Search

Background: The role of bisphosphonates (BP) when added to the (neo)adjuvant treatment of BC in enhancing the efficacy of therapy is still unknown. NEOZOTAC investigates the efficacy of ZA added to neoadjuvant chemotherapy in patients with HER2-negative BC. Trial design: NEOZOTAC is a Dutch multicenter study. Patients are 1:1 randomized to 3-weekly TAC (docetaxel 75mg/m², adriamycin 50 mg/m² and cyclophosphamide 500 mg/m² i.v., day 1) chemotherapy supported by pegfilgrastim (6 mg sc), day 2 with or without ZA (4 mg i.v. within 24 hr after chemotherapy) q3 weeks. Eligibility criteria: Main inclusion criteria: stage II or III, measurable, HER2-negative BC, age ≥ 18 years, WHO 0-2, adequate bone marrow-, renal-, and liver function, absence of prior BP usage and absence of active dental problems. Study endpoint: The primary endpoint is the pathologic complete response (pCR) rate. Secondary endpoints are toxicity, clinical response, tumor heterogeneity in core biopsy vs. operation specimen, and (disease free) survival. Optional side studies include fluorescent imaging (SoftScan®), changes in bone markers, single nucleotide polymorphisms and the insulin-like growth factor pathway, circulating tumor and endothelial cells and the falsenegative rate of the sentinel node biopsy after neoadjuvant chemotherapy. Statistical Methods: Using a 5% significance level based on the two-sided Fishers exact test with a power of 80%, 250 patients (125/arm) are needed to show an improvement of the pCR-rate from 17% to 34% in the experimental arm. Randomization was done according to the Pococks minimisation technique stratified by cT, cN, and estrogen receptor status. Toxicity is analyzed using the Exact (2-sided) Chi-Square test. Results: From July 2010 to April 2012, 250 patients from 25 participating sites were randomized. Toxicity data of 173 patients are currently available and data of all 250 patients will be presented at SABCS. Patient characteristics are presented in table 1. Hematological and non-hematological toxicities were not significantly different between both treatment arms. Main grade 3/4 NCI-CTCv4 toxicities were neutropenia (8%), followed by febrile neutropenia (7%), fatigue (6%), diarrhea, hypertension, nausea (3%) and vomiting (1.2%). Bone pain, myalgia, and hypocalcemia occurred in one patient in the TAC-ZA arm (0.6%). Osteonecrosis of the jaw was not observed. Conclusions: Neoadjuvant TAC supported by pegfilgrastim plus ZA is feasible. No significant difference in toxicity are reported compared with the control arm. [ABSTRACT FROM AUTHOR]

Background The efficacy and feasibility of chemotherapy in elderly metastatic breast cancer (MBC) patients (pts) have been studied in various phase II studies. However, results of prospective randomized studies in elderly MBC pts are scarce. Methods In this phase III multicenter study, MBC pts ≥ 65 years eligible for first-line chemotherapy were randomized between pegylated liposomal doxorubicin (PEGdoxo) (45mg/m², IV, q 4 wks) or capecitabine (Cape) (1000 mg/m² PO bid, days 1-14, q 3 wks). Other eligibility criteria were ECOG performance status (PS) ≤ 2 (3 allowed if due to pain or pre existing comorbidity), adequate bone marrow and organ functions. Stratification factors were PS (0-1 vs 2-3), HER2 status, visceral/non-visceral disease, adjuvant hormonal therapy (HTx), and HTx for MBC. Baseline geriatric assessment (GA) included functional status, instrumental activities of daily living, cognition, mood, comorbidity, polypharmacy and nutritional status. Chemotherapy was continued for 24 wks in the absence of progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression-free survival (PFS), secondary endpoints were response rate, overall survival (OS), toxicity (CTC criteria) and compliance. Results Between April 2007 and August 2011, 78 pts were randomized to PEGdoxo (n = 40) or Cape (n = 38). The study was prematurely closed due to slow accrual and supply problems with PEGdoxo. Mean age was 74 years (range 65-86; 75+ 54%; 80+ 13%). Pt characteristics were balanced between the two arms: PS 0-1 77%, ER+ 68%, HER2+ 5%, visceral/non- visceral disease 76%/24%, adjuvant HTx 46%, HTx for MBC 56%, ≥ 3 metastatic sites 50%. Only 22 out of 75 pts with a baseline GA had no geriatric condition (29%), while 32 pts (43%) and 21 pts (28%) had one or ≥ 2 geriatric conditions, respectively. Chemotherapy was given for 6 months in 38%, with a mean dose intensity of 84% in both arms. Reasons for early treatment discontinuation were: PD (31%), toxicity (28%), pt withdrawal (3%). After a median follow up of 32 months, 74 pts had PD and 56 pts had died. The median PFS was 5.7 and 7.7 months with PEGdoxo and Cape (HR 0.68, 95% CI: 0.42-1.11, p = 0.12) and the median OS was 13.8 and 16.8 months, respectively (HR 0.84, 95% CI: 0.49-1.42, p = 0.51). Response was evaluable in 64 pts, with a partial response (PR) in 7 (21%) and 6 pts (19%), and stable disease in 21 (64%) and 17 pts (55%) for PEGdoxo and Cape, respectively. Toxicity was acceptable, mainly being grade 1-2, with for PEGdoxo/Cape grade 1 alopecia in 14/4 pts (grade 2 in 1 PEGdoxo pt), grade 3 fatigue in 5/5 pts, grade 3 HFS in 4/6 pts and grade 3 mucositis in 4/1 pts, respectively. Pts with ≥ 1 geriatric condition more frequently experienced grade 3-4 toxicity, after correcting for type of chemotherapy, age and PS (HR 2.24, 95% CI: 1.21-4.16). Pts aged 75+ had a twofold higher risk of dying, irrespective of treatment arm (HR 2.31, 95% CI: 1.31-4.07). Conclusions First-line chemotherapy with either PEGdoxo or Cape was feasible in elderly MBC pts, with adequate dose intensity and acceptable toxicity, even in non-fit pts or pts aged 75+. Baseline GA correlated with toxicity. [ABSTRACT FROM AUTHOR]

Background: The optimal duration of extended endocrine therapy beyond five years after initial aromatase inhibitor-based adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer is still unknown. Therefore, we conducted a clinical trial to compare two different extended endocrine therapy durations., Methods: In the randomized phase III IDEAL trial, postmenopausal patients with hormone receptor-positive breast cancer were randomly allocated to either 2.5 or five years of letrozole after the initial five years of any endocrine therapy. The primary end point was disease free survival (DFS), and secondary end points were overall survival (OS), distant metastasis-free interval (DMFi), new primary breast cancer, and safety. Hazard ratios (HRs) were determined using Cox regression analysis. All analyses were by intention-to-treat principle., Results: A total of 1824 patients were assigned to either 2.5 years (n = 909) or five years (n = 915) of letrozole, with a median follow-up of 6.6 years. A DFS event occurred in 152 patients in the five-year group, compared with 163 patients in the 2.5-year group (HR = 0.92, 95% confidence interval [CI] = 0.74 to 1.16). OS (HR = 1.04, 95% CI = 0.78 to 1.38) and DMFi (HR = 1.06, 95% CI = 0.78 to 1.45) were not different between both groups. A reduction in occurrence of second primary breast cancer was observed with five years of treatment (HR = 0.39, 95% CI = 0.19 to 0.81). Subgroup analysis did not identify patients who benefit from five-year extended therapy., Conclusion: This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Treatment decision making is often guided by evidence-based probabilities, which may be presented to patients during consultations. These probabilities are intrinsically imperfect and embody 2 types of uncertainties: aleatory uncertainty arising from the unpredictability of future events and epistemic uncertainty arising from limitations in the reliability and accuracy of probability estimates. Risk communication experts have recommended disclosing uncertainty. We examined whether uncertainty was discussed during cancer consultations and whether and how patients perceived uncertainty., Methods: Consecutive patient consultations with medical oncologists discussing adjuvant treatment in early-stage breast cancer were audiotaped, transcribed, and coded. Patients were interviewed after the consultation to gain insight into their perceptions of uncertainty., Results: In total, 198 patients were included by 27 oncologists. Uncertainty was disclosed in 49% (97/197) of consultations. In those 97 consultations, 23 allusions to epistemic uncertainty were made and 84 allusions to aleatory uncertainty. Overall, the allusions to the precision of the probabilities were somewhat ambiguous. Interviewed patients mainly referred to aleatory uncertainty if not prompted about epistemic uncertainty. Even when specifically asked about epistemic uncertainty, 1 in 4 utterances referred to aleatory uncertainty. When talking about epistemic uncertainty, many patients contradicted themselves. In addition, 1 in 10 patients seemed not to realize that the probabilities communicated during the consultation are imperfect., Conclusions: Uncertainty is conveyed in only half of patient consultations. When uncertainty is communicated, oncologists mainly refer to aleatory uncertainty. This is also the type of uncertainty that most patients perceive and seem comfortable discussing. Given that it is increasingly common for clinicians to discuss outcome probabilities with their patients, guidance on whether and how to best communicate uncertainty is urgently needed.

Background: Comprehensive geriatric assessment (CGA) is a multidimensional method to detect frailty in elderly patients. Time saving could be accomplished by identifying those individual items that classify elderly cancer patients at risk for feasibility of chemotherapy and for mortality., Material and Methods: Patients older than 70 years of age were assessed before the first chemotherapy administration. GA consisted of the Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). Predictive individual items for feasibility of chemotherapy and mortality were entered in the multivariable logistic regression and Cox-regression models, and a three-item sum scale was constructed: the Geriatric Prognostic Index (GPI)., Results: The 494 patients had a median age of 75 years (range 70-92 years). The majority of the patients had malignancies of the digestive tract (41.7%) followed by hematological tumors (22.3%). Three items of the MNA ('psychological distress or acute disease in the past three months', 'neuropsychological problems' and 'using > 3 prescript drugs') independently predicted for feasibility of chemotherapy. Two items of the MNA and one of the GFI ('declining food intake in past 3 months', 'using > 3 prescript drugs', and 'dependence in shopping') independently predicted for mortality. In comparison with patients without any positive item on the three-item GPI, patients with one, two or three positive items had hazard ratios (HRs) of 1.58, 2.32, and 5.58, respectively (all p < 0.001)., Conclusions: With only three items of the MNA, feasibility of chemotherapy can be predicted. The three-item GPI may help to identify elderly cancer patients at elevated risk for mortality.

Purpose: The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation., Methods: Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens., Results: After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation., Conclusion: The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation., (© 2015 by American Society of Clinical Oncology.)

The age-adjusted International Prognostic Index (IPI) is an important prognostic factor for patients with non-Hodgkin lymphoma (NHL). We investigated whether a geriatric assessment (GA) is of additional prognostic value in NHL. In this prospective cohort study of 44 patients aged 70 years or older with NHL receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), a GA was administered before the start of chemotherapy. GA was composed of the Mini Nutritional Assessment (MNA), Groningen Frailty Indicator (GFI), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Mini Mental State Examination (MMSE) and levels of albumin, creatinine, lactate dehydrogenase (LDH) and hemoglobin. Multivariate analyses were performed using logistic regression and the Cox regression model. After adjustment for sex, age, comorbidity and univariate laboratory values with p ≤ 0.1, abnormal MNA and GFI scores and low hemoglobin level were associated with not being able to complete the intended chemotherapy: odds ratio (OR) 8.29 (95% confidence interval [CI]: 1.24-55.6; p = 0.03), 9.17 (95% CI: 1.51-55.8; p = 0.02) and 5.41 (95% CI: 0.99-29.8; p = 0.05), respectively. Adjusted for sex, age, comorbidity, age-adjusted IPI and univariate laboratory values with p ≤ 0.1, frailty by GFI and low hemoglobin were associated with worse survival, with a hazard ratio (HR) of mortality of 2.55 (95% CI: 1.07-6.10; p = 0.04) and 4.90 (95% CI: 1.76-13.7; p = 0.002), respectively. We conclude that (risk of) malnutrition, measured with the MNA, frailty, measured with the GFI, and low hemoglobin level had additional predictive value for early treatment withdrawal, and GFI and hemoglobin were, independent of the age-adjusted IPI, predictive for an increased mortality risk.

Background: Elderly patients with non-Hodgkin's lymphoma (NHL) are often not treated with standard immunochemotherapy and this might have a negative impact on their survival. Little is known about the determinants that play a role in treatment decision-making of clinicians regarding elderly patients with NHL. The objective of this study was to gain more insight into these determinants., Methods: A survey was conducted amongst haematologists in the Netherlands. The survey contained questions about comorbidity, polypharmacy, social setting, nutritional status, depression, mild cognitive impairment, dementia, activities of daily living (ADL) and instrumental activities of daily living (IADL) in relation to treatment decisions in elderly NHL patients., Results: Of all comorbidities, respondents designated cognitive disorders and cardiovascular comorbidity as the most important factors when assessing whether an older patient with NHL is eligible for curative treatment. Also in decreasing degree of importance ADL, IADL and depressive disorder are frequently included in treatment decision-making. Almost half of the respondents feel that treatment of the elderly person is complicated as a result of a lack of scientific evidence., Conclusion: Haematologists are aware of coexisting problems in elderly patients and they frequently take comorbidities, cognitive disorders and functional status into consideration in treatment decision-making. Future studies are needed to determine the exact role that these factors should play in the treatment of elderly patients. Furthermore, haematologists feel that treatment of the elderly is complicated and there is a lack of scientific evidence, and therefore older adults should be better represented in clinical trials.

Introduction: In general, geriatric assessment (GA) provides the combined information on comorbidity and functional, nutritional and psychosocial status and may be predictive for mortality outcome of cancer patients. The impact of geriatric assessment on the outcome of older patients with colorectal cancer treated with chemotherapy is largely unknown., Methods: In a prospective study, 143 patients with colorectal cancer who were 70years and older were assessed before chemotherapy by Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE)., Results: Fifty-four (38%) patients received adjuvant chemotherapy and 89 (62%) patients received palliative chemotherapy. Malnutrition and frailty were prevalent in 39 (27%, assessed by MNA) and 34 (24%, by GFI) patients, respectively; whereas cognitive impairment was prevalent in 19 (13%, by IQCODE) and 11 (8%, by MMSE) patients, respectively. In patients with palliative chemotherapy, poor MNA scores were associated with receiving less than 4cycles of chemotherapy (p=0.008). Poor MNA and GFI scores were associated with increased hazard ratios (HR) for mortality for patients with palliative chemotherapy: HR=2.76 (95% confidence interval [CI]: 1.60-4.77; p<0.001) and HR=2.72 (95% CI: 1.58-4.69; p<0.001), respectively, after adjustment for several clinical parameters., Conclusions: Malnutrition and frailty were strongly associated with an increased mortality risk in patients who underwent palliative chemotherapy. Furthermore, a poor score on MNA was predictive for less tolerance of chemotherapy. Our findings may help the oncologist in future decision making and advice for elderly patients with colorectal cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Lactic acidosis is a rare complication of haematological malignancies with a poor prognostic outcome and unclear aetiology. Possible mechanisms include high rate of glycolysis by cancer cells, in part due to over-expression of hexokinase II. The insulin-like growth factor (IGF)-system has an important role in normal as well as tumour cell growth. We present a case of a 79-year-old man with a diffuse large B-cell lymphoma and lactic acidosis. Initially, the patient was successfully treated according to the R-CHOP scheme. After recurrence of disease, the patient was treated according to a protocol of the Dutch-Belgian Haemato-Oncology Group (HOVON-85 study). Eleven months after completion of the last therapy, the patient still appeared to be in complete remission. Serum levels of IGFs, pro-IGF-IIE[68-88], IGF binding proteins (IGFBPs)-1 to -4, acid labile subunit (ALS), as well as ternary IGF-I-IGFBP-3-ALS complex formation, were determined in samples taken before, during and after treatment, respectively. Before treatment patient's serum concentration of the growth hormone-dependent parameters of the IGF-system and IGF-II were clearly reduced when compared with patient's values during remission of disease. On the other hand, during acidosis a relatively higher proportion of IGFs is present in binary complexes, instead of 150 kDa complexes, that may allow an increased access of IGFs to target cells including the malignant ones. Pretreatment serum levels of IGFBP-1 and -2 were elevated, decreased during therapy and normalized at remission. Especially IGFBP-2 seems a suitable marker for disease activity.

Aim: To assess national trends over time in surgery for elderly patients with resectable breast cancer (BC) and to evaluate clinical outcome and cause of death after the omission of surgery in a regional cohort of elderly patients., Methods: National trends in 1995-2005 were calculated using cancer registry data. In addition, a chart review was performed in a cohort of patients aged ≥ 75 years, with early stage BC but no primary surgery, diagnosed at five Dutch hospitals in 1990-2005. Patient characteristics, comorbidity and reason for the omission of surgery were collected from the chart. Cause of death was retrieved from death certificate data registered at Statistics Netherlands., Results: Omission of surgery increased significantly over time for patients aged 80 years and older (p<0.05). Of the 187 patients in the regional cohort (median age 85.9 years (range 75.0-97.7), 174 (92%) received hormonal therapy. Omission of surgery was at the patient's request in 59 patients (32%). Of the 178 patients that died during follow-up, 60 patients (34%) died of BC. For 81 patients (45%), BC was not clinically relevant at the time of death. Median overall survival was 2.3 years (range 0.2-10.7) and did not differ between BC and other causes of death (p=0.9)., Conclusion: Omission of surgery for elderly patients with resectable BC has increased significantly over the past decade; instead patients often received primary endocrine treatment. Although this may appear an effective alternative to surgery, the potential for a longer term negative impact on disease control and quality of life deserves further investigation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aims: The aim of this study was to investigate non-compliance to aromatase inhibitors and factors associated with early treatment discontinuation in the extended adjuvant setting., Methods: The IDEAL trial is a prospective, open-label phase-III trial comparing 2.5 with 5 years of extended adjuvant letrozole (LET) in hormone receptor positive (HR+) postmenopausal early breast-cancer patients after 5 years of adjuvant endocrine therapy (ET). The purpose of this study was to assess non-compliance in the first 2.5 years of extended adjuvant therapy. Non-compliance was defined as early discontinuation of LET for all reasons, excluding death or recurrence., Results: At 2.5 years, 1215 patients were included in the analysis. Overall non-compliance probability was 18.4%, of which 85.1% discontinued due to toxicities. Analyses showed that patients with prior sequential therapy were less likely to discontinue treatment than when treated with AI or TAM upfront (logrank p = 0.004). Longer treatment-free intervals also predicted more non-compliance (logrank p = 0.011). Age was not predictive of non-compliance (p = 0.571). Prior surgery (mastectomy vs breast conserving surgery), both with or without radiotherapy and/or chemotherapy were also not associated with early treatment discontinuation (p = 0.228 and p = 0.585 respectively). Although having fewer than four positive lymph nodes predicted more non-compliance (logrank p = 0.050), age, tumor type and locoregional treatment did not., Conclusions: High non-compliance to extended ET was confirmed. Toxicities were the major reason for discontinuation, and this was not influenced by age. Longer treatment-free intervals and fewer positive lymph nodes predicted more non-compliance. Patients who underwent sequential therapy were least likely to discontinue extended adjuvant ET., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment. Here, we report the final analysis on overall survival., Patients and Methods: Patients with HER2-positive, advanced breast cancer who progressed during treatment with trastuzumab with or without 1st-line metastatic chemotherapy were prospectively randomised to X (2500mg/m(2) on days 1-14, q3w) or XH (6 (8)mg/kg, q3w). Overall survival was a pre-specified secondary end-point., Results: Median follow-up at June 2010 was 20.7months. Fifty nine of 74 and 60 of 77 patients died in the X and XH arm, respectively. Median overall survival was 20.6 and 24.9months with X and XH, respectively (HR=0.94 [0.65-1.35]; p=0.73). Performance status and metastatic site were independent prognosticators for overall survival. No difference between treatment arms was observed for patients who achieved clinical response or clinical benefit, respectively. Patients who continued/restarted anti-HER2 treatment (trastuzumab or lapatinib) after 2nd progression (N=52) had a post-progression survival of 18.8 compared with 13.3months for those who did not receive 3rd line treatment with anti-HER2 agents (N=88) (HR 0.63; p=0.02)., Conclusions: Final overall survival analysis of the GBG-26 study did not demonstrate a significant survival benefit for treatment beyond progression with trastuzumab. However, in a post-hoc analysis, patients receiving anti-HER2 treatment as 3rd line therapy showed a better post-progression survival than those not receiving this targeted treatment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21-23 was observed. In five patients a deep intronic mutation c.1129-5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129-5967 to c.1129-5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129-5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959-51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129-5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129-5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing.

A 35-year-old man presented at the outpatient department of pulmonary diseases with fever, rhinitis and coughing. He had recently been on holiday in California. Except for a body temperature of 39.7 degrees C there were no other abnormal findings at the physical examination. Chest X-ray showed a consolidation in the left upper lobe. Under antibiotic treatment his clinical condition deteriorated. Coccidioidomycosis was the suspected diagnosis and confirmed by the results of CT scanning and culture of bronchoalveolar lavage fluid. Treatment with itraconazole resulted in lasting improvement. The case stipulates the importance of travel history.

Background: To determine whether the reported increase in survival of patients with diffuse large B-cell malignant lymphoma (DLBCL) after the introduction of rituximab is also seen in a non-academic hospital in the Netherlands. A retrospective study., Methods: A dataset was made containing all newly diagnosed patients with DLBCL in a period of 2.5 years before until 2.5 years after introduction of rituximab in the standard treatment. Total follow-up time was 6.5 years with a minimal follow-up of 18 months., Results: The study population consisted of 65 patients; 32 in the prerituximab group (median follow-up time 60 months) and 33 in the postrituximab group (median follow-up time 29 months). Progression-free survival increased significantly in the postrituximab group (hazard ratio 0.31; 95% CI 0.12 to 0.78; p=0.013; log rank p=0.008). The overall survival also showed a significant increase (p=0.048). The 18-month progression-free survival increased from 59.4 to 81.8%; the overall survival at 18 months showed an increase from 65.5 to 81.8%., Conclusion: The introduction of rituximab in the treatment of DLB CL with CHOP chemotherapy has resulted in a significantly better prognosis for patients with DLBCL, treated in the Reinier de Graaf Gasthuis in Delft.

An 82-year-old man was admitted with a 1-week history of chilling fever and dry cough. Laboratory tests revealed pancytopenia and elevated levels of C-reactive protein and lactic dehydrogenase (LDH). Screening for infectious diseases was negative. A bone marrow biopsy showed aspecific findings. The combination of pancytopenia, persistent fever, elevated LDH and hepatomegaly (demonstrated by ultrasound examination of the abdomen) was suggestive of the haemophagocytic syndrome. This was confirmed by very high levels of ferritin and soluble interleukin-2 receptor in the blood. In addition, re-examination of the bone marrow showed several haemophagocytic histiocytes. A polymerase chain reaction for Epstein-Barr virus (EBV) revealed a very high viral load. Since the patient had a history of an increased level of anti-EBV immunoglobulin-G, this was explained by a reactivation of the EBV infection. On the sixth day in hospital the patient developed signs of bilateral pneumonia and subsequent multiple organ failure. Despite intensive treatment the patient died. Autopsy revealed no haematological or other malignancies, but did show haemophagocytosis in many organs. It was then concluded that the patient had a virus-associated haemophagocytic syndrome, due to a reactivation of EBV, for which no underlying cause was found.

Analysis of an 83-year-old male presenting with diarrhoea showed secretory diarrhoea. serum levels of gastrin and pancreatic polypeptide were elevated. Somatostatin-receptor scintigraphy revealed a hot spot in the left thoracic wall and subsequently, breast adenocarcinoma with neuroendocrine differentiation was diagnosed. Postoperatively, the patient made an uneventful recovery. The relationship between the clinical picture, the results of pathological examination and hormonal analysis is discussed and put into perspective.

We describe a 68-year-old woman with an episode of diarrhoea, malaise and weight loss, caused by infection with Cryptosporidium. The diagnosis was hampered because this patient had a low risk of HIV infection, a two-year history of Crohn's disease, and a simultaneous candidal infection. An infection with Cryptosporidium was demonstrated with electron microscopic examination, and subsequent tests revealed positive HIV serology. AIDS was probably contracted through her husband.

Three patients, a girl aged 10 and two women aged 59 and 64 years, had erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), respectively. SJS and TEN are rare illnesses with a high morbidity and mortality. The aetiology is mainly iatrogenic: a hypersensitivity reaction to certain pharmaceutical prescriptions. SJS and TEN should be differentiated from the more frequent erythema multiforme, a self-limiting disease without important residual symptoms, which is usually initiated by infection with herpes simplex virus. SJS and TEN are variants in a spectrum of exfoliative dermatoses with epidermal necrosis. SJS and TEN on the one hand and erythema multiforme on the other can be distinguished on the basis of aetiology, clinical symptoms and histopathology. The distinction can, however, be difficult, notably in the early stages. The girl recovered completely. The first woman was treated with corticosteroids and also recovered; she was thought to have developed the syndrome as a reaction to malarial prophylactics. The third patient died, despite extensive treatment, of multiorgan failure and sloughing of 70% of the skin, probably as a reaction to amoxicillin given for pneumococcal pneumonia.

In two patients, a woman aged 34 and a man aged 38, toxic shock-like syndrome was diagnosed. This is a serious and potentially lethal disease characterized by multiorgan failure, fever, skin lesions and shock and caused by the exotoxin of Streptococcus pyogenes. Both patients had an invasive Lancefield group A beta haemolytic streptococcal infection. The first patient presented with a skin wound at the right knee and later developed shock and thrombosis, in the second a flu-like disease was complicated by respiratory insufficiency, rhabdomyolysis and acute renal insufficiency. Timely recognition of this infection may reduce the risk of complications such as adult respiratory distress syndrome, disseminated intravasal coagulation and necrotizing fasciitis. Both patients eventually recovered after antibiotic and intensive supporting therapy. This infection can be life-threatening and the fatality rate is 15-35% even if patients received appropriate antimicrobial therapy, supportive care, and, where necessary, surgical debridement.

A 86-year-old woman hospitalized for analysis of persistent abdominal discomfort died, apparently of myocardial infarction, shortly after admission. Autopsy revealed extensive myocarditis caused by infection with Clostridium septicum. As a portal of entry a carcinoma of the colon was found. The association of colon carcinoma and bacteraemia with C. septicum is well established while colon carcinoma can lead to cardiac hypoxia through blood loss and anaemia. However, myocarditis caused by this organism is extremely rare.

A 86-year-old woman became psychotic one day after starting treatment with 800 mg norfloxacin daily. Discontinuation and short-term treatment with haloperidol were followed by rapid disappearance of symptoms within two days. Since 1984, the Netherlands Centre for Monitoring of Adverse Reactions to Drugs received 19 similar reports of which 12 were attributed to norfloxacin, 3 to ofloxacin and 4 to pipemidic acid. The risk appears to be relatively high in the elderly, especially if they have fever, renal dysfunction and a psychiatric history. Lowering the doses may solve this problem provided the bacterial susceptibility is taken into account.