Treatment outcome in presumed and confirmed AIDS-related primary cerebral lymphoma

A retrospective analysis identified 38 HIV seropositive patients with a diagnosis of presumed (n=26) or confirmed (n=12) primary cerebral lymphoma (PCNSL). All patients had failed to respond to empirical antitoxoplasma therapy and the clinical diagnosis of PCNSL was confirmed by brain biopsy (n=4), cerebrospinal fluid (CSF) examination for Epstein–Barr virus (EBV) by PCR (n=7) or postmortem examination (n=1). There was no difference in the age, performance status, CD4 counts, antiretroviral usage or interval since first HIV serodiagnosis between patients with presumed or confirmed PCNSL. 16 patients received either radiotherapy (n=14) or chemotherapy (n=2). Patients with confirmed or presumptive PCNSL were equally likely to receive treatment. The median overall survival, which was measured from the end of unsuccessful antitoxoplasma therapy, was 1.2 months for the whole cohort. There was no difference in overall survival between patients with presumptive (median 0.8 months) and confirmed (median 1.3 months) PCNSL (logrank P=0.69). This suggests that there may be little value in positively diagnosing PCNSL in the current diagnostic algorithm. Recent improvements in outcome have been reported with systemic chemotherapy in HIV-PCNSL and may influence the need for earlier definitive diagnosis in the future.     

Survival Outcomes of Adjuvant Chemotherapy in Elderly Patients with Stage III Colon Cancer

BackgroundThe survival impact of multi-agent (MAC) compared with single-agent (SAC) adjuvant chemotherapy (AC) in elderly patients with stage III colon cancer (CC) remains controversial. The aim of this study was to compare survival outcomes of MAC and SAC in this population utilizing the National Cancer Database (NCDB).Patients and MethodsPatients aged ≥70 years with pathological stage III CC diagnosed in 2004-2015 were identified in the NCDB. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazard models were used to identify associations between MAC vs. SAC and overall survival (OS).ResultsAmong 41 707 elderly patients (≥70 years old) with stage III CC, about half (n = 20 257; 48.5%) received AC; the majority (n = 12 923, 63.8%) received MAC. The median age was 79 (range 70-90). The majority were female (n = 11 201, 55.3%), Caucasians (88%) and had moderately differentiated tumor grade (n = 12 619, 62.3%), tumor size >4 cm (11 785, 58.2%), and negative surgical margins (18 496, 91.3%). Low-risk stage III CC constituted 50.6% (n = 10 264) of the study population. High-risk stage III CC was associated with worse OS compared with low-risk disease (HR 0.35, 0.34-0.36, P < .001). Multi-agent chemotherapy was associated with a better 5-year OS compared with SAC (P < .001). High-risk stage III patients who received MAC vs. SAC had an OS of 4.2 vs. 3.4 years, respectively (P < .001). Low-risk stage III patients who received MAC vs. SAC had a median OS of 8.5 vs. 7 years (P < .001). In univariate and multivariable analyses, male sex, positive surgical margin, insurance and facility types, age, year of diagnosis, tumor size, and Charlson-Deyo score of >2 were associated with worse OS (P < .05).ConclusionsAny adjuvant chemotherapy has a trend of survival benefits. Multi-agent chemotherapy seems to have an enhanced benefit in the 70-75 age group. Multi-agent chemotherapy seemed to have similar efficacy as SAC in those aged >76 years.     

[18F]-fluoro-ethyl-l-tyrosine PET: a valuable diagnostic tool in neuro-oncology,but not all that glitters is glioma

Background

To assess the sensitivity and specificity of [¹⁸F]-fluoro-ethyl-l-tyrosine (¹⁸F-FET) PET in brain tumors and various non-neoplastic neurologic diseases.

Methods

We retrospectively evaluated ¹⁸F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). ¹⁸F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense).

Results

Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed ¹⁸F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher ¹⁸F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). ¹⁸F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions.

Conclusions

¹⁸F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood–brain barrier and ¹⁸F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.     

Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for primary central nervous system lymphoma

Background

Primary central nervous system lymphomas (PCNSLs) are highly aggressive tumors. Chemotherapy has improved prognosis significantly; however, early diagnosis is crucial for effective treatment. Presently, the diagnosis of PCNSL depends on histopathology of tumor biopsies. We have previously demonstrated differential expression of microRNAs in cerebrospinal fluid (CSF) samples from patients with PCNSL. Based on promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic, colorectal, and lung cancer, we investigated RNU2-1f in the CSF of PCNSL patients.

Methods

CSF was collected from patients with PCNSL (n = 72) and control patients with various neurologic disorders (n = 47). Sequential CSF samples were collected from 9 PCNSL patients. RNU2-1f levels were measured by real-time polymerase chain reaction.

Results

Measurement of RNU2-1f levels in CSF enabled the differentiation of patients with PCNSL from controls with an area under the curve (AUC) of 0.909 with a sensitivity of 68.1% and a specificity of 91.4%. The diagnostic accuracy was further improved by combined determination of RNU2-1f and miR-21, resulting in AUC of 0.987 with a sensitivity of 91.7% and a specificity of 95.7%. In consecutive measurements of RNU2-1f, which were performed in 9 patients at different stages of the disease course, RNU2-1f CSF levels paralleled the course of the disease.

Conclusions

Our data suggest that the measurement of RNU2-1f detected in CSF can be used as a diagnostic marker and also as a possible marker for treatment monitoring. These promising results need to be evaluated within a larger patient cohort.     

Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer

BackgroundLimited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy.MethodsWe conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer.ResultsIn comparison to nonmucinous population (n = 98), mucinous histology (n = 20) was associated with a younger age (48 vs 54, P = .02), wild-type APC (80% vs 15.3%, P < .0001), and wild-type TP53 (40% vs 8.2%, P = .001). Guanine nucleotide binding protein, alpha stimulating (GNAS) mutations were exclusively found in mucinous tumors (20% vs 0, P < .0001). Genomic alterations associated with resistance to anti-EGFR therapy, such as ERBB2 amplification, PIK3CA mutation, MAP2K1 mutation, and KRAS amplification, were identified in patients with left-sided RAS/BRAF wild-type mucinous metastatic colorectal cancer. Mucinous histology was not associated with a worse outcome than non-mucinous histology (34.3 vs 42.2 months, P = .85). However, patients with left-sided RAS/BARF wild-type mucinous colorectal cancer treated with first-line anti-EGFR therapy had significantly worse progression-free survival (4 vs 6.5 months, hazard ratio [HR] = 5.3, 95% confidence interval [CI] 1.3-21.7, P = .01) than patients treated with the first-line vascular endothelial growth factor A antibody, bevacizumab. Anti-EGFR therapy was associated with limited responses and a short PFS across all lines of therapy in 12 patients with left-sided RAS/BRAF wild-type mucinous colorectal cancer.ConclusionsMucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.     

Surgery for primary CNS lymphoma? Challenging a paradigm

The standard of care for primary central nervous system lymphoma (PCNSL) is systemic chemotherapy with or without whole brain radiotherapy or intrathecal chemotherapy. In contrast to treatment for other brain tumors, efforts at resection are discouraged. This is a secondary analysis of the German PCNSL Study Group–1 trial, a large randomized phase III study comprising 526 patients with PCNSL. Progression-free survival (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.10–1.74; P = .005) and overall survival (HR: 1.33; 95% CI: 1.04–1.70; P = .024) were significantly shorter in biopsied patients compared with patients with subtotal or gross total resections. This difference in outcome was not due to age or Karnofsky performance status (KPS). When controlled for the number of lesions, the HR of biopsy versus subtotal or gross total resection remained unchanged for progression-free survival (HR = 1.37; P = .009) but was smaller for overall survival (HR = 1.27; P = .085). This analysis of the largest PCNSL trial ever performed challenges the traditional view that the extent of resection has no prognostic impact on this disease. Therefore, we propose to reconsider the statement that efforts at resection should be discouraged, at least if resection seems safe, as is often the case in treatment of single PCNSL lesions.     

Role of flow cytometry immunophenotyping in the diagnosis of leptomeningeal carcinomatosis

Purpose: To explore the contribution of flow cytometry immunophenotyping (FCI) in detecting leptomeningeal disease in patients with solid tumors.Experimental design: Cerebrospinal fluid (CSF) samples from 78 patients who received a diagnosis of epithelial-cell solid tumors and had clinical data suggestive of leptomeningeal carcinomatosis (LC) were studied. A novel FCI protocol was used to identify cells expressing the epithelial cell antigen EpCAM and their DNA content. Accompanying inflammatory cells were also described. FCI results (positive or negative for malignancy) were compared with those from CSF cytology and with the diagnosis established by the clinicians: patients with LC (n = 49), without LC (n = 26), and undetermined (n = 3).Results: FCI described a wide range of EpCAM-positive cells with a hyperdiploid DNA content in the CSF of patients with LC. Compared with cytology, FCI showed higher sensitivity (75.5 vs 65.3) and negative predictive value (67.6 vs 60.5), and similar specificity (96.1 vs 100) and positive predictive value (97.4 vs 100). Concordance between cytology and FCI was high (Kp = 0.83), although misdiagnosis of LC did not show differences between evaluating the CSF with 1 or 2 techniques (P = .06). Receiver-operator characteristic curve analyses showed that lymphocytes and monocytes had a different distribution between patients with and without LC.Conclusion: FCI seems to be a promising new tool for improving the diagnostic examination of patients with suspicion of LC. Detection of epithelial cells with a higher DNA content is highly specific of LC, but evaluation of the nonepithelial cell compartment of the CSF might also be useful for supporting this diagnosis.     

Preoperative plasma vitamin D in patients with localized colorectal cancer: Age-dependent association with inflammation,postoperative complications,and survival

IntroductionAging is often associated with low-grade chronic inflammation and a senescent immune system. Vitamin D is a regulator of immune function, and low plasma vitamin D is associated with poor health. The association between plasma vitamin D and inflammatory biomarkers and risk of postoperative complications and survival in patients with colorectal cancer (CRC) is unknown. Our aim was to investigate these associations and how they are influenced by age.Materials and methodsCirculating vitamin D and the inflammatory biomarkers C-reactive protein (CRP), interleukin (IL)-6, and YKL-40 were measured in 398 patients with stage I–III CRC preoperatively. Older patients (≥70 years, n = 208) were compared to younger patients (<70 years, n = 190).The relation between vitamin D and complications and high inflammatory biomarker levels was presented by odds ratios ([OR], 95% confidence interval [CI]). Associations with survival were presented with hazard ratios ([HR], 95% CI).ResultsPlasma vitamin D was higher in older patients than in younger patients (75 vs. 67 nmol/L, P = 0.001). High vitamin D was associated with low plasma CRP in younger patients (OR = 0.35, 95% CI 0.17–0.76), but not in older patients (OR = 0.93, 0.49–1.76). High vitamin D in older patients with CRC was associated with reduced risk of major complications (OR = 0.52, 0.28–0.95). This was not found in younger patients (OR = 1.47, 0.70–3.11). Deficient vitamin D (<25 nmol/L) was associated with short overall survival compared to sufficient (>50 nmol/L) irrespective of age (HR = 3.39, 1.27–9.37, P = 0.02).ConclusionFor patients with localized CRC, high vitamin D levels before resection were associated with reduced risk of high inflammatory biomarkers for younger patients and reduced risk of major postoperative complications for older patients. Vitamin D deficiency was associated with reduced survival regardless of age.     

Serum neopterin levels in patients with breast cancer

The aim of this study was to determine the importance of serum neopterin level in female patients with breast cancer of various clinical stages. The study consisted of 75 female patients with breast cancer who were diagnosed and treated at the Gazi University Department of Medical Oncology. The patients were classified into three representative groups and a control group: group A (n = 26), patients with newly diagnosed primary breast cancer and without metastasis; group B (n = 33), patients with metastatic breast cancer who had undergone treatment for their diseases and on whom metastasis was detected during their follow-up; group C (n = 16), off-therapy patient whose cancer had been in remission for at least 5 years; group D (n = 20) healthy controls. The median serum neopterin levels of the 75 patients with breast cancer 11.0 (range, 0–23.6) nmol/L were significantly higher than those of controls (8.3 (range, 1.2–12.0) nmol/L). In group B patients, neopterin levels (12.6 (range, 0–23.6) nmol/L) were statistically significantly higher than those of controls, primary breast cancer patients, and off-therapy patients (P < .05). In group B, patients with visceral metastases had higher neopterin levels than did those with bone or local metastases; however, that difference was not statistically significant. The median serum neopterin levels of the primary breast cancer patients in group A (8.8 (range, 0–20) nmol/l) were not statistically significantly different from those in controls and off-therapy patients. Serum neopterin levels were significantly elevated in patients with metastatic breast cancer. Neopterin seems to be an indicator of metastatic cancer rather than a marker for local cancer. In patients with metastatic breast cancer, determining the serum neopterin levels may be useful in estimating survival; however, additional long-term follow-up will be needed.     

Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer

IntroductionLymphocytopenia and circulating tumor cells (CTCs) have been reported as independent prognostic factors for overall survival (OS) in metastatic breast cancer (MBC), and both have been associated with bone metastases. Our objective was to compare the prognostic significance of lymphocytopenia, CTC count, and extensive bone metastases (> 2 lesions) assessed by fluorine-18 (¹⁸F) fluorodeoxyglucose positron emission tomography/computed tomography (FDG–PET/CT) in patients with MBC.Patients and MethodsThis is a retrospective study that included patients with MBC who were starting a new line of systemic therapy. The study population consisted of patients treated at the University of Texas MD Anderson Cancer Center between 2004 and 2008 for whom baseline CTC count, lymphocyte counts, and FDG–PET/CT scans were available. Patients were stratified according to estrogen receptor status (positive vs. negative), human epidermal growth factor receptor 2 (HER2) status (amplified vs. constitutive), baseline CTC counts per 7.5 mL of blood (< 5 CTCs/7.5 mL of blood vs. ≥ 5 CTCs/7.5 mL of blood), lymphocytopenia (< 1000 vs. ≥ 1000/μL), and extensive bone metastases (> 2 vs. ≤ 2 lesions).ResultsIn 195 assessable patients, the median OS was 27 months (range, 1 to > 45 months). In multivariate analysis, lymphocytopenia, ≥ 5 CTCs/7.5 mL of blood, estrogen receptor status, and line of therapy were the only predictive factors for progression-free survival (PFS) (2P = .001, 2P = .032, 2P = .029, and 2P = .002, respectively) and OS (2P = .001, 2P = .009, 2P = .004, and 2P = .024, respectively).ConclusionCTC measurement and lymphocytopenia are independent prognostic factors for PFS and OS in patients with MBC.     

Cerebrospinal Fluid Concentrations of Gefitinib in Patients With Lung Adenocarcinoma

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have high response and disease control rates in patients with central nervous system (CNS) metastases. However there have been only a few case reports on the penetration of gefitinib into the cerebrospinal fluid (CSF). The aim of this study was to investigate the CSF concentration of gefitinib in Chinese patients with lung adenocarcinomas.MethodsFrom March 2007 to December 2010, 22 patients were sequentially enrolled in this study at Peking Union Medical College Hospital (PUMCH). CSF and plasma samples were collected at the same time from each patient after at least 7 doses of gefitinib. The concentrations of gefitinib in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry. The clinical factors that may affect gefitinib penetration were analyzed.ResultsThe mean plasma and CSF concentrations of gefitinib were 491.8 ± 184.2 ng/mL and 6.2 ± 4.6 ng/mL, respectively, and the mean ratio of CSF-plasma concentration was 1.3% ± 0.7%. There was a good correlation between CSF and plasma gefitinib concentrations (R = 0.556, P = .006). The presence of CNS metastases was associated with increased gefitinib CSF penetration (1.46% vs. 0.95%; P = .042).ConclusionsThe concentration of gefitinib in CSF was low, and it was significantly related to the plasma gefitinib concentration. Because of the inadequate CNS drug exposure, patients in whom the extracranial lesions were well controlled may benefit from increasing gefitinib dose for the new intracranial lesions.     

Cerebrospinal fluid interleukin-10 is a potentially useful biomarker in immunocompetent primary central nervous system lymphoma (PCNSL)

The diagnosis of primary central nervous system lymphoma (PCNSL) by radiographical examination is often difficult because of its similarity to other brain tumors. To test whether interleukin-10 (IL-10) and IL-6 can be used to distinguish PCNSL from other brain tumors that are radiographically similar, cerebrospinal fluid (CSF) levels of IL-10 and IL-6 were measured in 66 patients with intracranial tumors (PCNSLs: 26 cases; other brain tumors: 40 cases). In the patients with PCNSLs, the median CSF levels of IL-10 and IL-6 were 27 pg/mL and 5.4 pg/mL, respectively. The CSF IL-10 and IL-6 levels were significantly higher in PCNSLs than in the other brain tumors. To validate the diagnostic value of CSF IL-10 in PCNSL, we prospectively examined 24 patients with brain lesions that were suspected to be PCNSL. We observed that the CSF IL-10 levels were significantly higher in PCNSLs than in other brain tumors. At an IL-10 cutoff level of 9.5 pg/mL, the sensitivity and specificity were 71.0% and 100%, respectively. After therapy, the CSF IL-10 levels were decreased in all patients and were increased at relapse in most of these patients. Immunohistochemically, all PCNSLs, except for 1 unclassified PCNSL, expressed both IL-10 and IL-10 receptor-A. In the patients with high CSF IL-10, IL-10 expression levels in tumor were relatively higher, compared with low CSF IL-10; however, there was no significant difference between these groups. In addition, elevated CSF level of IL-10 was significantly associated with having a shorter progression-free survival (hazard ratio, 3.37; 95% confidence interval, 0.985-11.528; log-rank, P= .038). These results indicate that the CSF level of IL-10 may be a useful diagnostic and prognostic biomarker in patients with PCNSLs.     

Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO)

BackgroundNeopterin is produced by activated macrophages upon stimulation with interferon-γ (IFN-γ) and thus, elevated neopterin concentrations in patients indicate cellular inate immune response. Most studies in patients with malignant diseases found an association between higher neopterin concentrations and reduced survival and impaired prognosis. Nevertheless, neopterin is not a classical tumor marker since it is not produced by the cancer cells themselves.Patients and methodsIn a study conducted by the Austrian Gynecologic Oncology Group (AGO) in 114 patients with ovarian cystadenomas and 223 patients with invasive ovarian cancer, patients' urinary neopterin was determined before and after primary therapy. The relevance of neopterin in long-term median follow-up was assessed.ResultsElevated levels (cut-off 250 µmol/mol creatinine) were found less frequently in women with benign ovarian cystadenomas (24%) than in patients with malignant disease (58%). After 10 years, only 57% of ovarian cancer patients with elevated urinary neopterin levels survived without disease progression following primary therapy when compared with 86% of women with normal levels (P < 0.001). Along with residual tumor, FIGO stage, age and histological type, neopterin was significantly associated with overall survival (OS) and progression-free survival (PFS). The median PFS was 52 and 12 months and the median OS was 81 and 24 months for patients with normal and elevated neopterin, respectively, P < 0.001. In a multivariate Cox regression analysis, only residual tumor, neopterin and age were independently associated with OS, while only residual tumor was predictive for PFS. Thirty patients with early-stage invasive ovarian cancer (FIGO I and II) were analyzed separately. Of 3 patients with elevated neopterin, 2 died of disease in contrast to 2 out of 27 patients with normal neopterin (P = 0.004).ConclusionIn ovarian cancer, the negative impact of elevated urinary neopterin levels indicates a detrimental effect of cancer-associated inflammatory reaction.     

The value of bone marrow biopsy for staging of patients with primary CNS lymphoma

BackgroundIn patients with presumed primary CNS lymphoma (PCNSL), a systemic manifestation is found only in a small minority. Although bone marrow biopsy (BMB) is recommended for staging, its diagnostic value is unclear.MethodsA retrospective analysis of 392 patients with presumed PCNSL from 3 university hospitals and 33 patients with secondary CNS lymphoma (SCNSL) and initial CNS involvement from a multicenter Germany-wide prospective registry was performed.ResultsA BMB was performed and documented in 320/392 patients with presumed PCNSL; 23 had pathologic results. One harbored the same lymphoma in the brain and bone marrow (BM), 22 showed findings in BM discordant to the histology of brain lymphoma; n = 12 harbored a low-grade lymphoma in the BM, the other showed B-cell proliferation but no proof of lymphoma (n = 5), monoclonal B cells (n = 3), or abnormalities not B-cell-associated (n = 2). In the group of SCNSL with initial CNS manifestation, 32/33 patients underwent BMB; 7 were documented with bone marrow involvement (BMI); 1 had concordant results in the brain and BM with no other systemic manifestation. Six had additional systemic lymphoma manifestations apart from the brain and BM.ConclusionsIn only 2 out of 352 (0.6%) patients with CNS lymphoma (320 presumed PCNSL and 32 SCNSL), BMB had an impact on diagnosis and treatment. While collected in a selected cohort, these findings challenge the value of BMB as part of routine staging in presumed PCNSL.     

Serum soluble tumour necrosis factor receptor 55 is increased in patients with haematological neoplasias and is associated with immune activation and weight loss

Enhanced concentrations of soluble forms of the receptor for tumour necrosis factor (TNF)-α have been detected in the serum of cancer patients. We determined serum concentrations of soluble TNF receptor p55 (sTNF-R55) in patients with haematological neoplasias, 50 patients suffering from non-Hodgkin's lymphoma (n = 35), Hodgkin's disease (n = 10) and multiple myeloma (n = 5). Compared with healthy controls and with patients with potential thyroid disease, significantly elevated concentrations of sTNF-R55 were found (mean ± standard error: 2.68 ± 0.22 vs. 1.23 ± 0.21 ng/ml, P < 0.0001 and 2.18 ± 0.32 ng/ml, P = 0.03). Likewise, neopterin concentrations were raised (19.6 ± 3.66 vs. 5.3 ± 0.25 nmol/l in controls, P < 0.0001). We found a significant correlation between sTNF-R55 and neopterin concentrations (Rs = 0.544, P < 0.001). Patients with weight loss showed higher sTNF-R55 concentrations than patients with stable weight. Our results confirm the relevance of sTNF-R55 concentrations in serum of patients with cancer.     

Mesothelin Levels in Urine are Affected by Glomerular Leakage and Tubular Reabsorption

BackgroundMesothelin is a soluble biomarker of malignant mesothelioma. Levels in serum, however, are also influenced by other factors, including age and glomerular filtration rate (GFR). The measurement of mesothelin in urine has recently gained interest, but the renal handling of this protein has not been sufficiently examined.Patients and MethodsA total of 75 patients with benign kidney disease were prospectively included in the study. Mesothelin levels were measured in the serum and in the urine of all the participants by using enzyme-linked immunosorbent assay. Urinary albumin and alpha 1-microglobulin (A1M) levels, which are markers of glomerular leakage and of decreased tubular reabsorption, respectively, and the estimated GFR (eGFR) of each participant were obtained. All urine analyte levels were standardized (std) against urinary creatinine levels.ResultsAbsolute mesothelin levels in urine (median, 0.58 nmol/L; interquartile range [IQR], 0.25-1.03 nmol/L) were significantly lower than those in serum (median, 1.74 nmol/L; IQR, 1.35-2.43 nmol/L; P < .001). Urinary mesothelin_std levels positively correlated with serum mesothelin (r = 0.35, P < .01), albumin_std (r = 0.51, P < .001), and A1M_std levels (r = 0.71, P < .001). Neither age nor eGFR were associated with urinary mesothelin_std levels. Similarly, multiple linear regression analysis indicated that only albumin_std and A1M_std levels were significantly positively associated with the urinary mesothelin_std levels (adjusted R² = 0.49).ConclusionMesothelin levels in urine are affected by impaired glomerular and tubular function, which can influence the interpretation of mesothelin measurements and might cause false-positive results. These effects need to be accounted for to improve the further validation and possible clinical use of urinary mesothelin.     

Prevalence and predictors of fatigue in glioblastoma: a prospective study

BackgroundThe main goal of this study was to assess frequency, clinical correlates, and independent predictors of fatigue in a homogeneous cohort of well-defined glioblastoma patients at baseline prior to combined radio-chemotherapy.MethodsWe prospectively included 65 glioblastoma patients at postsurgical baseline and assessed fatigue, sleepiness, mean bedtimes, mood disturbances, and clinical characteristics such as clinical performance status, presenting symptomatology, details on neurosurgical procedure, and tumor location and diameter as well as pharmacological treatment including antiepileptic drugs, antidepressants, and use of corticosteroids. Data on fatigue and sleepiness were measured with the Fatigue Severity Scale and the Epworth Sleepiness Scale, respectively, and compared with 130 age- and sex-matched healthy controls.ResultsWe observed a significant correlation between fatigue and sleepiness scores in both patients (r = 0.26; P = .04) and controls (r = 0.36; P < .001). Only fatigue appeared to be more common in glioblastoma patients than in healthy controls (48% vs 11%; P < .001) but not the frequency of sleepiness (22% vs 19%; P = .43). Female sex was associated with increased fatigue frequency among glioblastoma patients but not among control participants. Multiple linear regression analyses identified depression, left-sided tumor location, and female sex as strongest associates of baseline fatigue severity.ConclusionsOur findings indicate that glioblastoma patients are frequently affected by fatigue at baseline, suggesting that factors other than those related to radio- or chemotherapy have significant impact, particularly depression and tumor localization.     

The CSF IL-10 concentration is an effective diagnostic marker in immunocompetent primary CNS lymphoma and a potential prognostic biomarker in treatment-responsive patients

IntroductionWe aimed to confirm the diagnostic value and to evaluate the pre- and post-therapeutic prognostic value of cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and IL-6 in patients with diffuse large B-cell primary central nervous system lymphoma (PCNSL).Patients and methodsIL-10 and IL-6 concentrations were measured in 79 patients with PCNSL at diagnosis and in 40 control individuals. Fifty-four PCNSL patients underwent repeat assessments starting at diagnosis.ResultsThe IL-10 concentration distinguished PCNSL from other neurologic diseases with a sensitivity of 88.6% and a specificity of 88.9% with a cutoff of 4 pg/ml. In a multivariate analysis of PCNSL patients, CSF involvement was associated with a higher IL-10 concentration (mean log (IL-10) of 4.4 versus 2.5 pg/ml, respectively, p = 0.0004). The pre-therapeutic IL-10 concentration had no prognostic impact on outcome. The IL-10 concentration decreased after treatment for most patients tested. Among patients with complete remission or partial remission, as evaluated by magnetic resonance imaging (MRI), a persistent detectable IL-10 level in the CSF at the end of treatment was associated with a negative impact on progression-free survival (PFS) (1-year PFS: 15%, 95% confidence interval [CI]: 2.5–38% versus 59%, 95% CI: 32–78%, respectively, p = 0.0004).ConclusionOur study confirmed that IL-10 is a useful biomarker for the diagnosis of PCNSL. We highlight new findings showing that the IL-10 level in the CSF could be used as a surrogate marker for CSF involvement and that the post-treatment IL-10 concentration could complement standard MRI for therapeutic response assessment in PCNSL.     

Is There a Role for Radiotherapy in the Primary Management of Primary Central Nervous System Lymphoma? A Single-centre Case Series

AimsIn recent years, the optimum primary management of primary central nervous system lymphoma (PCNSL) has evolved from combined modality chemoradiotherapy to chemotherapy alone. We describe a single-centre case series of PCNSL with a view to assessing the role of radiotherapy in primary disease management.Materials and methodsWest of Scotland PCNSL cases between 2001 and 2010 were identified by neuropathology. Observational data were collected retrospectively from case notes and electronic systems.ResultsForty-nine patients fulfilled the eligibility criteria. The median age was 61 years. Chemotherapy with a view to consolidation radiotherapy on completion was delivered to 61% (n = 30). Regimens varied, but were generally methotrexate-based. Chemotherapy was discontinued prematurely in 80% (n = 24) due to progressive disease (n = 12), intolerable toxicity (n = 7) or death (n = 4). In all patients who progressed or did not tolerate chemotherapy, treatment was changed to immediate salvage radiotherapy; modal irradiation was 40 Gy. Radiotherapy alone was delivered to those not suitable for chemotherapy (18%, n = 9) and best supportive care to those with poor performance status (18%, n = 9). The overall median survival was 8 months. In those receiving single modality radiotherapy or chemotherapy, the median survival was 5 and 8 months, respectively. For those completing chemoradiotherapy in its entirety, 3 year survival was 100%; in groups receiving salvage radiotherapy despite progressive disease or chemotherapy toxicity, moderate survival was maintained with immediate radiotherapy with 3 year survival rates of 33 and 60%, respectively.ConclusionsAlthough chemotherapy alone remains the optimal treatment of PCNSL, out with clinical trials only a minority of patients complete chemotherapy due to toxicity and disease progression; in such patients, immediate salvage radiotherapy provides an effective and safe alternative with maintenance of good outcomes.     

Early complete response during chemotherapy predicts favorable outcome in patients with primary CNS lymphoma

In primary central nervous system lymphoma (PCNSL), 2 international prognostic scores have been developed to estimate the outcome according to certain “prognostic groups”. However, these scores do not predict the individual course of a single patient under therapy. In this analysis, we addressed the question of whether early tumor remission in patients still under therapy, according to magnetic resonance imaging (MRI) criteria, helps to predict long-term outcome. Eighty-eight patients treated with 6 polychemotherapy cycles within a pilot/phase II trial underwent MRI scanning within 72 hours prior to initiation of therapy, after the second chemotherapy cycle, and after completion of chemotherapy. Response was assessed by contrast-enhanced MRI of the brain according to the Macdonald criteria. Median follow-up was 42 months (range, 0–124 months). Patients achieving a complete radiographic response after 2 courses of chemotherapy (n = 18) had a significantly longer median overall survival (OS) (not reached) and median time-to-treatment failure (TTF) (not reached) than patients with complete response (CR) after termination of treatment but with only a partial response after the second cycle (n = 24) (OS: 55 months; TTF: 32 months) (P < .01). Early complete tumor response assessed by MRI after the second of sixth scheduled chemotherapy cycles was highly predictive for both OS and TTF in patients with PCNSL treated in this series.