EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

BACKGROUND: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. PATIENTS AND METHODS: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. RESULTS: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. CONCLUSION: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. CLINICALTRIALS.GOV: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.

BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Durable remission of both multicentric Castleman's disease and Kaposi's sarcoma with valganciclovir, rituximab and liposomal doxorubicin in an HHV-8-positive, HIV-negative patient.

WHAT IS KNOWN AND OBJECTIVE: Human herpesvirus-8 (HHV-8)-positive, HIV-negative multicentric Castleman's disease is a rare lymphoproliferative disorder with no standardized treatment. Concurrent Kaposi's sarcoma, another HHV-8-related disease, is uncommon in HIV-negative patients. The role of antiviral therapy and rituximab in HIV-negative patients is not well established. CASE DESCRIPTION: We report a case of a 5-year, durable remission of HHV-8-positive, HIV-negative comorbid multicentric Castleman's disease and Kaposi's sarcoma treated with long-term valganciclovir, following initial rituximab and liposomal doxorubicin. WHAT IS NEW AND CONCLUSION: Currently, there is no defined role for antiviral therapy in the treatment of HIV-negative HHV-8-positive multicentric Castleman's disease and Kaposi's sarcoma. Ganciclovir followed by indefinite, continuous valganciclovir is thought to have contributed significantly to the durable response in this case.

A dose escalation study of gemcitabine plus oxaliplatin in combination with imatinib for gemcitabine-refractory advanced pancreatic adenocarcinoma.

BACKGROUND: Targeting platelet-derived growth factor receptor-ß (PDGFR-ß) is a potential strategy to reduce tumour-related interstitial fluid pressure, enhance cytotoxic drug uptake and reduce chemoresistance. This study aimed to define safe doses of gemcitabine plus oxaliplatin when combined with imatinib (potent PDGFR-ß inhibitor) in patients with advanced gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Using a 3 + 3 dose escalation design, patients of performance status zero or one were entered into five sequential dose levels (DLs) of gemcitabine [day 1, from 400 (DL1) to 1000 mg/m(2) (DL4)] and oxaliplatin [day 2, 85 (DL1-4) and 100 mg/m(2) (DL5)] two weekly. Imatinib 400 mg od was given for 7 days (day minus 2-5) each cycle. RESULTS: Twenty-seven patients received 168 cycles in total. Median age was 61 years (44-74 years). Dose-limiting toxicities occurred in two of two patients at DL5 (G4 thrombocytopenia, G3 lethargy), defined as the maximum tolerated dose and one of six patients at DL4 (G3 lethargy). DL4 was expanded. There were 2 of 27 partial responses and 14 of 27 stable disease [disease control 52%, 95% confidence interval (CI) 32% to 71%]. Median progression-free survival and overall survival were 4.6 (95% CI 2.1-7.0) and 5.6 months (95% CI 2.5-8.7), respectively. CONCLUSION: In gemcitabine-refractory PC, gemcitabine (1000 mg/m(2)) and oxaliplatin (85 mg/m(2)) can be safely combined with imatinib given on a 7 days on and 7 days off intermittent schedule.

Lymphatic and blood vessels in basal and triple-negative breast cancers: characteristics and prognostic significance.

Basal and triple-negative breast cancer phenotypes are characterised by unfavourable biological behaviour and outcome. Although certain studies have examined their pathological and molecular profile, the vascular characteristics of lymphatic and blood vessels have not been examined. Immunohistochemical staining with podoplanin, CD34 and CD31 was used to examine lymphatic and microvessel density, as well as vascular invasion in 197 basal-like and in 99 triple-negative breast tumours and compared against 200 non-basal and 334 non-triple-negative cases. All specimens were lymph node negative. Vascular invasion was identified as blood or lymphatic vascular invasion by the differential expression of markers. All measurements were correlated with clinicopathological features and prognosis. No significant difference was detected between the basal and triple-negative groups in terms of lymphatic or microvessel density or vascular invasion. However, both the basal and the triple-negative groups showed significantly higher microvessel density than did the non-basal and non-triple-negative groups (P=0.017 and P<0.001, respectively). Unlike microvessel density, no significant difference was detected in lymphatic density between the basal or triple-negative groups compared with their respective controls. Interestingly, vascular invasion, almost entirely lymphatic invasion, was detected in 27% of the basal and in 26% of the triple-negative groups with no significant difference in comparison with control groups. In both basal and triple negatives, vascular invasion was associated with poorer survival by univariate and multivariate analyses. The 20-year overall survival rate in basal-like tumours was 55% in vascular invasion-positive cases compared with 73% in vascular invasion-negative tumours (P=0.012), and 46% in triple-negative vascular invasion-positive compared with 79% in vascular invasion-negative tumours (P=0.001). Basal-like vs non-basal-like and triple-negative vs non-triple-negative tumours have similar vascular characteristics in terms of lymphatic vessel density and vascular invasion but higher microvessel density, suggesting that such groups may preferentially benefit from anti-angiogenic therapy. Vascular invasion was, in all phenotypes, almost entirely lymphatic vessel invasion and could stratify basal-like and triple-negative phenotypes into distinct prognostic groups.

Rechallenge with platinum plus fluoropyrimidine +/- epirubicin in patients with oesophagogastric cancer.

PURPOSE: There is no standard second-line therapy for patients with oesophagogastric cancer who progress following first-line chemotherapy for advanced disease or relapse following radical multi-modality therapy. The aim of this retrospective study was to evaluate survival following rechallenge with platinum plus fluoropyrimidine (PF) +/- epirubicin. METHODS: Patients treated with PF +/- epirubicin for oesophagogastric cancer at our institution were identified from the electronic prescribing database. Patients rechallenged with PF +/- epirubicin >3 months after completing initial chemotherapy were eligible. Primary endpoint was survival, calculated from day 1 of rechallenge treatment to date of death or last follow-up. Secondary endpoints were progression-free survival and response rate to PF-based re-challenge. RESULTS: Between 2000 and 2008, 950 patients treated with PF +/- epirubicin for oesophagogastric cancer were identified. 298 patients progressed or relapsed >3 months after completing chemotherapy, of whom 106 patients were rechallenged with PF-based chemotherapy. Median progression-free survival and overall survival were 5.1 and 10 months, respectively, from date of rechallenge for patients treated with initial radical intent and 3.9 and 6.6 months, respectively, in patients treated with palliative intent from diagnosis. In a survival analysis, no significant prognostic factors were identified. CONCLUSION: Selected patients with oesophagogastric cancer who relapse or progress >3 months after initial treatment with PF +/- epirubicin may benefit from re-introduction of PF-based chemotherapy.

Programmable matter by folding.

Programmable matter is a material whose properties can be programmed to achieve specific shapes or stiffnesses upon command. This concept requires constituent elements to interact and rearrange intelligently in order to meet the goal. This paper considers achieving programmable sheets that can form themselves in different shapes autonomously by folding. Past approaches to creating transforming machines have been limited by the small feature sizes, the large number of components, and the associated complexity of communication among the units. We seek to mitigate these difficulties through the unique concept of self-folding origami with universal crease patterns. This approach exploits a single sheet composed of interconnected triangular sections. The sheet is able to fold into a set of predetermined shapes using embedded actuation. To implement this self-folding origami concept, we have developed a scalable end-to-end planning and fabrication process. Given a set of desired objects, the system computes an optimized design for a single sheet and multiple controllers to achieve each of the desired objects. The material, called programmable matter by folding, is an example of a system capable of achieving multiple shapes for multiple functions.

Quantifying exposure to diagnostic medical radiation in patients with inflammatory bowel disease: are we contributing to malignancy?

BACKGROUND: While potential risks of diagnostic medical radiation are acknowledged, actual exposure of patients in routine clinical practice is poorly documented. AIM: To quantify such exposure to vulnerable abdominal organs in patients with inflammatory bowel disease who are already at risk of intestinal cancer. METHODS: All incidences of exposure to diagnostic medical radiation were documented in a consecutive series of 100 patients with inflammatory bowel disease (62 Crohn's disease, 37 ulcerative colitis, 1 indeterminate colitis) attending a hospital-based clinic. Total effective dose (mSv) was calculated using published tables. Predictors of high or no irradiation were evaluated by multivariate logistic regression analysis. RESULTS: Thirteen patients had no documented diagnostic irradiation. Twenty-three patients received an effective dose greater than 25 mSv. An at-risk effective dose >50 mSv was received by 11 patients. Dosage was higher in patients with Crohn's disease than ulcerative colitis (P = 0.02) and in patients undergoing surgery (P = 0.004). However, no predictive factors for high radiation dosage or for no exposure were identified. CONCLUSIONS: At-risk irradiation from diagnostic medical radiation is common in patients with inflammatory bowel disease, and might potentially contribute to the elevated risk of intra-abdominal and other cancers. The level of irradiation should be considered in clinical decisions regarding abdominal imaging.

Cycad toxins, Helicobacter pylori and parkinsonism: cholesterol glucosides as the common denomenator.

Understanding sporadic cases of age-dependent neurodegenerative diseases such as parkinsonism requires the evaluation of potential environmental factors. Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), a neurological disorder in which features of parkinsonism are present and for which no consistent genetic explanation has been found, has been linked to the consumption of cycad (Cycas micronesica). Similarly, epidemiological evidence suggests an association between parkinsonism and gastric ulcer caused by Helicobacter pylori infection. While common immunological and inflammatory changes have been proposed to account for the link between parkinsonism and H. pylori infection, we propose an alternate explanation based on our work on the "cycad theory" of ALS-PDC. Recent experiments in our laboratory have identified several sterol glucosides in cycad that have neurotoxic properties in vitro and that appear to be linked to the development of neurodegenerative disease in vivo. Specifically, mice fed cycad display behavioural symptoms of parkinsonism such as reduced gait length, as well as neuropathological signs such as a loss of striatal dopaminergic (DAergic) terminals and an upregulation of the dopamine D2 receptor. These cycad-derived sterol glucosides are structurally similar to cholesterol glucosides that account for a significant part pf the lipid profile of H. pylori. We hypothesize that cholesterol glucosides arising from H. pylori infection may act as neurotoxins, promoting the degeneration of the DAergic neurons affected in parkinsonism, in a similar reaction to that which is thought to link cycad consumption and ALS-PDC. This hypothesis will be tested in future studies that will include exposing mice to purified sterol or cholestorol glucosides derived from cycad and comparing these mice behaviourally and neuropathologically to ones chronically infected with H. pylori.

Advice on hair and scalp care during cranial radiotherapy: a prospective randomized trial.

BACKGROUND: The advice on hair washing during brain irradiation is aimed at minimizing radiation induced skin toxicity. We performed a prospective randomized trial to assess the effect of advice on scalp care on the local skin reaction in patients undergoing cranial radiotherapy. METHODS: One hundred and nine patients undergoing cranial radiotherapy were randomized into two groups. Patients in group 1 were advised not to wash hair during treatment and patients in group 2 to maintain normal pattern of hair washing. They were assessed weekly over a period of 10 weeks from the start of treatment. Symptoms of pain and itching were recorded using a modified RTOG/EORTC acute skin reaction scoring system and skin reaction was assessed clinically using erythema/desquamation score. The frequency of hair washing and the distress of changing the practice of normal hygiene were recorded on a diary card. Skin reaction scores were compared as a summary measure using area under the curve per week (AUC/week) and median scores, and the differences between groups were assessed by means of the t-test. RESULTS: One hundred and nine patients commencing cranial radiotherapy according to standard protocol were randomized into the trial (group 1, 55 patients; group 2, 54 patients). Patients asked to restrict hair washing, washed at a lower average frequency. There were no significant differences between scores of skin reaction in the two groups for each of the variables measured. CONCLUSIONS: The practice of normal hair washing is not associated with increased severity of adverse skin reaction. As a request to change the pattern of normal hygiene may cause distress, the current advice should be to maintain normal hair washing during cranial radiotherapy.

Racial differences in post-neonatal mortality in Chicago: what risk factors explain the black infant's disadvantage?

OBJECTIVES: To investigate the extent to which the place of residence affects the black to white differential in post-neonatal (28-365 days) mortality, we performed a univariate analysis and multivariate logistic regression of the 1982-1983 Illinois vital records. Chicago Police violent crime information and 1980 US Census income data. METHODS: Four environmental predictors of post-neonatal death were examined: a median family income of < $10,000 per year, a poverty prevalence of > 50%, violent crime rates of > 11/1000 and limited community access to primary medical care based on physician supply ratios. RESULTS: The post-neonatal mortality rate of black (n = 50,765) infants was three times that of white (n = 50,690) infants: 10/1000 versus 3/1000, respectively. Thirty-six percent of the white infants had none of the environmental risk factors, whereas only 13% of the black infants had none of the risk factors. For black infants, the presence of any one factor was associated with a slightly increased risk of post-neonatal mortality (9/1000 as compared to 7/1000 with no risk factors), whereas the presence of two or more risk factors was associated with a higher risk (11/1000). When the number of these environmental risk factors were taken into account, the OR for black infants declined from 3.0 (95% CI 2.5-3.6) to 1.7 (95% CI 1.5-1.9). When the differences in maternal age, education, marital status and infant birth weight were also taken into account the odds ratio of post-neonatal death for blacks was 1.5 (95% CI 1.3-1.7). CONCLUSIONS: We conclude that a substantial proportion of the black to white difference in post-neonatal mortality is associated with specific environmental conditions.

Nursing care study. Gynaecology: piercing pains.

PIP: A case history is reported of the traumatic experience of a woman hospitalized in order to remove her IUD. Sue, the 29-year-old patient who had 2 children (5-1/2 years and 1-1/2 years) had been referred to a gynecological clinic by her general practitioner for IUD removal. 6 weeks prior to her referral she had experienced 2 days of very severe pain and occasional pains since then--sharp, cramping pains that did not radiate and eased off following micturition. The pains were not related to bowels or intercourse. Attempts to remove the copper 7 IUD by the general practitioner and the family planning clinic failed. This was the case even though the strings were visible. Following routine preparation at the day surgery unit, Sue was given a general anesthetic. On examination the pelvic organs were all found to be normal and the strings of the copper 7 IUD were visible. Attempts to remove it with sponge-holding forceps and a curette were interrupted by a sudden vaginal blood loss. The laparoscope was introduced and a large hematoma of the right broad ligament was visible. Laparotomy through a lower midline incision was performed, and it was found that the IUD had perforated the right wall of the uterus. The right uterine vessels had been damaged when the removal was attempted. The hematoma was evacuated after ligation of the blood vessels and a right salpingo-oophorectomy was performed. The left tube and ovary had a normal appearance and were preserved. Hemostasis was secured and the abdomen was closed in layers as usual. A blood loss of about 2 liters was estimated. Sue was hospitalized for 3 weeks.^ieng

Variation of retention volume with molecular weight of polyethylene glycol and with carbon number of n-alkanols.

Analysis of McReynolds' data for n-alkanols on polyethylene glycols of various molecular weights shows a continuous variation in retention properties up to molecular weights greater than 6000 and probably greater than 20,000. It is concluded that polyethylene glycol used as a "standard" stationary phase should have either very high or closely controlled molecular weight. The relation between log Vg and carbon number of the alkanol is nonlinear at C4 and below with negative deviations around 10% for C2 and C3 and a positive deviation of 25% for C1.