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Background: The risk/benefit ratio of any treatment can only be fully assessed if long-term results of both efficacy and toxicity are taken into account. Whereas the combined modality treatment of locally advanced rectal cancer (LARC) has considerably improved prognosis, particularly with regard to local control, long-term results-including patient-reported outcomes-are underreported., Patients and Methods: Patients with LARC treated within a multicenter single-arm phase II study were prospectively assessed for at least 5 years after surgery. Study treatment consisted of capecitabine and oxaliplatin prior and concurrent to preoperative pelvic radiotherapy followed by total mesorectal excision. Progression-free survival time (first endpoint), overall survival time, and pattern of relapse were analyzed in the whole study population and in pre-planned exploratory subgroups. Patient-reported outcomes, including overall satisfaction with bowel, stoma, and urinary function, were assessed in 6-month intervals., Results: Five-year progression-free and overall survival rate was 61% (95% confidence interval [CI], 46%-73%) and 78% (95% CI, 63%-87%), respectively. Distant to local recurrence rate was 3:1, with only 8% of patients relapsing locally. Main predictors for recurrence in univariate analyses were tumor downstaging (hazard ratio, 0.16; 95% CI, 0.05-0.56; P = .0011) and nodal downstaging (hazard ratio, 0.17; 95% CI, 0.06-0.52; P = .0005). The self-reported burden of symptoms related to bowel function was high in up to one-third of patients. A total of 28% of patients were dissatisfied with their urinary, bowel, or stoma function for at least 1 observation period., Conclusion: Combined-modality treatment of LARC results in a high and durable local disease control rate, especially in patients with tumor and/or nodal downstaging, at the cost of relevant long-term toxicity. Long-term care is required for a proportion of patients with poor gastrointestinal and/or urinary function after multimodality therapy. Reporting of long-term follow-up, including patient-recorded outcomes should be mandatory for future trials in LARC., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the safety and efficacy of spot scanning proton beam therapy (PT) in the curative treatment of soft-tissue sarcoma (STS) in adults patients., Patients and Methods: We identified 13 STS patients treated with PT between July 1998 and May 2005 in our institutional database. Tumor histology varied with the most common histologic subtypes including liposarcoma and peripheral nerve sheet tumor. All tumors were located in vicinity of critical structures, such as the spinal cord, optic apparatus, bowel, kidney, or bowel. Of the patients, 6 and 5 patients received PT either as adjuvant therapy for non-R0 resection or for recurrence, respectively. Two patients received radical PT for unresectable disease. The median prescribed dose was 69.4 CGE (CGE = proton Gy x 1.1)-Gy (range, 50.4-76.0) at 1.8 to 2 CGE-Gy (median, 1.9) per fraction. Pre-PT anthracycline-based chemotherapy was delivered to 3 patients only. No patient has been lost to follow-up (median 48.1 months, range, 19.1-100.7 months)., Results: Of the 13 patients, all but 2 patients were alive. Local recurrence developed in 3 (23%) patients. The administered dose to these patients was < or =60 Gy-CGE. Distant control was achieved in all but 2 patients (lung metastasis), 1 of whom presented with a concomitant local recurrence. The 4-year local control and metastasis-free survival rates were 74.1% and 84.6%, respectively. Late grade > or =2 toxicity was observed in only 2 patients., Conclusions: Spot scanning PT is an effective and safe treatment for patient with STS in critical locations. The observed toxicity rate was acceptable.

Purpose: To evaluate the use of postoperative proton therapy (PT) in extracranial chordoma., Patients and Methods: Twenty-six patients were treated. Gross total resection was achieved in 18 patients. Nine patients had cervical, 2 had thoracic, 8 had lumbar, and 7 had sacro-coccygeal chordomas. Thirteen patients had implants. PT was administered after function-preserving surgery, using a gantry and spot scanning, without or with intensity modulation (IMPT; 6 patients), and/or photon-based radiotherapy (RT, 6 patients). Median total dose was 72 cobalt Gray equivalent (CGE; range, 59.4-74.4), with means of 70.5 and 73.2 CGE for patients with and without implants. Median follow-up time was 35 months (range, 13-73 months). Adverse events were scored using the Common Terminology Criteria for Adverse Events grading system (version 3.0)., Results: At 3 years, actuarial overall survival (OS) and progression-free survival (PFS) rates were 84% and 77%, respectively. One patient each died of local failure (LF), distant failure (DF), suicide, and secondary tumor. We observed 5 LFs and 3 DFs; 3-year LF-free and DF-free survival rates were 86%. We observed four radiation-induced late adverse events (Grade 2 sensory neuropathy; Grade 3 subcutaneous necrosis, and osteonecrosis; and Grade 5 secondary cancer). In univariate analysis, implants were associated with LF (p = 0.034). Gross residual tumor above 30 mL was negatively associated with OS (p = 0.013) and PFS (p = 0.025)., Conclusions: Postoperative PT for extracranial chordomas delivered with spot scanning offers high local control rates. Toxicity was acceptable. Implants were significantly associated with LF. Residual tumor above 30 mL impacted negatively on OS and PFS.

Purpose: Radiotherapy plays a major role in the treatment strategy of childhood sarcomas. Consequences of treatment are likely to affect the survivor's quality of life significantly. We investigated the feasibility of spot-scanning proton therapy (PT) for soft tissue tumors in childhood., Methods and Materials: Sixteen children with soft tissue sarcomas were included. Median age at PT was 3.3 years. In 10 children the tumor histology was embryonal rhabdomyosarcoma. All tumors were located in the head or neck, parameningeal, or paraspinal, or pelvic region. In the majority of children, the tumor was initially unresectable (Intergroup Rhabdomyosarcoma Study [IRS] Group III in 75%). In 50% of children the tumors exceeded 5 cm. Fourteen children had chemotherapy before and during PT. Median total dose of radiotherapy was 50 cobalt Gray equivalent (CGE). All 16 children were treated with spot-scanning proton therapy at the Paul Scherrer Institute, and in 3 children the PT was intensity-modulated (IMPT)., Results: After median follow-up of 1.5 years, local control was achieved in 12 children. Four children failed locally, 1 at the border of the radiation field and 3 within the field. All 4 children died of tumor recurrence. All 4 showed unfavorable characteristic either of site or histopathology of the tumor. Acute toxicity was low, with Grade 3 or 4 side effects according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria occurring in the bone marrow only., Conclusions: Proton therapy was feasible and well tolerated. Early local control rates are comparable to those being achieved after conventional radiotherapy. For investigations on late effect, longer follow-up is needed.

Epidermal growth factor receptor (EGFR) expression has been associated with clinical outcome in some studies of renal-cell carcinoma (RCC). We investigated the efficacy and safety of gefitinib (IRESSA), an EGFR tyrosine kinase inhibitor, in RCC patients. This phase II trial recruited 28 patients with advanced, metastatic, or relapsed RCC. Patients received oral gefitinib 500 mg/day. Objective responses (ORs) were assessed every 2 months according to RECIST. Baseline tumor biopsies were analyzed immunohistochemically for EGFR expression. At trial closure (March 2003), no ORs were seen but 14 patients (53.8%) had stable disease. At extended analysis (August 2004), median time to progression was 110 days (95% confidence interval [CI]: 55, 117); median overall survival was 303 days (95% CI 180, 444). Gefitinib was generally well tolerated. Skin rash and diarrhea were the most common drug-related adverse events (AEs) [54 and 39% of patients, respectively] and the most common drug-related grade 3/4 AEs (both 11%). The majority of tumor biopsies (91%) had > or =70% of tumor cells expressing membrane EGFR. Despite the lack of ORs in this study, disease control was observed in 53.8% of patients. Gefitinib was generally well tolerated and no unexpected drug-related AEs were observed.

Purpose: The cyclin D1 (CCND1) A870G gene polymorphism is linked to the outcome in patients with resectable non-small cell lung cancer (NSCLC). Here, we investigated the impact of this polymorphism on smoking-induced cancer risk and clinical outcome in patients with NSCLC stages I-IV., Methods: CCND1 A870G genotype was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP) of DNA extracted from blood. The study included 244 NSCLC patients and 187 healthy control subjects., Results: Patient characteristics were: 70% male, 77% smokers, 43% adenocarcinoma, and 27% squamous cell carcinoma. Eighty-one percent of the patients had stages III-IV disease. Median age at diagnosis was 60 years and median survival was 13 months. Genotype frequencies of patients and controls both conformed to the Hardy Weinberg equilibrium. The GG genotype significantly correlated with a history of heavy smoking (>or=40 py, P=0.02), and patients with this genotype had a significantly higher cigarette consumption than patients with AA/AG genotypes (P=0.007). The GG genotype also significantly correlated with tumor response or stabilization after a platinum-based first-line chemotherapy (P=0.04). Survival analysis revealed no significant differences among the genotypes., Conclusion: Evidence was obtained that the CCND1 A870G gene polymorphism modulates smoking-induced lung cancer risk. Further studies are required to explore the underlying molecular mechanisms and to test the value of this gene polymorphism as a predictor for platinum-sensitivity in NSCLC patients.

Since the end of 1996, we have treated more than 160 patients at PSI using spot-scanned protons. The range of indications treated has been quite wide and includes, in the head region, base-of-skull sarcomas, low-grade gliomas, meningiomas, and para-nasal sinus tumors. In addition, we have treated bone sarcomas in the neck and trunk--mainly in the sacral area--as well as prostate cases and some soft tissue sarcomas. PTV volumes for our treated cases are in the range 20-4500 ml, indicating the flexibility of the spot scanning system for treating lesions of all types and sizes. The number of fields per applied plan ranges from between 1 and 4, with a mean of just under 3 beams per plan, and the number of fluence modulated Bragg peaks delivered per field has ranged from 200 to 45 000. With the current delivery rate of roughly 3000 Bragg peaks per minute, this translates into delivery times per field of between a few seconds to 20-25 min. Bragg peak weight analysis of these spots has shown that over all fields, only about 10% of delivered spots have a weight of more than 10% of the maximum in any given field, indicating that there is some scope for optimizing the number of spots delivered per field. Field specific dosimetry shows that these treatments can be delivered accurately and precisely to within +/-1 mm (1 SD) orthogonal to the field direction and to within 1.5 mm in range. With our current delivery system the mean widths of delivered pencil beams at the Bragg peak is about 8 mm (sigma) for all energies, indicating that this is an area where some improvements can be made. In addition, an analysis of the spot weights and energies of individual Bragg peaks shows a relatively broad spread of low and high weighted Bragg peaks over all energy steps, indicating that there is at best only a limited relationship between pencil beam weighting and depth of penetration. This latter observation may have some consequences when considering strategies for fast re-scanning on second generation scanning gantries.

Purpose: Circulating cell-free DNA is present in increased amounts in the blood of cancer patients, but the clinical relevance of this phenomenon remains unclear. We conducted a clinical study to assess the value of circulating DNA as a prognostic marker in patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: A standard protocol for the quantification of circulating DNA by real-time polymerase chain reaction was set up and validated at two oncology units. One hundred eighty-five informed patients with NSCLC and 46 healthy controls were included in the study. DNA concentrations were determined in paired plasma and serum samples and analyzed for a relationship with leukocyte counts and lactate dehydrogenase (LDH) levels. DNA concentrations in healthy controls and in patients were compared, and cutoff levels for plasma and serum DNA were determined. Patient survival was analyzed relative to baseline DNA concentrations, and the relationship between tumor responses and changes in DNA concentrations was assessed in patients receiving chemotherapy., Results: We found a significant correlation between increased plasma DNA concentrations and elevated LDH levels (P = .009), advanced tumor stage (P < .003), and poor survival (P < .001). Tumor progression after chemotherapy was significantly (P = .006) associated with increasing plasma DNA concentrations. Serum DNA concentrations strongly correlated (P < .001) with leukocyte counts., Conclusion: Our data demonstrate that quantification of plasma DNA is an accurate technique amenable to standardization, which might complement current methods for the prediction of patient survival. This approach might be considered for evaluation in large prospective studies.

PSI is still the only location in which proton therapy is applied using a dynamic beam scanning technique on a very compact gantry. Recently, this system is also being used for the application of intensity-modulated proton therapy (IMPT). This novel technical development and the success of the proton therapy project altogether have led PSI in Year 2000 to further expand the activities in this field by launching the project PROSCAN. The first step is the installation of a dedicated commercial superconducting cyclotron of a novel type. The second step is the development of a new gantry, Gantry 2. For Gantry 2 we have chosen an iso-centric compact gantry layout. The diameter of the gantry is limited to 7.5 m, less than in other gantry systems (approximately 10-12 m). The space in the treatment room is comfortably large, and the access on a fixed floor is possible any time around the patient table. Through the availability of a faster scanning system, it will be possible to treat the target volume repeatedly in the same session. For this purpose, the dynamic control of the beam intensity at the ion source and the dynamic variation of the beam energy will be used directly for the shaping of the dose.

Peritoneal carcinoma is a rare primary tumor, described in the literature almost exclusively in women. This report describes our clinicopathological findings in a 51-year-old male patient with peritoneal carcinoma and ascites. Pathologic studies included routine histology, immunohistochemistry and electron microscopy on biopsy and autopsy tumor tissue. After chemotherapy, the patient achieved a complete remission twice, lasting for 14 months and 8 months, respectively, and died after 3 years. His clinical course was similar to that of female patients with peritoneal carcinoma or advanced ovarian cancer. Our case confirms the existence of primary peritoneal carcinoma in males. In addition, it shows that this entity responds to the same chemotherapy as used for ovarian cancer and primary peritoneal carcinoma in females., (Copyright 2003 S. Karger AG, Basel)

We report on the history and clinical findings of an injecting drug abuser in the Canton of Zurich who presented with multiple deep abscesses in the arms and legs. A diagnosis of wound botulism was made based on his clinical presentation with a rapidly progressing descending paralysis starting at the cranial nerves, a neuromuscular junction disorder on neurophysiologic testing, and normal findings on lumbar puncture. Several cases of wound botulism have occurred in i.v. drug abuse in Switzerland since 1997. We suspect subcutaneous injections of contaminated heroin containing Clostridium spores as sites of entry. Wound botulism caused by Clostridium botulinum is a rare cause of rapidly progressing, generalized, flaccid paralysis and should be considered in patients with a history of i.v. drug abuse presenting with descending paralysis.