Safety of Imatinib Mesylate in a Multicenter Expanded Access Program in Adult Patients with Gastrointestinal Stromal Tumors in the Adjuvant Setting.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors most often caused by activating mutations of the KIT gene. KIT tyrosine kinase inhibitors provide targeted therapy for the underlying genetic mutation, and adjuvant therapy is indicated for patients who are at significant risk of relapse following GIST resection. This is a report of the safety of imatinib in patients with GIST in the adjuvant setting in an expanded access program. METHODS: In this multicenter, open-label, single-arm trial, safety was assessed based on the frequency of adverse events (AEs). RESULTS: Three hundred patients were treated and analyzed; 40 patients discontinued treatment. Median overall exposure during the program was 181 days (range 9-420); most patients (260/300 treated) completed the study. Six patients had disease recurrence, 4 of whom discontinued. In line with previously published reports, the most frequent AEs were nausea, diarrhea, and periorbital edema. The AEs were mild to moderate in most cases (76%). CONCLUSIONS: These findings are in agreement with the known safety profile of imatinib and confirm the safety of imatinib at 400 mg/day in the adjuvant setting. The incidence of severe AEs was low.

Sequential Treatment Based on Sunitinib and Sorafenib in Patients with Metastatic Renal Cell Carcinoma.

OBJECTIVES: The aim of our study was to evaluate the outcome of alternative sequences of sunitinib followed by sorafenib versus sorafenib followed by sunitinib therapies in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: This single-center study analyzed patients with mRCC on systemic therapy between January 2005 and August 2011. Patients were treated with the recommended first-line therapy (sunitinib, sorafenib, pazopanib, or immunotherapy) until progression or intolerable toxicity and afterward switched to another guideline-recommended systemic therapy. Only patients starting first-line therapy on either sorafenib or sunitinib and switching to the other of these drugs were included in this analysis. RESULTS: Out of 266 patients (females: 85, males: 181) with a median age of 57.1 years (30 - 76 years), 57 patients with a sequence of sunitinib and sorafenib were identified. First-line sorafenib therapy was followed by sunitinib (So-Su) in 32 patients; sunitinib was followed by sorafenib (Su-So) in 25 patients. Progression-free survival (PFS) for patients with first-line sorafenib was 11.6 months and was 8.7 months for sunitinib. Overall survival (OS) rates for Su-So was 118.8 months and 83.3 months with So-Su (p = 0.82). No new safety signals were detected. CONCLUSION: None of the therapeutic first-line approaches was superior to the other. Sequencing tyrosine kinase inhibitor (TKI) therapy seems to be effective in mRCC and superior to single-line therapy. Further studies should focus on the efficacy of single treatment lines rather than treatment sequences to estimate more potent drugs based on PFS rather than overall survival (OS).

Imaging in Suspected Renal-Cell Carcinoma: Systematic Review.

OBJECTIVE: To systematically assessed the diagnostic performance of contrast-enhanced computed tomography (CT) compared to other imaging modalities for diagnosing and staging renal-cell carcinoma in adults. METHODS: A comprehensive literature search was conducted through various electronic databases. Data from the selected studies were extracted and pooled, and median sensitivity and specificity were calculated wherever possible. Forty studies analyzing data of 4354 patients were included. They examined CT, magnetic resonance imaging (MRI), positron emission tomography-CT, and ultrasound (US). RESULTS: For CT, median sensitivity and specificity were 88% (interquartile range [IQR] 81%-94%) and 75% (IQR 51%-90%), and for MRI they were 87.5% (IQR 75.25%-100%) and 89% (IQR 75%-96%). Staging sensitivity and specificity for CT were 87% and 74.5%, while MRI showed a median sensitivity of 90% and specificity of 75%. For US, the results varied greatly depending on the corresponding technique. Contrast-enhanced US had a median diagnostic sensitivity of 93% (IQR 88.75%-98.25%) combined with mediocre specificity. The diagnostic performance of unenhanced US was poor. For positron emission tomography-CT, diagnostic accuracy values were good but were based on only a small amount of data. Limitations include the strong heterogeneity of data due to the large variety in imaging techniques and tumor histotypes. Contrast-enhanced CT and MRI remain the diagnostic mainstay for renal-cell carcinoma, with almost equally high diagnostic and staging accuracy. CONCLUSION: For specific questions, a combination of different imaging techniques such as CT or MRI and contrast-enhanced US may be useful. There is a need for future large prospective studies to further increase the quality of evidence.

Redefining diagnosis-related groups (DRGs) for palliative care - a cross-sectional study in two German centres.

BACKGROUND: Hospital costs and cost drivers in palliative care are poorly analysed. It remains unknown whether current German Diagnosis-Related Groups, mainly relying on main diagnosis or procedure, reproduce costs adequately. The aim of this study was therefore to analyse costs and reimbursement for inpatient palliative care and to identify relevant cost drivers. METHODS: Two-center, standardised micro-costing approach with patient-level cost calculations and analysis of the reimbursement situation for patients receiving palliative care at two German hospitals (7/2012-12/2013). Data were analysed for the total group receiving hospital care covering, but not exclusively, palliative care (group A) and the subgroup receiving palliative care only (group B). Patient and care characteristics predictive of inpatient costs of palliative care were derived by generalised linear models and investigated by classification and regression tree analysis. RESULTS: Between 7/2012 and 12/2013, 2151 patients received care in the two hospitals including, but not exclusively, on the PCUs (group A). In 2013, 784 patients received care on the two PCUs only (group B). Mean total costs per case were € 7392 (SD 7897) (group A) and € 5763 (SD 3664) (group B), mean total reimbursement per case € 5155 (SD 6347) (group A) and € 4278 (SD 2194) (group B). For group A/B on the ward, 58%/67% of the overall costs and 48%/53%, 65%/82% and 64%/72% of costs for nursing, physicians and infrastructure were reimbursed, respectively. Main diagnosis did not significantly influence costs. However, duration of palliative care and total length of stay were (related to the cost calculation method) identified as significant cost drivers. CONCLUSIONS: Related to the cost calculation method, total length of stay and duration of palliative care were identified as significant cost drivers. In contrast, main diagnosis did not reflect costs. In addition, results show that reimbursement within the German Diagnosis-Related Groups system does not reproduce the costs adequately, but causes a financing gap for inpatient palliative care.

Effect of KIT and PDGFRA Mutations on Survival in Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib: An Exploratory Analysis of a Randomized Clinical Trial.

IMPORTANCE: Little is known about whether the duration of adjuvant imatinib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor α (PDGFRA) mutations. OBJECTIVE: To investigate the effect of KIT and PDGFRA mutations on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) treated with surgery and adjuvant imatinib. DESIGN, SETTING, AND PARTICIPANTS: This exploratory study is based on the Scandinavian Sarcoma Group VIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) multicenter clinical trial. Between February 4, 2004, and September 29, 2008, 400 patients who had undergone surgery for GISTs with a high risk of recurrence were randomized to receive adjuvant imatinib for 1 or 3 years. Of the 397 patients who provided consent, 341 (85.9%) had centrally confirmed, localized GISTs with mutation analysis for KIT and PDGFRA performed centrally using conventional sequencing. During a median follow-up of 88 months (completed December 31, 2013), 142 patients had GIST recurrence. Data of the evaluable population were analyzed February 4, 2004, through December 31, 2013. MAIN OUTCOMES AND MEASURES: The main outcome was RFS. Mutations were grouped by the gene and exon. KIT exon 11 mutations were further grouped as deletion or insertion-deletion mutations, substitution mutations, insertion or duplication mutations, and mutations that involved codons 557 and/or 558. RESULTS: Of the 341 patients (175 men and 166 women; median age at study entry, 62 years) in the 1-year group and 60 years in the 3-year group), 274 (80.4%) had GISTs with a KIT mutation, 43 (12.6%) had GISTs that harbored a PDGFRA mutation, and 24 (7.0%) had GISTs that were wild type for these genes. PDGFRA mutations and KIT exon 11 insertion or duplication mutations were associated with favorable RFS, whereas KIT exon 9 mutations were associated with unfavorable outcome. Patients with KIT exon 11 deletion or insertion-deletion mutation had better RFS when allocated to the 3-year group compared with the 1-year group (5-year RFS, 71.0% vs 41.3%; P < .001), whereas no significant benefit from the 3-year treatment was found in the other mutational subgroups examined. KIT exon 11 deletion mutations, deletions that involved codons 557 and/or 558, and deletions that led to pTrp557_Lys558del were associated with poor RFS in the 1-year group but not in the 3-year group. Similarly, in the subset with KIT exon 11 deletion mutations, higher-than-the-median mitotic counts were associated with unfavorable RFS in the 1-year group but not in the 3-year group. CONCLUSIONS AND RELEVANCE: Patients with KIT exon 11 deletion mutations benefit most from the longer duration of adjuvant imatinib. The duration of adjuvant imatinib modifies the risk of GIST recurrence associated with some KIT mutations, including deletions that affect exon 11 codons 557 and/or 558. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00116935.

Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial.

PURPOSE: Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO (Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial. PATIENTS AND METHODS: Eligible patients had macroscopically completely excised, KIT-positive GIST with a high risk of recurrence, as determined by using the modified National Institutes of Health criteria. After surgery, the patients were randomly assigned to receive imatinib for either 1 or 3 years. The primary objective was recurrence-free survival (RFS), and the secondary objectives included survival. RESULTS: A total of 400 patients were entered onto this open-label study between February 4, 2004, and September 29, 2008. During a median follow-up of 90 months, 171 recurrences and 69 deaths were detected. Patients assigned to the 3-year group had longer RFS than those assigned to the 1- year group; 5-year RFS was 71.1% versus 52.3%, respectively (hazard ratio [HR], 0.60; 95% CI 0.44 to 0.81; P < .001), and survival was 91.9% versus 85.3% (HR, 0.60; 95% CI, 0.37 to 0.97; P = .036). Patients in the 3-year group survived longer in the subset with centrally confirmed GIST and without macroscopic metastases at study entry (93.4% v 86.8%; HR, 0.53; 95% CI, 0.30 to 0.93; P = .024). Similar numbers of cardiac events and second cancers were recorded in the groups. CONCLUSION: Three years of adjuvant imatinib therapy results in longer survival than 1 year of imatinib. High 5-year survival rates are achievable in patient populations with high-risk GIST.

Is glutamine deficiency the link between inflammation, malnutrition, and fatigue in cancer patients?

PURPOSE: Evaluation of potential associations between plasma glutamine levels and the incidence of cancer related fatigue, physical performance, poor nutritional status, and inflammation in patients with solid tumors. STUDY DESIGN: Mono-center cross-sectional study recruiting 100 (34 women) consecutive patients (September 2009-March 2011; ≥18 y) with solid tumors and causal tumor therapy. METHODOLOGY: Fasting venous blood was harvested for routine clinical chemistry, amino acid (HPLC) and inflammation marker analyses. Clinical assessments included global, physical, affective and cognitive fatigue (questionnaire) and Karnofsky performance status. Nutritional status was evaluated using bioelectrical impedance analysis, the Prognostic Inflammatory and Nutritional Index and plasma protein levels. Regression analyses were performed to correlate continuous variables with plasma glutamine (95% confidence intervals). RESULTS: Nutritional status was impaired in 19% of the patients. Average plasma glutamine concentration (574.0 ± 189.6 µmol/L) was within normal range but decreased with impaired physical function. Plasma glutamine was linked to the ratio extracellular to body cell mass (p < 0.044), CRP (p < 0.001), physical (p = 0.014), affective (p = 0.041), and global fatigue (p = 0.030). Markers of inflammation increased with low physical performance. CONCLUSIONS: The data support our working hypothesis that in cancer patients systemic inflammation maintains a catabolic situation leading to malnutrition symptoms and glutamine deprivation, the latter being associated with cancer related fatigue.

Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib.

BACKGROUND: Little is known about the factors that predict for gastrointestinal stromal tumor (GIST) recurrence in patients treated with adjuvant imatinib. METHODS: Risk factors for GIST recurrence were identified, and 2 risk stratification scores were developed using the database of the Scandinavian Sarcoma Group (SSG) XVIII trial, where 358 patients with high-risk GIST with no overt metastases were randomly assigned to adjuvant imatinib 400 mg/day either for 12 or 36 months after surgery. The findings were validated in the imatinib arm of the American College of Surgeons Oncology Group Z9001 trial, where 359 patients with GIST were randomized to receive imatinib and 354 were to receive placebo for 12 months. RESULTS: Five factors (high tumor mitotic count, nongastric location, large size, rupture, and adjuvant imatinib for 12 months) were independently associated with unfavorable recurrence-free survival (RFS) in a multivariable analysis in the SSGXVIII cohort. A risk score based on these 5 factors had a concordance index with GIST recurrence of 78.9%. When a simpler score consisting of the 2 strongest predictive factors (mitotic count and tumor site) was devised, the groups with the lowest, intermediate high, and the highest risk had 5-year RFS of 76.7%, 47.5%, and 8.4%, respectively. Both scores were strongly associated with RFS in the validation cohort (P < .001 for each comparison). CONCLUSIONS: The scores generated were effective in stratifying the risk of GIST recurrence in patient populations treated with adjuvant imatinib. Patients with nongastric GIST with a high mitotic count are at a particularly high risk for recurrence.

Analysis of orthopedic surgery of bone metastases in breast cancer patients.

BACKGROUND: Breast cancer is the most common malignancy and the second leading cause of death in women. Because bone metastases are a common finding in patients with breast cancer, they are of major clinical concern. METHODS: In 115 consecutive patients with bone metastases secondary to breast cancer, 132 surgical procedures were performed. Medical records and imaging procedures were reviewed for age, treatment of the primary tumor, clinical symptoms, surgical treatment, complications, and survival. RESULTS: The overall survival of patients with metastatic breast cancer was dependent on the site and the amount of the metastases. Age was not a prognostic factor for survival. If the result of the orthopaedic surgery was a wide resection (R0) survival was significantly better than in the R1 (marginal resection - tumor resection in sane tissue) or R2 (intralesional resection) situation. Concerning the orthopaedic procedures there was no survival difference. CONCLUSION: In conclusion a wide (R0) resection and the absence of pathological fracture and visceral metastases were predictive for longer survival in univariate analysis. Age and the type of orthopaedic surgery had no impact on survival in multivariate analysis. The resection margins lost significance. The standard of care for patients with metastatic breast cancer to the bone requires a multidisciplinary approach.

One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial.

CONTEXT: Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo. OBJECTIVE: To investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery. DESIGN, SETTING, AND PATIENTS: Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria. INTERVENTION: Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery. MAIN OUTCOME MEASURES: The primary end point was RFS; the secondary end points included overall survival and treatment safety. RESULTS: Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32-0.65; P < .001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22-0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence. CONCLUSION: Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00116935.

Response to nilotinib as a first-line treatment for metastatic gastrointestinal stromal tumors.

PURPOSE: Effective and safe treatment options are needed for patients with advanced gastrointestinal stromal tumors (GIST) who are initially unresponsive to the tyrosine kinase inhibitor (TKI) imatinib, or develop acquired secondary imatinib resistance. CASE REPORT: We report a 39-year-old woman with primary rectal GIST who underwent abdominoperineal resection in December 2004, achieving R0 margins. In August 2009, the patient was referred to our clinic, and we detected metastatic GIST of the liver, as well as peritoneal and gluteal lesions. The patient was treated with imatinib 400 mg/day for 3 weeks and subsequently switched to nilotinib (400 mg bid) after enrolling in a clinical trial. After 8 weeks of nilotinib treatment, a response was observed in the liver metastasis, and metabolic activity was no longer detected. Also, the gluteal and peritoneal lesions were no longer detected. After 16 weeks of nilotinib treatment, a cystic mass was identified in the liver metastasis. Tumor rupture was considered a strong possibility, prompting resection of the liver metastasis. Greater than 80% of the resected tumor mass was necrotic, consistent with the lack of metabolism observed 8 weeks prior. The patient resumed nilotinib treatment (400 mg bid) shortly after surgery and continues treatment while remaining disease-free for more than 9 months with normal liver function. CONCLUSION: This is the first report demonstrating the feasibility of nilotinib (400 mg bid) for the first-line treatment of metastatic GIST. Furthermore, these results underscore that responses to TKIs may be underestimated by Response Evaluation Criteria in Solid Tumors.

Activity and side effects of imatinib in patients with gastrointestinal stromal tumors: data from a German multicenter trial.

Gastrointestinal stromal tumors (GIST) are mesenchymal tumors that in the past were classified as leiomyosarcomas or leiomyomas not responding to standard sarcoma chemotherapy. In several phase I and II trials the efficacy and safety of imatinib was shown before the largest trial ever performed in a single sarcoma entity revealed response rates (CR/PR) of 52 %. This multicenter phase II trial presented here was performed to open access to imatinib for patients with unresectable or metastastatic GIST when the EORTC 62005 trial had been closed before imatinib was approved in Germany. It was designed to follow the best clinical response and to assess the efficacy, safety and tolerability of imatinib 400mg/d in patients with unresectable or metastatic gastrointestinal stromal tumor. - 95 patients were treated in this trial with Imatinib 400mg/d. Four patients (4.6 %) attained a complete response and 26 patients (29.9%) a partial response to imatinib treatment. Forty-one patients (47.1 %) revealed a stable disease and 16 patients (18.4 %) had a progressive disease. - Of the progressive patients 22% showed a partial response and 67 % showed stable disease after escalating the dose to 800 mg. According to SWOG tumor response classification, 66 patients (70%) were free of progression within the first year of treatment. - Seventy-one patients (74.7%) experienced adverse events or severe adverse events with a suspected relationship to the study drug. Among these, the most common were nausea (n=27 patients, 28.4 %), eyelid edema and peripheral edema in 23 patients each (24.2 %), diarrhea in 20 patients (21.1 %), muscle cramps in 15 patients (15.8 %) and fatigue in 13 patients (13.7 %). - Imatinib 400 mg/d led to disease stabilisation in 81,6% of patients with unresectable or metastatic malignant GIST. Thirty-four percent of patients attained a tumor remission (partial or complete response). The safety profile of imatinib based on adverse event assessment is favorable. Imatinib is generally well tolerated in patients with gastrointestinal stromal tumors.

Gastrointestinal stromal tumours in children and young adults: a clinicopathologic series with long-term follow-up from the database of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Studies on gastrointestinal stromal tumours (GIST) in the paediatric population are limited to case reports or small case series. PATIENTS AND METHODS: We conducted a retrospective study to describe the long-term outcome of children and adolescents with GIST registered in the database of the Cooperative Weichteilsarkom Studiengruppe (CWS). RESULTS: Sixteen patients (female, n = 11) were identified. Median age at diagnosis was 13.5 years. In four female patients presence of thoracic masses in addition to GIST led to the diagnosis of complete or incomplete Carney triad. Three female patients had metastatic disease at diagnosis, the remaining thirteen GIST were localised. The stomach was the most common primary site of the tumour, followed by the small bowel and colon/abdomen. All patients underwent tumour resection. Receptor tyrosine kinase inhibitors (RTKI) were administered in five patients. With a median follow-up of 96 months all patients are alive, nine of them in first CR. Four female patients developed local or distant recurrence; three of them achieved second CR and one a PR. Two individuals have extensive progressive (n = 1) or stable (n = 1) disease. Estimated progression-free survival at 5 years is 0.63 (95%CI: 0.50-0.86). CONCLUSIONS: Although long-term overall survival is favourable, approximately 30 percent of patients develop disease progression. International cooperation in registration, tissue collection and molecular studies are required to obtain reliable data on the clinical course of these rare tumours in the paediatric population. Biological studies are a prerequisite for initiation of studies with RTKI.

Perfusion patterns of metastatic gastrointestinal stromal tumor lesions under specific molecular therapy.

RATIONALE AND OBJECTIVE: The aim of this pilot study was the evaluation of CT perfusion patterns in metastatic GIST lesions under specific molecular therapy with sunitinib or imatinib both in responders and non-responders. PATIENTS AND METHODS: 24 patients with metastatic GIST under tyrosine kinase inhibition were retrospectively evaluated. A total of 46 perfusion and venous phase CT scans were acquired. Volume of distribution, blood flow, blood volume, permeability and hepatic perfusion index measurements of metastatic lesions were carried out. Lesions were classified as "good response" or "poor response" to therapy, and perfusion parameters were compared for these two types of lesions. RESULTS: 24 patients were evaluated. In the extrahepatic abdominal lesions (N = 15), good responders showed significant lower perfusion values than poor responders (volume of distribution: 3.3 ± 2.0 vs. 13.0 ± 1.8 ml/100ml, p = 0.001). The same tendency was observed in intrahepatic lesions (N = 31) (liver volume of distribution: 2.1 ± 0.3 vs. 7.1 ± 1.3 ml/100ml, p = 0.003); (hepatic perfusion index: 24.3 ± 7.9 vs. 76.1 ± 1.5%, p = 0.0001). CONCLUSION: Our data indicate that there are characteristic perfusion patterns of metastatic GIST lesions showing a good or poor response to molecular pharmacotherapy. Perfusion should be further evaluated in cross-sectional imaging studies as a possible biomarker for treatment response in targeted therapies of GIST.

Adjuvant cisplatin-based chemotherapy for resected NSCLC: one size fits all?

The standard of care for resected stage II - IIIA non-small-cell lung cancer includes adjuvant chemotherapy based on the results of randomized trials using cisplatin regimens. A recent meta-analysis (Lung Adjuvant Cisplatin Evaluation) showed no survival benefit for this modality in stage IB disease. Therefore, the role for stage IB disease remains controversial. The Lung Adjuvant Cisplatin Evaluation meta-analysis, which is based on pooled data of five randomized trials, has shown a 5.3% absolute survival benefit at 5 years. However, long-term results of the International Adjuvant Lung Cancer Trial evaluating adjuvant cisplatin-based chemotherapy in resected non-small-cell lung cancer indicated a possible late adjuvant chemotherapy-related over-mortality. Tumor stage currently is the benchmark standard use for identifying patients who would benefit from adjuvant treatment. In the knowledge of late adjuvant chemotherapy-related over-mortality it is therefore critical to identify subsets of patients who would or would never benefit from adjuvant cisplatin. This review will discuss the extent to which individualized adjuvant treatment can be provided.

Long term survival in anti-Hu associated adult neuroblastoma.

We report on a young lady suffering from adult neuroblastoma and anti-Hu associated paraneoplastic encephalomyelitis (PEM) with a tumour free survival of nine years up to now. Treatment included tumour surgery, radiation, high dose chemotherapy, and stem cell transplantation. Serological testing demonstrated a marked decline in anti-Hu antibody titres under therapy, and subsequent disappearance of the antibody 31 months after second tumour resection.

Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib.

BACKGROUND: Sunitinib inhibits KIT and other members of the split-kinase-domain family of receptor tyrosine kinases. Sunitinib prolongs survival in adult patients with imatinib-resistant gastrointestinal stromal tumor (GIST). We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib. PROCEDURE: Sunitinib therapy was provided through a treatment-use protocol. Patients were 10-17 years old at enrollment. All patients had GIST resistant to imatinib therapy. Sunitinib was administered daily for 4 weeks in 6-week treatment cycles. KIT and platelet-derived growth factor receptor alpha (PDGFRA) genotyping of tumor tissue were performed. RESULTS: One patient achieved a partial response, five patients had stable disease and one patient had progressive disease on sunitinib. The duration of disease stabilization was between 7 and 21+ months, with a mean of 15 months. Time to tumor progression was longer on sunitinib than on prior imatinib treatment for five of six patients. Two patients experienced grade 3 adverse events. All other adverse events were grade 1-2. None of the five patients tested had mutations in KIT or PDGFRA. CONCLUSION: Sunitinib treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib-resistant GIST.

Tissue levels of reduced folates in patients with colorectal carcinoma after infusion of folinic acid at various dose levels.

PURPOSE: In patients with colorectal cancer (CRC), modulation of 5-fluorouracil (5-FU) by folinic acid (FA) improves response rate and overall survival compared with 5-FU alone. However, the optimal dose of FA is still debated. We investigated reduced folate pools in various tissues from patients with CRC without and after prior administration of FA. EXPERIMENTAL DESIGN: A total of 186 specimens (normal colorectal mucosa, primary colorectal tumor, normal liver, and liver metastases) from 86 consecutive patients with CRC were obtained and investigated for levels of reduced folates. Before surgery, patients did (n = 52) or did not (n = 34) receive FA as 15-minute i.v. infusion. FA-dose levels chosen were 20, 200, or 500 mg/m2. Tissue lysates were analyzed for reduced folate levels by means of the tritium release assay. RESULTS: In normal mucosa, combined pools of tetrahydrofolate and 5,10-methylenetetra-hydrofolate were significantly elevated at all FA dose levels compared with untreated controls. In primary tumor, only 200 and 500 mg/m2 FA resulted in a significant increase of reduced folates with highest values measured after 500 mg/m2 FA. In specimens from normal liver, folate levels did not increase after administration of FA. By contrast, in specimens from liver metastases, reduced folate levels were low without FA pretreatment compared with levels from normal liver samples. Infusion of 500 mg/m2 FA caused a significant increase of reduced folate levels in liver metastases. CONCLUSIONS: From a pharmacologic point of view, high-dose FA should be recommended for optimal modulation of 5-FU in patients with mCRC.

Familial gastrointestinal stromal tumors caused by the novel KIT exon 17 germline mutation N822Y.

Gastrointestinal stromal tumors (GISTs) are most often associated with oncogenic mutations of the KIT gene resulting in activation of the tyrosine kinase receptor KIT. Familial GIST syndrome based on a hereditary predisposition to develop GIST owing to a germline mutation is exceedingly rare. We describe a kindred with familial GIST displaying a novel germline mutation in exon 17. Three siblings (2 females, 1 male; 42 to 49 y) underwent surgery for multiple intra-abdominal tumors within a 3-year period. Their father had been operated on for gastric and jejunal tumors 20 years previously. The GIST was confirmed by immunohistochemistry in each sibling. Tumor and blood samples of the family members were analyzed for mutations in KIT and platelet-derived growth factor receptor (PDGFRalpha) genes. All examined lesions were of spindle cell type with expression of CD117. The tumor material exhibited a novel point mutation in codon 822 in exon 17 resulting in the replacement of asparagine by tyrosine (N822Y). The same mutation was detected in the father's blood sample. One healthy brother of the 3 siblings showed a wild-type sequence of the KIT gene. The germline mutation in exon 17 of the KIT gene identified in this kindred is very different from previously reported mutations of the KIT gene in familial GIST. Although the penetrance of KIT mutations is as yet unknown, assessment of the unaffected kindred of GIST patients for the presence of this mutation could help to distinguish individuals at high risk from those at virtually no risk.

Adjuvant therapeutic vaccination in patients with non-small cell lung cancer made lymphopenic and reconstituted with autologous PBMC: first clinical experience and evidence of an immune response.

BACKGROUND: Given the considerable toxicity and modest benefit of adjuvant chemotherapy for non-small cell lung cancer (NSCLC), there is clearly a need for new treatment modalities in the adjuvant setting. Active specific immunotherapy may represent such an option. However, clinical responses have been rare so far. Manipulating the host by inducing lymphopenia before vaccination resulted in a magnification of the immune response in the preclinical setting. To evaluate feasibility and safety of an irradiated, autologous tumor cell vaccine given following induction of lymphopenia by chemotherapy and reinfusion of autologous peripheral blood mononuclear cells (PBMC), we are currently conducting a pilot-phase I clinical trial in patients with NSCLC following surgical resection. This paper reports on the first clinical experience and evidence of an immune response in patients suffering from NSCLC. METHODS: NSCLC patients stages I-IIIA are recruited. Vaccines are generated from their resected lung specimens. Patients undergo leukapheresis to harvest their PBMC prior to or following the surgical procedure. Furthermore, patients receive preparative chemotherapy (cyclophosphamide 350 mg/m2 and fludarabine 20 mg/m2 on 3 consecutive days) for induction of lymphopenia followed by reconstitution with their autologous PBMC. Vaccines are administered intradermally on day 1 following reconstitution and every two weeks for a total of up to five vaccinations. Granulocyte-macrophage-colony-stimulating-factor (GM-CSF) is given continuously (at a rate of 50 microg/24 h) at the site of vaccination via minipump for six consecutive days after each vaccination. RESULTS: To date, vaccines were successfully manufactured for 4 of 4 patients. The most common toxicities were local injection-site reactions and mild constitutional symptoms. Immune responses to chemotherapy, reconstitution and vaccination are measured by vaccine site and delayed type hypersensitivity (DTH) skin reactions. One patient developed positive DTH skin tests so far. Immunohistochemical assessment of punch biopsies taken at the local vaccine site reaction revealed a dense lymphocyte infiltrate. Further immunohistochemical differentiation showed that CD1a+ cells had been attracted to the vaccine site as well as predominantly CD4+ lymphocytes. The 3-day combination chemotherapy consisting of cyclophosphamide and fludarabine induced a profound lymphopenia in all patients. Sequential FACS analysis revealed that different T cell subsets (CD4, CD8, CD4CD25) as well as granulocytes, B cells and NK cells were significantly reduced. Here, we report on clinical safety and feasibility of this vaccination approach during lymphoid recovery and demonstrate a patient example. CONCLUSION: Thus far, all vaccines were well tolerated. The overall trial design seems safe and feasible. Vaccine site reactions associated with infusion of GM-CSF via mini-pump are consistent with the postulated mechanism of action. More detailed immune-monitoring is required to evaluate a potential systemic immune response. Further studies to exploit homeostasis-driven T cell proliferation for the induction of a specific anti-tumor immune response in this clinical setting are warranted.