and after ECT, 18 patients underwent computed tomography (CT) scan, 11 patients underwent morphological and functional magnetic resonance (MR) scan (dynamic contrast enhanced-MRI) calculating wash-in slope (WIS) and wash-out slope (WOS); diffusion weighted imaging calculating pseudo-diffusivity (Dp), perfusion fraction (fp) and tissue diffusivity (Dt); 10 patients underwent positron emission tomography (PET). Response evaluation criteria in solid tumour (RECIST) on MR and CT were used to assess tumour therapy response. Choi on CT, PET response criteria in solid tumors (PERCIST) on PET and functional parameters on MR were used to evaluate treatment response. RESULTS For each patient no significant reduction was measurable by CT and MR using RECIST. According Choi criteria a partial response was obtained in 18/18 (100.0%) patients. According PERCIST criteria 6/10 (60.0%) patients showed a partial response, 3/10 (30.0%) stable disease and 1/10 (10.0%) progression disease. Moreover, using functional MR parameters, a significant reduction of viable tumour after ECT can be observed. According ΔWIS and ΔWOS 9/11 (81.8%) patients exhibited a partial response and 2/11 (18.2%) stable disease; 8/11 (72.7%) patients were considered in partial response by ΔDp evaluation and 3/11 (27.3%) in stable disease; according ΔDt 7/11 (63.6%) patients showed a partial response, 1/11 (9.1%) showed progression of disease and 3/11 (27.3%) were stable. Perfusion fraction fp showed a significant reduction after ECT only in four patients. No significant difference was observed after ECT in signal intensity of T1-weighted images and T2-weighted images, and in equilibrium-phase of contrast study, according to χ2 test was observed. A good correlation was reported between ΔHounsfield unit and Δmaximum standardized uptake value and between Δfp and ΔWOS, with a significant statistically difference (P < 0.05) using Spearman correlation coefficient. CONCLUSION Perfusion and diffusion MR derived parameters, Choi, PERCIST criteria are more performant than morphological MR and CT criteria to assess ECT treatment response.

AimThe aim of the present study was to assess the estimated "per patient" total cost for a single Oncologic Italian Cancer Center participating in a multicenter clinical trial with new anticancer biological agents using the activity-based costing (ABC) methodology.MethodologyNine randomized phase 3 clinical trials employing biological agents at the National Cancer Institute of Napoli, Italy, were analyzed to indentify "per patient" costs of each trial, according to the ABC methodology. The average consumption of resources for a patient completing the entire planned treatment was estimated for each trial. Through interviews of the personnel (doctors, nurses and technicians) and by analyses of the clinical trials protocols, the main activities of the 9 clinical trials were identified and, for each trial, the complete health care pathway of the patients and the treatment programmes were minutely reconstructed. Drug costs were not included because provided by Sponsors.Principal findingsThe average costs of the pre-study, treatment, monitoring, follow-up, audit, and administrative activities accounted for 2.357, 4.783, 700, 372, 1.263, and 9 Euro, respectively. The average total cost estimated for all "per patient" activities, including overhead costs, was 11.379 Euro. Staff costs accounted for € 5.988, while costs of diagnostic test accounted for 3.494 Euro. Clinical trials with immunotherapeutic drugs accounted for higher costs (+601 Euro as oncological staff costs, +1.318 Euro as intermediate services cost and +384 Euro as overheads).ConclusionsThe average total cost estimated for all "per patient" activities of a clinical trial with new anticancer biological agents was 11.379 Euro using the ABC methodology.

Programmed death 1 (PD-1) blocking antibodies now represent a major advance in the treatment of patients with classical Hodgkin lymphoma (cHL) who relapse after autologous stem cell transplantation (ASCT) and pre- and/or post-ASCT brentuximab vedotin or after at least three lines of therapy. However, uncertainties still remain on the optimal use of these agents in refractory Hodgkin disease. A panel of experts was convened to produce a consensus document aimed at providing practice recommendations for the optimal use of PD-1 blocking antibodies in cHL, especially on pretreatment selection and evaluation of cHL patients' response and treatment length, management of PD-1 blockade therapy-treated patients, evaluation and management of toxicity. Our hope is that these recommendations might help hematologists to improve optimal management of patients with pretreated cHL.

Background Pancreatic adenocarcinoma is currently one of the deadliest cancers with high mortality rate. This disease leads to an aggressive local invasion and early metastases, and is poorly responsive to treatment with chemotherapy or chemo-radiotherapy. Radical resection is still the only curative treatment for pancreatic cancer, but it is generally accepted that a multimodality strategy is necessary for its management. Therefore, new alternative therapies have been considered for local treatment. Conclusions Chemotherapeutic resistance in pancreatic cancer is associated to a low penetration of drugs into tumour cells due to the presence of fibrotic stroma surrounding cells. In order to increase the uptake of chemotherapeutic drugs into tumour cells, electrochemotherapy can be used for treatment of pancreatic adenocarcinoma leading to an increased tumour response rate. This review will summarize the published papers reported in literature on the efficacy and safety of electrochemotherapy in pre-clinical and clinical studies on pancreatic cancer.

Purpose: Radioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation. Methods: This was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records. Results: Most radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1–45.9) versus 30.9 months (19.6–46.8); p = 0.243); stage B: 18.4 months (11.2–19.4) versus 22.8 months (10.9–34.2); p = 0.815; and stage C: 8.8 months (7.1–10.8) versus 10.8 months (7.7–12.6); p = 0.976. Conclusions: Radioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment.

UNLABELLED: Previous studies indicate that FDG PET/CT may predict pathological response in patients undergoing neoadjuvant chemo-radiotherapy for locally advanced rectal cancer (LARC). Aim of the current study is evaluate if pathological response can be similarly predicted in LARC patients after short course radiation therapy alone. METHODS: Thirty-three patients with cT2-3, N0-2, M0 rectal adenocarcinoma treated with hypo fractionated short course neoadjuvant RT (5x5 Gy) with delayed surgery (SCRTDS) were prospectively studied. All patients underwent 3 PET/CT studies at baseline, 10 days from RT end (early), and 53 days from RT end (delayed). Maximal standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) of the primary tumor were measured and recorded at each PET/CT study. We use logistic regression analysis to aggregate different measures of metabolic response to predict the pathological response in the course of SCRTDS. RESULTS: We provide straightforward formulas to classify response and estimate the probability of being a major responder (TRG1-2) or a complete responder (TRG1) for each individual. The formulas are based on the level of TLG at the early PET and on the overall proportional reduction of TLG between baseline and delayed PET studies. CONCLUSIONS: This study demonstrates that in the course of SCRTDS it is possible to estimate the probabilities of pathological tumor responses on the basis of PET/CT with FDG. Our formulas make it possible to assess the risks associated to LARC borne by a patient in the course of SCRTDS. These risk assessments can be balanced against other health risks associated with further treatments and can therefore be used to make informed therapy adjustments during SCRTDS.

BACKGROUND: Animal models of para-renal cancer can provide useful information for the evaluation of tumor response to loco-regional therapy experiments in solid tumors. The aim of our study was to establish a rabbit para-renal cancer model using locally implanted VX2 tumors. METHODS: In order to generate a rabbit model of para-renal cancer, we established four hind limb donor rabbits by using frozen VX2 tumor samples. Following inoculation, rabbits were monitored for appetite and signs of pain. Viable tumors appeared as palpable nodules within 2 weeks of inoculation. Tumor growth was confirmed in all rabbits by high-resolution ultrasound analysis and histology. Once tumor growth was established, hind limb tumors extraction was used for tumor line propagation and para-renal tumor creation. Twenty-one rabbit models bearing para-renal cancer were established by implanting VX2 tumor into the para-renal capsula. Tumors developed into discreet 2-3 cm nodules within 1-3 weeks of implantation. Serial renal ultrasonography follow-up, starting 1 week after tumor implantation, was performed. Two weeks after tumor implantation, rabbits were euthanized and tumors and other organs were collected for histopathology. RESULTS: Tumor growth after VX2 tumor fragment implantation was confirmed in all rabbits by high-resolution ultrasound (US) imaging examinations of the para-renal regions and was measured with digital caliper. The para-renal injection of VX2 tumor fragments, achieved tumor growth in 100% of cases. All data were confirmed by histological analysis. CONCLUSIONS: We generated for the first time, a model of para-renal cancer by surgical tumor implantation of VX2 frozen tumor fragments into rabbit's para-renal region. This method minimizes the development of metastases and the use of non-necrotic tumors and will optimize the evaluation of tumor response to loco-regional therapy experiments. Background: Animal models of para-renal cancer can provide useful information for the evaluation of tumor response to loco-regional therapy experiments in solid tumors. The aim of our study was to establish a rabbit para-renal cancer model using locally implanted VX2 tumors. Methods: In order to generate a rabbit model of para-renal cancer, we established four hind limb donor rabbits by using frozen VX2 tumor samples. Following inoculation, rabbits were monitored for appetite and signs of pain. Viable tumors appeared as palpable nodules within 2 weeks of inoculation. Tumor growth was confirmed in all rabbits by high-resolution ultrasound analysis and histology. Once tumor growth was established, hind limb tumors extraction was used for tumor line propagation and para-renal tumor creation. Twenty-one rabbit models bearing para-renal cancer were established by implanting VX2 tumor into the para-renal capsula. Tumors developed into discreet 2-3 cm nodules within 1-3 weeks of implantation. Serial renal ultrasonography follow-up, starting 1 week after tumor implantation, was performed. Two weeks after tumor implantation, rabbits were euthanized and tumors and other organs were collected for histopathology. Results: Tumor growth after VX2 tumor fragment implantation was confirmed in all rabbits by high-resolution ultrasound (US) imaging examinations of the para-renal regions and was measured with digital caliper. The para-renal injection of VX2 tumor fragments, achieved tumor growth in 100% of cases. All data were confirmed by histological analysis. Conclusions: We generated for the first time, a model of para-renal cancer by surgical tumor implantation of VX2 frozen tumor fragments into rabbit's para-renal region. This method minimizes the development of metastases and the use of non-necrotic tumors and will optimize the evaluation of tumor response to loco-regional therapy experiments.

Background:This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin-and irinotecan-based systemic chemotherapy regimens.Methods:Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2).Results:Of 50 eligible patients, 38 (76%) had received ≥4 lines of chemotherapy. Most presented with synchronous disease (72%)

Background: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. Methods/Design: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500–825 mg/m2/bid), on days 1–21, or (b) capecitabine as above plus VPA (oral daily day −14 to 21, with an intra-patient titration for a target serum level of 50–100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power. Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-istones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT. Discussion: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT. EudraCT Number: 2012-002831-28. Trial registration: ClinicalTrials.gov number, NCT01898104

"\"Markers predictive of treatment effect might be useful to improve the treatment of patients with metastatic solid tumors. Particularly, early changes in tumor metabolism measured by PET\\\/CT with F-18-FDG could predict the efficacy of treatment better than standard dimensional Response Evaluation Criteria In Solid Tumors (RECIST) response. Methods: We performed PET\\\/CT evaluation before and after 1 cycle of treatment in patients with resectable liver metastases from colorectal cancer, within a phase 2 trial of preoperative FOLFIRI plus bevacizumab. For each lesion, the maximum standardized uptake value (SUV) and the total lesion glycolysis (TLG) were determined. On the basis of previous studies, a

Background & Aims The European Network on Radioembolization with Yttrium-90 resin microspheres study group (ENRY) conducted a retrospective study to evaluate the outcomes among elderly (≥70 years) and younger patients (

BACKGROUND To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. PATIENTS AND METHODS A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. RESULTS Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P

Background The present article reports the updated survival outcome of the 200 patients enrolled in the Southern Italy Cooperative Oncology Group 9908 trial, which compared 12 weekly cycles of cisplatin–epirubicin–paclitaxel (PET) with 4 triweekly (once every 3 weeks) cycles of epirubicin–paclitaxel (ET) in patients with locally advanced breast cancer (LABC). Methods The effects of treatment, pathologically documented response (pathological response), pre- and post-treatment biomarkers on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) are analysed. Results At a median follow-up of 74 (range 48–105 months) months, the 5-year RFS, DMFS, and OS were 64 % versus 53% (P = 0.11), 73% versus 55% (P = 0.04), and 82% versus 69% (P = 0.07) in PET and ET, respectively. At multivariate analysis, after adjusting treatment effect for pretreatment biomarkers, PET independently predicted better DMFS (P = 0.018) and OS (P = 0.03), whereas the impact on RFS was of borderline significance (0.057). PET treatment was significantly better than ET treatment only in high-grade or highly proliferating tumours. The better outcome in PET arm was the results of both the higher rate of patients with optimal pathological response and the lower rate of patients with biologically aggressive residual tumour. Conclusions The PET weekly regimen significantly improves both DMFS and OS in LABC patients, compared with the triweekly ET combination. The therapeutic advantage is limited to patients with highly aggressive tumours.

To report an unusual case of persistent thyrotoxicosis after treatment of Graves' disease, because of coexistence of struma ovarii.We report the clinical history, imaging studies, laboratory and pathologic data, and treatment in a patient with persistent hyperthyroidism after surgical treatment of Graves' disease. In addition, we discuss some aspects of the pathogenesis of hyperthyroidism due to functioning struma ovarii.A 42-year-old woman underwent near-total thyroidectomy for treatment of Graves' disease. Post-operatively, hyperthyroidism was still present. Methimazole was administered again, and performance of a 131I whole-body scan demonstrated a focus of intense uptake in the pelvis. Pelvic ultrasonography revealed a mass (11 by 8 by 7.1 cm) arising from the right ovary, with both solid and cystic components. Abdominal surgical exploration was performed, and the final histologic diagnosis was struma ovarii. The symptoms of hyperthyroidism diminished, and 3 weeks postoperatively, the thyroid hormone levels were in the hypothyroid range.In patients with refractory hyperthyroidism after thyroid surgical treatment, radioiodine scanning should be performed to diagnose or exclude the functioning profile of ovarian masses.

Huntington's disease (HD) is caused by a CAG repeat mutation translating as a polyglutamine (poly(Q)) expansion in the huntingtin protein, whose main pathogenic mechanism is a gain of toxic function. In the case of large expansions beyond 60 repeats onset may result in juvenile HD (JHD, onset before 20 years of age). However, the triplet number does not represent the only onset modifier even in case of large expansions, mechanisms other than the size of the mutation contribute to the phenotype. In this review we discuss the possibility that some of the pathogenic mechanisms contributing to age at onset and progression may differ in the early onset HD compared with the classical adult pathology.

Somatostatin receptor scintigraphy is useful in diagnosing tumors with increased expression of somatostatin receptors. The correct use of this technique reveals the localization of neuroendocrine primary tumors and unknown metastases in approximately 90% of patients. However, somatostatin receptor scintigraphy also can image many other human tumors expressing somatostatin receptors, including malignant lymphomas and thymomas. The sensitivity of somatostatin receptor scintigraphy to image somatostatin receptor-positive tumors is very high, but due to the variable expression of specific receptor subtypes, the specificity can be relatively low. This drawback is crucial in evaluating lymphoproliferative diseases, or, in general, when immune cells are involved. The sensitivity of somatostatin receptor scintigraphy for Hodgkin's lymphoma is 95%-100%, whereas for non-Hodgkin's lymphoma it is around 80%. It has been shown that the uptake of [(111)In-DTPA(0)]octreotide in lymphomas is lower compared to the uptake in neuroendocrine tumors. This is mainly attributed to the low number of receptors on immune cells compared to neuroendocrine cells; however, ligand-induced internalization and differential receptor regulation may also participate in determining this phenomenon. Therefore, caution should be taken when interpreting data from some studies. Several new ligands are currently under study to improve these limits and the expression of other neuropeptide receptors is being investigated to provide a molecular basis for in vivo multireceptor targeting of tumors. With the use of currently available somatostatin analogs, somatostatin receptor scintigraphy does not seem to have a significant impact in patients with lymphomas for diagnostic purposes. There are a few exceptions, however. Among these, the staging and restaging of extragastric lymphoma MALT-type may present some advantages. Conversely, somatostatin receptor scintigraphy in the imaging of thymic malignancies could enhance both our diagnostic and therapeutic capabilities. Somatostatin receptor scintigraphy is diagnostically relevant in differentiating malignant from benign lesions, especially in those patients with associated paraneoplastic syndromes, and is the main criterion to select patients suitable for therapy with somatostatin analogs. Recent findings emerging from in vitro studies on somatostatin receptor physiology in immune cells will certainly reopen and expand the potential applications of somatostatin analogs for in vivo diagnostic and therapeutic options.

The eye complications associated most typically withhyperthyroidism caused by Graves’ disease range fromdiscomfort and lid retraction to disfiguring proptosis,diplopia and sight loss (1, 2). Usually called Graves’ophthalmopathy, this condition is better termedthyroid-associated ophthalmopathy (TAO), emphasis-ing the wide spectrum of thyroid disorders in thesepatients. TAO is one of the most difficult autoimmunedisorders to investigate; it is characterised by enlarge-ment of the extraocular muscles and an increase inthe retrobulbar fat, which cause eye proptosis, themain clinical manifestation of the disease (Table 1).Involvement of the cornea, the optic nerve and orbitalsoft tissues may occur during the natural course ofthe disease (3).An exact in vivo characterisation of the underlyingpatho-physiological mechanism of TAO has remaineddifficult because the affected retrobulbar space is noteasily accessible. The identification of patients withGraves’ ophthalmopathy is based primarily on clinicalsigns and symptoms affecting one or both eyes (4).Additional information can be obtained from conven-tional imaging methods such as magnetic resonanceimaging (MRI) or computed tomography (CT), whichallow gross changes in the retrobulbar space (e.g.muscle swelling, oedema or fibrosis) to be recognised(1, 2). By using histology, orbital infiltration withactivated T lymphocytes and evidence of local release ofcytokines and interactions of lymphocytes with retro-bulbar fibroblasts have been demonstrated, suggestingthat TAO is an organ-specific autoimmune disease (1,2, 5, 6). Although it is accepted that the pathogenesisof TAO is almost certainly multifactorial, the triggerevent seems to be the activation of T cells directedagainst a thyroid follicular cell antigen(s) that thenrecognise and bind to a similar antigen(s) in orbitaltissue (1, 2, 6). Thereafter, these activated orbital T cellsrelease a variety of substances and stimulate excessiveproduction of glycosaminoglycans and collagen byorbital fibroblasts. This causes the inflammatory andoedematous changes of thyroid ophthalmopathy (7). Infact, during the early stages of the disease, macro-phages, highly specialised T cells, mast cells and,occasionally, plasma cells infiltrate the orbital connec-tive, adipose and muscle tissue. Several cytokines, suchas interferon-g, tumour necrosis factor-a, interleukin-1 and transforming growth factor-b, as well as growthfactors, such as insulin-like growth factor-I (IGF-I) andplatelet-derived growth factor, have been detectedwithin the orbital tissues (5–8). All these substancesare probably produced both by infiltrating immuno-competent cells and by residential fibroblasts, adipo-cytes, myocytes and microvascular endothelial cells(9). Cytokines and growth factors stimulate cellproliferation, glycosaminoglycan synthesis and expres-sion of immunomodulatory molecules in orbitalfibroblasts and microvascular endothelial cells (Table2).No consensus exists regarding the common anti-gen in the orbit and thyroid, the thyrotrophin(thyroid-stimulating hormone, TSH) receptor or avariant, or on the role of circulating antibodiesagainst extraocular muscle and fibroblast compo-nents. The finding of expression of the TSH receptorin retro-orbital tissue may provide the link, pre-viously lacking, between orbital involvement andthyroid disease in Graves’ disease. Thyroid-stimulat-ing antibodies directed against the TSH receptorcould interact with the orbital components thatexpress the receptor, thus stimulating glycosamino-glycans, cellular matrix proteins and connectivetissue production and bringing about antibody-dependent cell-mediated cytotoxicity mediated bynatural killer cells. On the other hand, T cells thatreact with the TSH receptor will be targeted to theorbit where, in the presence of the antigen, they willsecrete various cytokines that stimulate fibroblasts toproliferate, to express the major complex of histo-compatibility class II antigens and to synthesizecollagen and connective tissue (10).

Corticosteroid treatment is successfully used in Graves' ophthalmopathy, and its effect varies according to the phase of the disease. The infiltration of the orbit by activated lymphocytes may explain the effectiveness of corticosteroid therapy. Scintigraphy with [111In-DTPA-D-Phe1]-octreotide was recently used to reveal the presence of activated lymphocytes in foci of autoimmune diseases, because elevated amounts of somatostatin receptors are expressed in the surface of these cells. The aim of the current study was to evaluate whether the degree of orbital [111In-DTPA-D-Phe1]-octreotide uptake is able to predict the response to corticosteroid therapy in patients with Graves' ophthalmopathy. Ten patients with Graves' ophthalmopathy entered the study. In all patients scintigraphy was performed, and subsequently, corticosteroid therapy (methylprednisolone, 1 g i.v. for 2 consecutive days a week for 6 weeks) was given. Clinical activity of Graves' ophthalmopathy was evaluated before and after treatment by calculating the ophthalmopathy index (OI). Planar and single photon emission computed tomography (SPECT) images of the head were obtained 24 h after the i.v. injection of 120-190 MBq of [111In-DTPA-D-Phe1]-octreotide. Radioligand uptake within each orbit (O) and brain (B) was measured using the region of interests (ROI) method and the O-to-B ratio was determined. According to the O-to-B ratio, the images were classified using the following three points score: 0 = O-to-B ratio < or =1; 1 = O-to-B ratio between 1 and 2.5; 2 = O-to-B ratio > or =2.5. The value of OI, measured before and after corticosteroid treatment, was correlated to the scintigraphic score. A significant change of OI was observed between posttreatment and pretreatment evaluation both in orbits with score 2 (OI: 15.4 +/- 1.5 vs. 9.6 +/- 0.5, P < 0.005) and in those with score 1 or 0 (OI: 12.9 +/- 1.5 vs. 11.5 +/- 1.4, P < 0.05) at the scintigraphy. However, when the OI was calculated excluding the changes in the soft tissue, which generally occur in all patients independently from the phase of the disease, a significant change of OI was observed only in the orbits with score 2 (OI: 12.9 +/- 1.3 vs. 8.3 +/- 0.5, P < 0.01) but not in those with score 0 or 1 (OI: 11.2 +/- 1.3 vs. 10.4 +/- 1.3). In particular, 6 weeks after corticosteroid treatment, the patients with orbital score 2 at the scintigraphy had a significant improvement of soft tissue changes, proptosis, lagophthalmos, extraocular muscle movements impairment, and diplopia, whereas patients with score 0 or 1 had only a significant improvement of the soft tissue inflammation. In conclusion, the current preliminary data suggested that [111In-DTPA-D-Phe1]-octreotide scintigraphy is able to predict the clinical response to corticosteroid treatment in patients with Graves' ophthalmopathy, and may be considered an useful approach to select the patients for the proper treatment.

The efficacy of dopaminergic agents in the medical treatment of pituitary adenomas is well known. Quinagolide is a nonergot derivative dopamine agonist, which binds dopamine D2 receptors with high affinity. The treatment with this drug is reported to suppress hormone levels and to cause tumor shrinkage in prolactinomas and in a few GH-secreting pituitary adenomas. In clinically nonfunctioning pituitary adenomas (NFPA), the efficacy of quinagolide treatment is controversial. The scintigraphy of the pituitary region using 123I-methoxybenzamide (123I-IBZM) allows us to visualize in vivo the expression of dopamine D2 receptors on pituitary tumors. In this study, the pituitary scintigraphy with 123I-IBZM was performed in 14 patients with macroadenoma before starting a long-term treatment with quinagolide: 6 NFPA with high circulating alpha-subunit levels, 4 PRL-secreting, and 4 GH-secreting adenomas. A 3-point score was used to grade the ligand accumulation within the pituitary adenomas: 0 = negative, 1 = moderate uptake (equal to that recorded in the cerebral cortex), and 2 = intense uptake (equal to that recorded in the basal nuclei). The treatment with quinagolide was carried out at the dose of 0.3-0.6 mg/day for 6-12 months. Clinical, biochemical and hormonal assessment was repeated monthly during the first 3 months, then quarterly. Sellar magnetic resonance imaging was performed before and after 6 and 12 months of quinagolide treatment, to evaluate tumor shrinkage (> 25% of baseline size). In all 14 patients, a significant positive correlation was found between the degree of 123I-IBZM uptake and the clinical response to quinagolide treatment (r = 0.90; P < 0.001). In particular, the normalization of serum alpha-subunit and PRL levels, respectively, was achieved in 3 patients with NFPA and in 2 patients with prolactinoma, who showed intense 123I-IBZM uptake in the pituitary region. In 4 of these 5 patients with positive scan, a significant tumor shrinkage occurred between 6 and 12 months after the beginning of quinagolide treatment. In all patients with GH-secreting adenoma, no significant uptake of 123I-IBZM was found and no significant decrease of circulating GH and/or insulin-like growth factor-I levels, and tumor shrinkage was obtained during long-term treatment with quinagolide. In conclusion, the pituitary scintigraphy with 123I-IBZM can be considered a useful tool to indicate adenomas with significant expression of functioning D2 receptors. This innovative technique may predict the response to long-term treatment with quinagolide in patients with NFPA, where the lack of pituitary hormone hypersecretion makes difficult the monitoring of medical treatment efficacy.

Iodine-131 metaiodobenzylguanidine (MIBG) scintigraphy, computed tomography (CT) and ultrasonography (US) were used to localize tumour lesions in 28 children with histologically proven neuroblastoma. Overall, a total of 73 lesions were detected on imaging studies. MIBG scintigraphy, CT and US localized 63 (86%), 49 (67%) and 36 (49%) of these lesions, respectively. The findings of the three imaging techniques were concordant in respect of only 31 (42%) of the lesions. The best agreement among MIBG scintigraphy, CT and US was observed for abdominal lesions (the techniques were concordant for 22 of 23 lesions, i.e. 96%). MIBG scintigraphy detected nine out of ten (90%) liver metastases, but agreement with CT and US was observed in only six instances (60%). The imaging findings were concordant in respect of only two (33%) out of six lymph node metastases; the MIBG scan was normal in the other four cases. Imaging agreement was observed for a lesion located in the pelvis. MIBG and CT findings were concordant in four lesions located in the chest, but US was not performed. MIBG scintigraphy depicted the majority (96%) of the skeletal lesions (23/24); CT showed five of these, but, again, US was not performed. The imaging findings were not concordant as regards the remaining five lesions located in different anatomical sites. The results indicated that MIBG imaging is more sensitive that CT and US in localizing the majority of neuroblastoma lesions. Since the metastatic spread of neuroblastoma is unpredictable, we recommend MIBG scintigraphy as the initial imaging modality for staging of these patients. US and, particularly, CT should be performed thereafter to clarify the anatomical detail of the lesions detected on MIBG scans, or when MIBG findings are normal or equivocal.

BackgroundParathyroid carcinoma is a rare malignancy, with an incidence of 0.5 to 4% of all cases of primary hyperparathyroidism. Surgery is the only curative treatment.Case presentationWe report the case of a 66-year-old man referred for a large suspicious substernal goitre associated with severe hypercalcemia due to hyperparathyroidism. After normalization of serum calcium levels, patient underwent surgery. The voluminous cervicomediastinal firm mass could not be removed through the cervical incision; therefore a cervicothoracic approach was employed. Histopathology revealed a giant parathyroid cancer of 450 grams. A review of the literature was also undertaken to summarize the current treatment approaches for this rare malignancy.ConclusionParathyroid cancer is usually not recognized either preoperatively or intra-operatively.En blocresection of the tumour with the adjacent tissue is the treatment of choice and it is very important to avoid the rupture of the capsule during operation. Neither tumour size, nor the lymph node status appears to play a role in prognosis. The management of parathyroid carcinoma is a challenge even for experienced surgeons.