NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer.

PURPOSE: Analysis of methylation markers in liquid biopsies is a promising technique for the follow-up of patients with metastatic colorectal cancer (mCRC), because they can be used in all patients, regardless of their mutational status. Therefore, we studied the value of NPY methylation analysis in circulating tumor DNA (ctDNA) for accurate response monitoring in patients with mCRC in the PANIB trial. EXPERIMENTAL DESIGN: The PANIB trial was a randomized phase II trial designed to compare FOLFOX plus panitumumab and FOLFOX plus bevacizumab in patients with RAS wild-type unresectable mCRC. The results of sequential liquid biopsies were correlated with results of imaging. RESULTS: Forty patients were included from six Belgian hospitals. Analysis of the liquid biopsies revealed that higher baseline levels of methylated ctDNA was associated with a significantly shorter overall survival [HR, 1.015; 95% confidence interval (CI), 1.005-1.025; P = 0.002]. Furthermore, 37 patients provided at least two liquid biopsies. Thirty-one of them showed a decrease in the methylation ratio after the start of therapy, which corresponded with stable disease or response on imaging at the first evaluation. When comparing the panitumumab and bevacizumab arm, significantly higher objective response and early tumor shrinkage rates were observed in the panitumumab arm (P = 0.048 and 0.015, respectively). However, due to a small study population, the trial was underpowered to detect a significant difference in survival. CONCLUSIONS: The results of this study confirm that baseline methylated ctDNA is a prognostic marker and indicate that NPY methylation is a promising marker for response monitoring in patients with mCRC.

Plain language summary of results from the JAVELIN Bladder 100 study: avelumab maintenance treatment for advanced urothelial cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article originally published in The New England Journal of Medicine. It is about initial results (collected in October 2019) from the JAVELIN Bladder 100 study (a clinical trial), which looked at avelumab maintenance treatment in people with advanced urothelial cancer. Urothelial cancer is the most common type of bladder cancer. People with advanced urothelial cancer often receive chemotherapy. If this is the first treatment people with advanced disease are given, it is called first-line treatment. If the cancer stops growing or shrinks with first-line chemotherapy, people can be given different treatment to try to prevent the cancer from growing again. This is called maintenance treatment. It may help people live longer. WHAT HAPPENED IN THE JAVELIN BLADDER 100 STUDY?: In the JAVELIN Bladder 100 study, researchers wanted to find out if maintenance treatment with avelumab would help people with advanced urothelial cancer live longer. Avelumab is a type of medicine called immunotherapy. Immunotherapy helps the body's immune system fight cancer. 700 people took part in the study. To take part, they must have already been treated with first-line chemotherapy. Also, their cancer must have shrunk or not grown with this treatment. They were then treated with either avelumab maintenance treatment plus best supportive care or best supportive care alone. Best supportive care means treatments that help improve symptoms and quality of life. These treatments do not affect the cancer directly and can include medicines to relieve pain. WHAT WERE THE RESULTS?: Researchers found that people treated with avelumab maintenance treatment plus best supportive care lived, on average, 7 months longer than people who received best supportive care alone. People treated with avelumab had more side effects than those not treated with avelumab, but most were not severe. Common side effects with avelumab included persistent tiredness, itchy skin, urinary tract infection, and diarrhea. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from the JAVELIN Bladder 100 study support the use of avelumab as maintenance treatment for people with advanced urothelial cancer whose cancer has shrunk or not grown with first-line chemotherapy. ClinicalTrials.gov NCT number: NCT02603432.

Joint Belgian recommendation on screening for DPD-deficiency in patients treated with 5-FU, capecitabine (and tegafur).

OBJECTIVES: Fluoropyrimidines such as 5-Fluorouracil (5-FU), capecitabine and tegafur are drugs that are often used in the treatment of maliginancies. The enzyme dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme of 5-FU catabolism. Genetic variations within the DPYD gene (encoding for DPD protein) can lead to reduced or absent DPD activity. Treatment of DPD deficient patients with fluoropyrimidines can result in severe and, rarely, fatal toxicity. Screening for DPD deficiency should be implemented in practice. METHODS: The available methods in routine to screen for DPD deficiency were analyzed and discussed in several group meetings involving members of the oncological, genetic and toxicological societies in Belgium: targeted genotyping based on the detection of 4 DPYD variants and phenotyping, through the measurement of uracil and dihydrouracil/uracil ratio in plasma samples. RESULTS: The main advantage of targeted genotyping is the existence of prospectively validated genotype-based dosing guidelines. The main limitations of this approach are the relatively low sensitivity to detect total and partial DPD deficiency and the fact that this approach has only been validated in Caucasians so far. Phenotyping has a better sensitivity to detect total and partial DPD deficiency when performed in the correct analytical conditions and is not dependent on the ethnic origin of the patient. CONCLUSION: In Belgium, we recommend phenotype or targeted genotype testing for DPD deficiency before starting 5-FU, capecitabine or tegafur. We strongly suggest a stepwise approach using phenotype testing upfront because of the higher sensitivity and the lower cost to society.

Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up.

PURPOSE: As noninvasive biomarkers are an important unmet need for neuroendocrine neoplasms (NEN), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in patients with NEN. EXPERIMENTAL DESIGN: Longitudinal plasma samples were collected from patients with well-differentiated, metastatic gastroenteropancreatic and lung NEN. cfDNA was subjected to shallow whole-genome sequencing to detect genome-wide copy-number alterations (CNA) and estimate circulating tumor DNA (ctDNA) fraction, and correlated to clinicopathologic and survival data. To differentiate pancreatic NENs (PNEN) from pancreatic adenocarcinomas (PAAD) using liquid biopsies, a classification model was trained using tissue-based CNAs and validated in cfDNA. RESULTS: One hundred and ninety-five cfDNA samples from 43 patients with NEN were compared with healthy control cfDNA (N = 100). Plasma samples from patients with PNEN (N = 21) were used for comparison with publicly available PNEN tissue (N = 98), PAAD tissue (N = 109), and PAAD cfDNA (N = 96). Thirty percent of the NEN cfDNA samples contained ctDNA and 44% of the patients had at least one ctDNA-positive (ctDNA+) sample. CNAs detected in cfDNA were highly specific for NENs and the classification model could distinguish PAAD and PNEN cfDNA samples with a sensitivity, specificity, and AUC of 62%, 86%, and 79%, respectively. ctDNA-positivity was associated with higher World Health Organization (WHO) grade, primary tumor location, and higher chromogranin A and neuron-specific enolase values. Overall survival was significantly worse for ctDNA+ patients and increased ctDNA fractions were associated with poorer progression-free survival. CONCLUSIONS: Sequential genome-wide profiling of plasma cfDNA is a novel, noninvasive biomarker with high specificity for diagnosis, prognosis, and follow-up in metastatic NENs.

Impact of solid cancer on in-hospital mortality overall and among different subgroups of patients with COVID-19: a nationwide, population-based analysis.

BACKGROUND: Cancer seems to have an independent adverse prognostic effect on COVID-19-related mortality, but uncertainty exists regarding its effect across different patient subgroups. We report a population-based analysis of patients hospitalised with COVID-19 with prior or current solid cancer versus those without cancer. METHODS: We analysed data of adult patients registered until 24 May 2020 in the Belgian nationwide database of Sciensano. The primary objective was in-hospital mortality within 30 days of COVID-19 diagnosis among patients with solid cancer versus patients without cancer. Severe event occurrence, a composite of intensive care unit admission, invasive ventilation and/or death, was a secondary objective. These endpoints were analysed across different patient subgroups. Multivariable logistic regression models were used to analyse the association between cancer and clinical characteristics (baseline analysis) and the effect of cancer on in-hospital mortality and on severe event occurrence, adjusting for clinical characteristics (in-hospital analysis). RESULTS: A total of 13 594 patients (of whom 1187 with solid cancer (8.7%)) were evaluable for the baseline analysis and 10 486 (892 with solid cancer (8.5%)) for the in-hospital analysis. Patients with cancer were older and presented with less symptoms/signs and lung imaging alterations. The 30-day in-hospital mortality was higher in patients with solid cancer compared with patients without cancer (31.7% vs 20.0%, respectively; adjusted OR (aOR) 1.34; 95% CI 1.13 to 1.58). The aOR was 3.84 (95% CI 1.94 to 7.59) among younger patients (<60 years) and 2.27 (95% CI 1.41 to 3.64) among patients without other comorbidities. Severe event occurrence was similar in both groups (36.7% vs 28.8%; aOR 1.10; 95% CI 0.95 to 1.29). CONCLUSIONS: This population-based analysis demonstrates that solid cancer is an independent adverse prognostic factor for in-hospital mortality among patients with COVID-19. This adverse effect was more pronounced among younger patients and those without other comorbidities. Patients with solid cancer should be prioritised in vaccination campaigns and in tailored containment measurements.

Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance. METHODS: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety. RESULTS: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. CONCLUSIONS: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).

Real life safety and effectiveness of nivolumab in older patients with non-small cell lung cancer: Results from the Belgian compassionate use program.

OBJECTIVES: To compare real life effectiveness and safety of nivolumab in patients with non-small cell lung cancer (NSCLC), according to age and Eastern Cooperative Group performance status (ECOG-PS). METHODS: We performed a retrospective analysis of patients treated with nivolumab for NSCLC within a Belgian compassionate use program from July 2015 until December 2016. Safety and effectiveness were compared between patients aged ≥70 years and < 70 years and between ECOG-PS 0/1 and ≥ 2. RESULTS: A total of 324 patients with NSCLC were included. There was no significant difference between older (≥70) and younger (<70 years) patients with regards to progression free survival (PFS) (4 months (95%CI 2.6;4.8) versus 3.7 months (95%CI 1;7), p = 0.483) and overall survival (OS) (9.3 months (95% CI 5.5;13.1 months) versus 8.4 months (95%CI 6.3; 10.5), p = 0,638). Patients with an ECOG-PS ≥2 had a significant lower median PFS and OS compared to patients with an ECOG-PS 0-1 (2.2 (95%CI 1.4; 2.9) versus 5.6 months (95%CI 4.1; 7.1), p = 0.001 and 3.4 (95%CI 2.3; 4.5) versus 11.1 months (95%CI 8.9; 13.2), p < 0.001 respectively). No significant difference in all grades or grade 3/4 adverse events (AEs) were observed between the different age groups (p = 0.526 and p = 0.603 respectively). Patients with an ECOG-PS 0/1 had significantly more all grades AEs (p = 0.009) but no difference in grade 3/4 AEs was observed (p = 0.406) compared to ECOG-PS ≥2. CONCLUSION: This real life retrospective study confirms that safety and effectiveness of nivolumab is similar between different age groups, but that effectiveness is driven by performance status.

TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. RESULTS: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). CONCLUSIONS: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

Circulating tumor cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer.

BACKGROUND: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making. OBJECTIVE: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies. DESIGN, SETTINGS, AND PARTICIPANTS: In a prospective, multicentre study blood samples for CTC enumeration were collected from patients with mCRPC at baseline (n = 174). In patients who responded for minimally 10-12 weeks a follow-up sample was collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For baseline analysis, patients were stratified in <5 or ≥5 CTCs/7.5 mL, whereas for the analysis of CTC dynamics at 10-12 weeks, in patients with stable, increasing or decreasing CTC counts. Progression-free survival (PFS), overall survival (OS), and PSA changes at 10-12 weeks were compared between groups. RESULTS: Patients demonstrating increasing CTCs on therapy had a shorter median PFS (4.03 vs 12.98 vs 13.67 months, HR 3.6, 95%CI 1.9-6.8; P < 0.0001) and OS (11.2 months vs not reached, HR 9.5, 95%CI 3.7-24; P < 0.0001), compared to patients with decreasing or stable CTCs. Multivariable Cox regression showed that prior chemotherapy (HR 4.1, 95%CI 1.9-8.9; P = 0.0003), a high baseline CTC count (HR 1.5, 95%CI 1.2-1.9; P = 0.002) and increasing CTCs at follow-up (HR 3.3, 95%CI 1.4-7.6; P = 0.005) were independent predictors of worse PFS. Previous chemotherapy (HR 7, 95%CI 1.9-25; P = 0.003), high baseline CTC counts (HR 2.2, 95%CI 1.4-3.7; P = 0.002) and increasing CTCs during therapy (HR 4.6, 95%CI 1.4-15; P = 0.01) were independently associated with shorter OS. ≥30% and ≥50% PSA responses less frequently occurred in patients with CTC inclines at 10-12 weeks on therapy (χ2 test: P < 0.01). CONCLUSIONS: CTC dynamics during therapy are associated with PSA response and provide independent clinical prognostication over PSA declines. Hence the study demonstrates the pharmacodynamic properties of CTCs.

Which Factors Predict Overall Survival in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Abiraterone Acetate Post-Docetaxel?

BACKGROUND: Abiraterone acetate (AA) increases overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. However, survival time varies substantially between individuals. Our goal was to identify prognostic factors that better estimate OS. MATERIALS AND METHODS: This is a retrospective multicentric analysis of 368 patients with mCRPC starting AA with prednisone after docetaxel. Cox proportional hazards statistics were applied. A multivariate model was constructed based on significant univariate predictors by using a manual stepwise forward and backward selection strategy. Model performance was determined by using receiver operating characteristic (ROC) curves. RESULTS: Univariate analysis identified 20 significant OS predictors. A multivariate model was constructed, based on 220 patients, incorporating 5 independent risk factors for decreased OS at the time of AA initiation: hemoglobin < 12 g/dL (hazard ratio [HR] 2.02), > 10 metastases (HR 1.80), ECOG performance status ≥ 2 (HR 1.88), radiographic progression (HR 1.50), and time since diagnosis < 90 months (HR 1.66, all P < .05). Patients were stratified into 3 groups: good (0-2 risk factors, median OS 22.6 months), intermediate (3 risk factors, median OS 13.9 months), and poor prognosis (4-5 risk factors, median OS 6.2 months). The area under the ROC curve based on the event "death by the time of median OS (13.3 months)" was 0.736 (95% confidence interval 0.670-0.803). CONCLUSION: We identified 5 readily available risk factors independently associated with decreased OS. The resulting model may be used for patient counseling in daily clinical practice, as well as patient stratification in clinical trials.

Abiraterone acetate post-docetaxel for metastatic castration-resistant prostate cancer in the Belgian compassionate use program.

BACKGROUND: Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011-July 2012). PATIENTS AND METHODS: Records from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000mg per day with 10mg prednisone or equivalent were retrospectively reviewed (September 2013-December 2014). Prostate-specific antigen (PSA) response (decrease≥50%), time to PSA progression (increase>50% over PSA nadir in case of PSA response/>25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied. RESULTS: Overall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status≥2. Median age was 73 years, median PSA was 103ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6-4.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design. CONCLUSIONS: These real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies.

Intra-hepatic Mitomycin C bolus infusion in the treatment of extensive liver metastases of breast cancer.

BACKGROUND: In the treatment of extensive liver metastasis of breast cancer (LMBC), locally administered Mitomycin C (MMC) to the liver might be an effective approach with limited toxicity. PATIENTS AND METHODS: We retrospectively reviewed the records of 30 patients with LMBC treated with intra-hepatic MMC at our institution. MMC (12 mg) was administered by transcatheter bolus infusion into the hepatic arteries every 4 weeks. Tumour response according to RECIST criteria, progression free survival (PFS), overall survival (OS) and duration of response (DR) were used to evaluate efficacy. RESULTS: There was a local response in the liver and a global response in respectively 33 and 26%. The median PFS, DR and OS were 3, 4 and 7 months, respectively. There was more benefit in patients without documented metastases outside the liver and without severe liver dysfunction. Thrombocytopenia, leucocytopenia and an allergic reaction were observed after MMC administration in 20 (67%), 12 (40%) and 4 patients (13%), respectively. CONCLUSION: Intra-hepatic MMC bolus infusion as treatment of extensive LMBC is associated with limited toxicity and has a significant response rate in the liver. Prospective investigations are required to define the place of this modality for treating patients with breast cancer liver metastases.

Recurrent low- to intermediate-grade chondrosarcoma of the thumb with lung metastases: an objective response to trofosfamide.

BACKGROUND: Low- to intermediate-grade chondrosarcoma is usually a slow-growing and highly chemotherapyresistant tumor type. CASE REPORT: The 76-year-old female patient presented with low- to intermediate-grade chondrosarcoma of the distal phalanx of the right thumb in 1993 and was treated with an excision of the carpometacarpal joint. Approximately 10 years later, the patient presented with recurrent local disease at the trapezoid bone, which was resected. Eight months later she presented with local recurrence at the carpal joint and lung metastases. Subsequently she was treated chemotherapeutically with pegylated liposomal doxorubicin as part of a clinical trial. Due to tumor progression after 2 cycles, she was switched to oral trofosfamide (150 mg daily). A follow-up CT scan after 8 months demonstrated a partial remission that was confirmed by a second scan after 9 months of treatment. The treatment was well tolerated. After 18 months of continued treatment, she was still in remission and on trofosfamide. CONCLUSION: Trofosfamide at a daily dose of 150 mg may be effective in low- to intermediate-grade chondrosarcoma.

From prolonged febrile illness to fever of unknown origin: the challenge continues.

BACKGROUND: Epidemiological changes and the ongoing expansion of the diagnostic armamentarium warrant a regular update of the spectrum of diseases that present as prolonged febrile illnesses. METHODS: We prospectively collected a series of 290 immunocompetent patients referred to our university hospital between 1990 and 1999 with a febrile illness (temperature >38.3 degrees C) of uncertain cause, lasting at least 3 weeks. Patients were categorized in 4 groups according to the timing of diagnosis: early diagnosis (within 3 in-hospital days or 3 outpatient visits), intermediate diagnosis (between days 4 and 7), late diagnosis (after day 7), and no diagnosis during index contact or follow-up. RESULTS: A final diagnosis was established early in 67 patients (23.1%), intermediate in 38 (13.1%), and late in 87 (30.0%). In the remaining 98 (33.8%), no diagnosis was made. The cause of the fever remained obscure in 50 (47.6%) of 105 patients with episodic fever vs 48 (25.9%) of 185 patients with continuous fever (P<.001). Among the 192 patients with a final diagnosis, noninfectious inflammatory diseases represented the most prevalent diagnostic category (35.4%), surpassing infections (29.7%), miscellaneous causes (19.8%), and malignancies (15.1%). Fourteen disorders accounted for over 59% of diagnoses, whether diagnosis was reached early, intermediate, or late. Hematological malignancies made up 11.5% of diagnoses, but were responsible for 14 (58.3%) of the 24 fatalities related to the febrile illness. Of the 80 patients discharged alive without diagnosis and for whom follow-up was available, 3 died, but the deaths were considered to be unrelated to the feverish illness. CONCLUSIONS: Prolonged febrile illnesses remain a diagnostic challenge. Despite the technological progress of the late 20th century, the origin of the fever remains elusive in many patients, especially in those with episodic fevers. Noninfectious inflammatory diseases emerge as the most prevalent diagnostic category.