Complete Remission and Long-term Survival of a Patient with a Diffuse Large B-cell Lymphoma Under Viscum album Extracts After Resistance to R-CHOP: A Case Report.

BACKGROUND: A nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a lymphoproliferative neoplasm with a fair prognosis, but the possibility of a malignant transformation into a diffuse large B-cell lymphoma (DLBCL) is high. DLBCL progresses aggressively. Introduction of rituximab into therapy had led to improved outcomes. The use of Viscum album extracts (VAE) in cancer is established, but their application in lymphoma are rare. CASE PRESENTATION: A 65-year-old patient was diagnosed with DLBCL stage IIa with splenomegaly, transformed from a NLPHL, after a 30-year history of repeatedly enlarged inguinal lymph nodes. The patient initially rejected chemotherapy. After his tumor pain increased, he accepted the consecutive therapies bendamustine plus vincristine plus prednisolone, trofosfamide, and rituximab plus cyclophosphamide plus hydroxydaunorubicin plus vincristine plus prednisone (R-CHOP), inducing only a slight regression of the splenic lesions. VAE was additionally applied to R-CHOP. Five months after termination of chemotherapy - under continued VAE therapy in increasing dosage- regression of paraaortal lesions was found. The patient fully recovered under continuous VAE application and is in ongoing complete remission and in a good state of health 17 years after the initial diagnosis. CONCLUSION: As complete remission of lymphoproliferative disorders after VAE treatment has been previously reported, further investigations of VAE in lymphoma seem highly worthwhile.

Hyperfibrinogenemia is a poor prognostic factor in diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas worldwide. Previous studies indicated that hyperfibrinogenemia was a poor predictor in various tumors. The purpose of our study was to evaluate the prognostic effect of hyperfibrinogenemia in DLBCL. Data of 228 patients, who were diagnosed with DLBCL in our hospital between May 2009 and February 2016, were analyzed retrospectively. The Kaplan-Meier method and Cox regression were performed to find prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curve and the areas under the curve were used to evaluate the predictive accuracy of predictors. Comparison of characters between groups indicated that patients with high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (4-8) and advanced stage (III-IV) were more likely to suffer from hyperfibrinogenemia. The Kaplan-Meier method revealed that patients with hyperfibrinogenemia showed inferior PFS (P < 0.001) and OS (P < 0.001) than those without hyperfibrinogenemia. Multivariate analysis showed that hyperfibrinogenemia was an independent prognostic factor associated with poor outcomes (HR = 1.90, 95% CI: 1.15-3.16 for PFS, P = 0.013; HR = 2.65, 95% CI: 1.46-4.79 for OS, P = 0.001). We combined hyperfibrinogenemia and NCCN-IPI to build a new prognostic index (NPI). The NPI was demonstrated to have a superior predictive effect on prognosis (P = 0.0194 for PFS, P = 0.0034 for OS). Hyperfibrinogenemia was demonstrated to be able to predict poor outcome in DLBCL, especially for patients with advanced stage and high NCCN-IPI score. Adding hyperfibrinogenemia to NCCN-IPI could significantly improve the predictive effect of NCCN-IPI.

A new prognostic model using the NCCN-IPI and neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has been known to predict the prognosis in diffuse large B-cell lymphoma (DLBCL). We planned to design a new prognostic model in DLBCL using well-known prognostic index and NLR. METHODS: The data of 232 DLBCL patients treated with first-line R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) from 2004 to 2017 were retrospectively reviewed. Patients with NLR ≥6 and <6 were determined as the high and low NLR groups, respectively. Treatment response and survival were compared according to NLR status. Nomograms for predicting 5-year progression-free survival (PFS) and overall survival (OS) rates were constructed using NLR and other prognostic factors based on the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) NCCN-IPI. RESULTS: The high NLR group had a low complete response (CR) rate compared to low NLR group (51.6% vs. 83.5%; p<0.001). The 5-year PFS and OS rates were 27.4% and 30% in the high NLR group and 61.1% and 63.7% in the low NLR group, respectively (both p<0.001). Multivariate analyses confirmed that NLR is one of the independent risk factors for failure to achieve CR and for worse PFS and OS. The nomogram showed superior discrimination ability for predicting 5-year PFS and OS rates compared with NCCN-IPI (c index 0.78 vs. 0.75 and 0.79 vs. 0.75, respectively). CONCLUSIONS: High NLR was associated with poor treatment response and worse PFS and OS in DLBCL. The nomogram developed from NCCN-IPI-based variables and NLR may help the clinicians to predict the prognosis individually in DLBCL patients, although it needs to be validated in the independent cohort.

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).

Analysis of prognostic value of complete response by PET-CT and further stratification by clinical and biological markers in DLBCL patients.

Positron emission tomography-computed tomography (PET-CT) is performed as the standard method for response assessment of diffuse large B cell lymphoma (DLBCL) patients. However, a substantial proportion of patients experience relapse even if they have achieved complete response (CR) defined by PET-CT. We validated the prognostic value of CR by PET-CT and applied the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) and cell of origin (COO) to patients with CR by PET-CT to evaluate their additional predictive ability for survival outcomes. We retrospectively analyzed DLBCL patients who were treated with R-CHOP or an R-CHOP-like regimen and who achieved CR by PET-CT or CT only. A total of 185 patients were analyzed: 114 patients achieved CR by PET-CT and 71 patients by CT only. Patients with CR by PET-CT had significantly better overall survival (OS) than those with CR by CT (5-year OS, 87.5 vs. 62.4%, P = 0.003). Patients with high risk according to the NCCN-IPI had a dismal outcome despite achieving CR by PET-CT (5-year OS, 61.8%). In contrast, low-, low-intermediate-, and high-intermediate-risk patients had excellent outcomes (5-year OS, 100, 89.7, and 93.5%, respectively). Among patients with CR by PET-CT, patients with germinal center B cell (GCB) DLBCL (n = 40) had significantly better survival than those with non-GCB DLBCL (n = 57) (5-year OS, 96.9 vs. 75.5%, P = 0.039). We demonstrated that CR by PET-CT was a better predictor of survival outcomes than CR by CT only. The NCCN-IPI and COO subtypes could identify a subpopulation of poor-risk patients among those who achieved CR by PET-CT.

Prognostic value of total lesion glycolysis of baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography in diffuse large B-cell lymphoma.

PURPOSE: We evaluated the prognostic value of total lesion glycolysis (TLG) measured in baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). METHODS: A total of 91 patients with newly diagnosed DLBCL underwent 18F-FDG PET/CT scans before R-CHOP therapy. Metabolic tumor volume (MTV) was measured with the marginal threshold of normal liver mean standard uptake value (SUVmean) plus 3 standard deviations (SD). TLG was the sum of the products of MTV and SUVmean in all measured lesions. The predictive value was estimated by Log-rank test and Cox-regression analysis. RESULTS: Median follow-up was 30 months (range, 5-124 months). The 5-year estimated progression-free survival (PFS) of the low and high TLG group were 83% and 34%, respectively (p<0.001). The 5-year overall survival (OS) of the same groups were 92% and 67%, respectively (p<0.001). Patients with high TLG level were more likely to relapse than those with low TLG level even though they had got complete or partial remission in R-CHOP therapy (40% versus 9%, p=0.012). Multivariate analysis revealed TLG was the only independent predictor for PFS (Hazard ratio=5.211, 95% confidence interval=2.210-12.288, p<0.001) and OS (Hazard ratio=9.136, 95% confidence interval=1.829-45.644, p=0.002). Other factors including MTV, National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and Ann Arbor Stage were not independently predictive for survivals. CONCLUSION: Baseline TLG is the only independent predictor for PFS and OS in DLBCL patients treated with R-CHOP therapy.

Prognostic value of interim FDG-PET in R-CHOP-treated diffuse large B-cell lymphoma: Systematic review and meta-analysis.

This study aimed to systematically review and meta-analyze the prognostic value of interim (18)F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). MEDLINE and EMBASE were systematically searched for suitable studies. Included studies were methodologically appraised, and results were summarized both descriptively and meta-analytically. Nine studies, comprising a total of 996 R-CHOP-treated DLBCL patients, were included. Overall, studies were of moderate methodological quality. The area under the summary receiver operating curve (AUC) of interim FDG-PET in predicting treatment failure and death were 0.651 and 0.817, respectively. There was no heterogeneity in diagnostic odds ratios across available studies (I(2)=0.0%). At multivariable analysis, 2 studies reported interim FDG-PET to have independent prognostic value in addition to the International Prognostic Index (IPI) in predicting treatment failure, whereas 3 studies reported that this was not the case. One study reported interim FDG-PET to have independent prognostic value in addition to the IPI in predicting death, whereas 2 studies reported that this was not the case. In conclusion, interim FDG-PET in R-CHOP-treated DLBCL has some correlation with outcome, but its prognostic value is homogeneously suboptimal across studies and it has not consistently proven to surpass the prognostic potential of the IPI. Moreover, there is a lack of studies that compared interim FDG-PET to the recently developed and superior National Comprehensive Cancer Network-IPI. Therefore, at present there is no scientific base to support the clinical use of interim FDG-PET in R-CHOP-treated DLBCL.

Stratifying diffuse large B-cell lymphoma patients treated with chemoimmunotherapy: GCB/non-GCB by immunohistochemistry is still a robust and feasible marker.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches.

Unusual primary central nervous system lymphoma location involving the fourth ventricle and hypothalamus.

A previously healthy 65-year-old man presented with a two-week history of weight loss, headaches, blurred vision, asthenia and quickly worsening walking impairment. He denied photophobia, neck stiffness, fever, nausea or vomiting.Neurological examination showed global motor slowing, tendency to fall asleep during the clinical examination, generalized weakness against resistance to head and limbs, and osteotendon reflexes present in the upper limbs, but not evoked in the lower limbs. No sensitive deficit or focal neurologic sign was recognizable.Non-contrast multislice computed tomography (MSCT) of the head was performed in the emergency department, showing diffuse periventricular white matter and thalamic mild hyperdensity.Lumbar puncture, blood tests, including serology for HIV and other infections, were negative.On the third day the patient, showing decreased consciousness, underwent magnetic resonance imaging (MRI) with contrast medium injection. MRI revealed the presence of multiple pseudonodular avidly enhancing lesions, supra and infratentorial, crossing the midline, involving the ventricular system, including the fourth ventricle, with extension into the surrounding white matter, the corpus callosum, the thalamus and the hypothamalus.A stereotactic biopsy led to a diagnosis of diffuse large B-cell lymphoma, primarily located in the central nervous system (PCNSL).After the completion of the first phase of treatment (immunotherapy with intravenous Rituximab and corticosteroid), the MRI showed a marked regression of tumor masses.

Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection.

UNLABELLED: European and Asian studies report conflicting data on the risk of hepatitis B virus (HBV) reactivation in rheumatologic patients with a previously resolved HBV (prHBV) infection undergoing long-term biologic therapies. In this patient category, the safety of different immunosuppressive biologic therapies, including rituximab, was assessed. A total of 1218 Caucasian rheumatologic patients, admitted consecutively as outpatients between 2001 and 2012 and taking biologic therapies, underwent evaluation of anti-HCV and HBV markers as well as liver amino transferases every 3 months. Starting from January 2009, HBV DNA monitoring was performed in patients with a prHBV infection who had started immunosuppressive biologic therapy both before and after 2009. Patients were considered to have elevated aminotransferase levels if values were >1× upper normal limit at least once during follow-up. We found 179 patients with a prHBV infection (14 treated with rituximab, 146 with anti-tumor necrosis factor-alpha, and 19 with other biologic therapies) and 959 patients without a prHBV infection or other liver disease (controls). The mean age in the former group was significantly higher than the controls. Patients with a prHBV infection never showed detectable HBV DNA serum levels or antibody to hepatitis B surface antigen/hepatitis B surface antigen seroreversion. However, when the prevalence of elevated amino transferases in patients with prHBV infection was compared to controls, it was significantly higher in the former group only for aminotransferase levels >1× upper normal limit but not when aminotransferase levels >2× upper normal limit were considered. CONCLUSION: Among patients with a prHBV infection and rheumatologic indications for long-term biologic therapies, HBV reactivation was not seen; this suggests that universal prophylaxis is not justified and is not cost-effective in this clinical setting.

Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration.

The subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after s.c. administration remains a major challenge. In this work we investigated the effects of excipient dependent hyperosmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as the animal model, we compared the effects of NaCl, mannitol and O-phospho-L-serine (OPLS) on the plasma concentration of rituximab over 5 days after s.c. administration. An increase was observed in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, compared with isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to the improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph nodes in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatics, as estimated by the model, increased from 0.05% in isotonic buffer to 13% in hypertonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. The data suggest that hypertonic solutions may be a viable option for improving s.c. bioavailability.

Radiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National Comprehensive Cancer Network lymphoma outcomes project.

BACKGROUND: The role of consolidation radiotherapy was examined for patients with diffuse large B-cell lymphoma who were treated at institutions of the National Comprehensive Cancer Network during the rituximab era. METHODS: Failure-free survival (FFS) and overall survival (OS) were analyzed in terms of patient and treatment characteristics. Potential associations were investigated with univariate and multivariate survival analysis and matched pair analysis. RESULTS: There were 841 patients, and most (710 or 84%) received 6 to 8 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); 293 (35%) received consolidation radiation therapy (RT). Failure occurred for 181 patients: 126 patients (70%) who did not receive RT and 55 patients (30%) who did. At 5 years, both OS and FFS rates were better for patients who had received RT versus those who did not (OS, 91% vs 83% [P = .01]; FFS, 83% vs 76% [P = .05]). A matched pair analysis (217 pairs matched by age, stage, International Prognostic Index [IPI] score, B symptoms, disease bulk, and response to chemotherapy) showed that the receipt of RT improved OS (hazard ratio [HR], 0.53 [P = .07]) and FFS (HR, 0.77 [P = .34]) for patients with stage III/IV disease, but too few events took place among those with stage I/II disease for meaningful comparisons (HR for OS, 0.94 [P = .89]; HR for FFS, 1.81 [P = .15]). A multivariate analysis suggested that the IPI score and the response to chemotherapy had the greatest influence on outcomes. CONCLUSIONS: There was a trend of higher OS and FFS rates for patients who had received consolidation RT after R-CHOP (especially for patients with stage III/IV disease), but the difference did not reach statistical significance.

Yttrium 90-ibritumomab tiuxetan plus rituximab maintenance as initial therapy for patients with high-tumor-burden follicular lymphoma: a Wisconsin Oncology Network study.

INTRODUCTION: Yttrium 90-ibritumomab tiuxetan (90Y-IT) radioimmunotherapy has proved to be effective in relapsed follicular lymphoma (FL). We conducted a clinical trial in which 90Y-IT followed by maintenance rituximab (MR) was evaluated as initial therapy for high-tumor-burden FL. METHODS: Eligible patients had histologically confirmed FL and met the GELF (Groupe d'Etude des Lymphomes Folliculaires) criteria for high tumor burden. All patients received a single dose of 90Y-IT. Patients with platelet counts of 150,000/mm³ or higher received 0.4 mCi/kg, and patients with platelet counts between 100,000/mm³ and 149,000/mm³ received 0.3 mCi/kg. At 6 months, patients without progressive disease (PD) received rituximab weekly for 4 weeks at a dose of 375 mg/m² (consolidation therapy), followed by MR consisting of the same dose every 3 months for a planned 5 years. RESULTS: From January 2005 through November 2007, a total of 16 patients were enrolled. The median age was 52 years (range, 37-75). The major toxicity from 90Y-IT was myelosuppression, with 88% and 31% of the patients experiencing grade 3 and grade 4 hematologic toxicity, respectively. The responses to 90Y-IT induction therapy were as follows: 7 patients with complete response/unconfirmed complete response (CR/Cru), 4 with partial response (PR), 3 with stable disease (SD), and 2 with progressive disease (PD). We identified 6 patients with early PD (range, 4-16 months) and 10 patients with prolonged remission (range, 37-101+ months). Compared with the patients who had prolonged remission, the patients who had early PD tended to have larger baseline nodal masses. The median progression-free survival (PFS) has not been reached after a median follow-up period of 48 months. The 3-year PFS and overall survival (OS) rates were 56% (95% CI, 37%-87%) and 93% (95% CI, 80%-100%), respectively. CONCLUSION: The overall response rate (ORR) to 90Y-IT was 69% in patients who had previously untreated, high-tumor-burden FL, which is lower than what is observed with contemporary rituximab/chemotherapy combinations. MR after 90Y-IT did convert all PRs to CRs. Alternative therapies should be considered for patients who have FL with large nodal masses (>9 cm), whereas very durable responses are possible in patients who have intermediate-size masses (>9 cm).

CD30 expression in de novo diffuse large B-cell lymphoma: a population-based study from British Columbia.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable therapeutic responses and alternative therapies are needed for patients with unfavourable treatment outcomes after standard treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). One promising candidate is brentuximab vedotin, an antibody-drug conjugate targeting CD30-expressing cells. However, CD30 (TNFRSF8) expression patterns in DLBCL are not well described thus far. Here, we examined CD30 expression in a population-based cohort of immunocompetent patients from British Columbia with de novo DLBCL using immunohistochemistry. 385 cases of formalin-fixed paraffin-embedded DLBCL in tissue microarrays were evaluated. 95 cases (25%) harboured CD30+ tumour cells. Using a > 0% cut-off, CD30 expression was predictive of superior 5-year progression-free survival within R-CHOP treated germinal centre B-cell-like (GCB) DLBCL (86% vs. 64%, P = 0·020), which was independent of the International Prognostic Index. Epstein-Barr virus (EBV) was identified in 11 (3%) cases, all of which were non-GCB (P = 0·001) and almost exclusively positive for CD30 expression (10/11) (P < 0·001). We conclude CD30 is expressed in a substantial proportion of DLBCL and CD30 immunohistochemistry may be a useful prognostic marker in R-CHOP treated GCB-DLBCL. The significant association of CD30 with EBV-positive non-GCB DLBCL suggests a distinct pathobiology for these cases.

The management of an orbital diffuse large B-cell lymphoma.

BACKGROUND: The orbit represents a rare site of presentation of non-Hodgkin lymphoma. The diagnosis and management of orbital lymphomas may be challenging because these neoplasms present few specific features. METHODS: A 69-year-old woman presented with painless swelling of the left lower eyelid of 5 years' duration. Magnetic resonance imaging and incisional biopsy were necessary to establish a diagnosis of orbital diffuse large B-cell lymphoma. Staging was completed, thanks to a computed tomographic study of the chest and abdomen. RESULTS: The patient underwent systemic chemotherapy with 1 regimen (doxorubicin, vincristine, prednisone, 6-mercaptopurine, and methotrexate), followed by 1 R-COMP-14 regimen (rituximab, cyclophosphamide, nonpegylated liposome-encapsulated doxorubicin, vincristine, and prednisone). Complete resolution of the disease was obtained. CONCLUSIONS: Although not typically performed by the head and neck surgeon, an understanding of the staging process is crucial for multidisciplinary management of orbital lymphomas.

Rituximab as an effective alternative therapy in refractory idiopathic inflammatory myopathies.

OBJECTIVES: To assess the efficacy and safety of B-lymphocyte depletion therapy (BCDT) utilising rituximab in refractory idiopathic inflammatory myositis. METHODS: We retrospectively evaluated 16 adult patients with active dermatomyositis (DM) or polymyositis (PM) who received 1 gram rituximab intravenous infusions two weeks apart after failing to respond to conventional therapy. The clinical and biochemical response were analysed by the Myositis Intention to Treat index (MITAX) and the serum creatine kinase (CK) levels at baseline and 6 and 12 months after treatment. The primary efficacy outcome was 20% improvement in the MITAX index and 30% reduction in CK. RESULTS: Eight patients responded to treatment and achieved both the MITAX and CK levels objectives within 6 months of rituximab therapy. Five out of these 8 responders remained clinically stable at 12 months and CK levels were still reduced or normalised. Of note, 4 patients who did not respond were re-assessed and had their diagnoses corrected. All patients showed adequate B cell depletion (BCD) with re-population occurring for a 15.4 months average (range 3-42 months). Those simultaneously treated with cyclophosphamide achieved more long-lasting depletion (average 18.6 months). CONCLUSIONS: The heterogeneous clinical and serological characteristics of patients diagnosed with IIM probably explain why some, but not all patients respond to rituximab. Myositis overlap and anti-synthetase syndromes seem to respond better than other patient subsets.

Evidence for therapeutic drug monitoring of targeted anticancer therapies.

Therapeutic drug monitoring (TDM) provides valuable guidance for dose adjustment of antibiotics, immunosuppressives, antiepileptics, and other drugs, but its use for traditional anticancer therapies has been limited. Perhaps the most important obstacle is the impractical requirement of multiple blood samples to adequately define systemic exposure of drugs that have a short elimination half-life and are given by intermittent intravenous injections. However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement. Recent evidence indicates that certain PK parameters, including trough levels, are correlated with clinical outcomes for many of these agents, including imatinib, sunitinib, rituximab, and cetuximab. Although the current evidence is insufficient to mandate TDM in routine practice, a concerted investigation should be encouraged to determine whether the steady-state trough measurements of targeted agents will have a practical place in the clinical care of patients with cancer.

Controlled release of Rituximab from gold nanoparticles for phototherapy of malignant cells.

Releasing drug molecules at their targets with high spatial and temporal accuracy could aid numerous clinical applications which require low systemic damage and low side effects. Nano-carriers of drugs are an attractive solution for such task, allowing specific accumulation in tumors and gradual release of their payload. Here, we utilize gold nanospheres conjugated to Rituximab, an anti-CD20 monoclonal antibody-based drug, for carrying and releasing the drug upon irradiation of specifically tailored femtosecond laser pulses. The released anti-CD20 molecules retain their functionality and ability of triggering the complement-dependent cytotoxicity. This effect comes in addition to cell necrosis caused by the plasmonic nanometric shock waves emanating from the nanospheres and rupturing the plasma membranes. Main advantages of the presented technique include high spatial and temporal resolution, low toxicity and high repeatability and consistency due to the morphological stability of the nanospheres.