Low-threshold SARS-CoV-2 testing facility for hospital staff: Prevention of COVID-19 outbreaks?

BACKGROUND: The ongoing global SARS-CoV-2 pandemic has caused over 4.7 million infections greatly challenging healthcare workers (HCW) and medical institutions worldwide. The SARS-CoV-2 pandemic has shown to significantly impact mental and physical health of HCW. Thus, implementation of testing facilities supporting HCW are urgently needed. METHODS: A low-threshold SARS-CoV-2 testing facility was introduced at the University Hospital Bonn, Germany, in March 2020. Irrespective of clinical symptoms employees were offered a voluntary and free SARS-CoV-2 test. Furthermore, employees returning from SARS-CoV-2 risk regions and employees after risk contact with SARS-CoV-2 infected patients or employees were tested for SARS-CoV-2 infection. Pharyngeal swabs were taken and reverse transcription polymerase chain reaction for detection of SARS-CoV-2 was performed, test results being available within 24 h. Profession, symptoms and reason for SARS-CoV-2 testing of employees were recorded. RESULTS: Between 9th March and April 30, 2020, a total of 1510 employees were tested for SARS-CoV-2 infection. 1185 employees took advantage of the low-threshold testing facility. One percent (n = 11) were tested positive for SARS-CoV-2 infection, 18% being asymptomatic, 36% showing mild and 36% moderate/severe symptoms (missing 10%). Furthermore, of 56 employees returning from SARS-CoV-2 risk regions, 18% (10/56) were tested SARS-CoV-2 positive. After risk contact tracking by the hospital hygiene 6 patient-to-employee transmissions were identified in 163 employees with contact to 55 SARS-CoV-2 positive patients. CONCLUSION: In the absence of easily accessible public SARS-CoV-2 testing facilities low-threshold SARS-CoV-2 testing facilities in hospitals with rapid testing resources help to identify SARS-CoV-2 infected employees with absent or mild symptoms, thus stopping the spread of infection in vulnerable hospital environments. High levels of professional infection prevention training and implementation of specialized wards as well as a perfectly working hospital hygiene network identifying and tracking risk contacts are of great importance in a pandemic setting.

Polyketide ß-branching: diversity, mechanism and selectivity.

Covering: 2008 to August 2020 Polyketides are a family of natural products constructed from simple building blocks to generate a diverse range of often complex chemical structures with biological activities of both pharmaceutical and agrochemical importance. Their biosynthesis is controlled by polyketide synthases (PKSs) which catalyse the condensation of thioesters to assemble a functionalised linear carbon chain. Alkyl-branches may be installed at the nucleophilic α- or electrophilic ß-carbon of the growing chain. Polyketide ß-branching is a fascinating biosynthetic modification that allows for the conversion of a ß-ketone into a ß-alkyl group or functionalised side-chain. The overall transformation is catalysed by a multi-protein 3-hydroxy-3-methylglutaryl synthase (HMGS) cassette and is reminiscent of the mevalonate pathway in terpene biosynthesis. The first step most commonly involves the aldol addition of acetate to the electrophilic carbon of the ß-ketothioester catalysed by a 3-hydroxy-3-methylglutaryl synthase (HMGS). Subsequent dehydration and decarboxylation selectively generates either α,ß- or ß,γ-unsaturated ß-alkyl branches which may be further modified. This review covers 2008 to August 2020 and summarises the diversity of ß-branch incorporation and the mechanistic details of each catalytic step. This is extended to discussion of polyketides containing multiple ß-branches and the selectivity exerted by the PKS to ensure ß-branching fidelity. Finally, the application of HMGS in data mining, additional ß-branching mechanisms and current knowledge of the role of ß-branches in this important class of biologically active natural products is discussed.

First-line therapy, autologous stem-cell transplantation, and post-transplantation maintenance in the management of newly diagnosed mantle cell lymphoma.

Background: In Ontario, no clearly defined standard of care for the management of mantle cell lymphoma (mcl) has been developed, and substantial variability from centre to centre is evident. This guidance document was prompted by the need to harmonize practice in Ontario with respect to first-line, conditioning, and post-transplantation maintenance therapy for patients newly diagnosed with transplantation-eligible mcl. Methods: The medline and embase databases were systematically searched from January 2013 to January 2020 for evidence, and the best available evidence was used to draft recommendations relevant to first-line therapy, autologous stem-cell transplantation, and post-transplantation maintenance in the management of transplantation-eligible newly diagnosed mcl. Final approval of this guidance document was obtained from the Stem Cell Transplant Advisory Committee. Recommendations: These recommendations apply to all cases of transplantation-eligible newly diagnosed mcl:■ Alternating cycles of r-chop (rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisolone) and r-dhap [rituximab plus dexamethasone-high-dose cytarabine-cisplatin] is the recommended first-line treatment for symptomatic patients newly diagnosed with mcl before autologous stem-cell transplantation (asct).■ Rituximab plus hyperfractionated cyclophosphamide-vincristine-doxorubicin-dexamethasone (r-hypercvad), alternating with methotrexate and cytarabine, is not recommended for the treatment of patients with newly diagnosed mcl.■ beam (carmustine-etoposide-cytarabine-melphalan), beac (carmustine-etoposide-cytarabine-cyclophosphamide), and total-body irradiation-based regimens are reasonable conditioning options for patients with mcl who have responded to first-line therapy and who are undergoing asct.■ Maintenance therapy with rituximab is recommended for patients with newly diagnosed mcl who have undergone asct.

Management of Early-stage Hodgkin Lymphoma: A Practice Guideline.

In the past, treatment for patients with early-stage Hodgkin lymphoma consisted mainly of radiotherapy. Now, chemotherapy alone and chemoradiotherapy are treatment options. These guidelines aim to provide recommendations on the optimal management of early-stage Hodgkin lymphoma. We conducted a systematic review searching MEDLINE, EMBASE, the Cochrane Library and other literature sources from 2003 to 2015, and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Two authors independently reviewed and selected studies, and appraised the evidence quality. The document underwent internal and external review by content, methodology experts, a patient representative and clinicians in Ontario. We have issued recommendations for patients with classical Hodgkin lymphoma and with nodular lymphocyte predominant Hodgkin lymphoma; with favourable and unfavourable prognosis; and for the use of positron emission tomography to direct treatment. We have provided our interpretation of the evidence and considerations for implementation. Examples of recommendations are: 'Patients with early-stage classical Hodgkin lymphoma should not be treated with radiotherapy alone'; 'chemotherapy plus radiotherapy or chemotherapy alone are recommended treatment options for patients with early-stage non-bulky Hodgkin lymphoma'; 'The Working Group does not recommend the use of a negative interim positron emission tomography scan alone to identify patients with early-stage Hodgkin lymphoma for whom radiotherapy can be omitted without a reduction in progression-free survival'. Through the use of GRADE, recommendations were geared towards patient important outcomes and their strength reflected the available evidence and its interpretation from the patients' point of view.

Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: a subgroup analysis from the phase III CCTG LY.12 trial.

Background: High-dose therapy and autologous stem cell transplantation (ASCT) is often considered for older patients (age >60 years) with relapsed/refractory aggressive lymphomas. Although registry data support the safety and potential efficacy of this approach, there are no prospective trials evaluating outcomes of ASCT in older patients. We evaluated the result of second-line chemotherapy and ASCT in older versus younger patients in the CCTG randomized LY.12 trial. Patients and methods: From August 2003 to November 2011, 619 patients with relapsed/refractory aggressive lymphoma were randomized to gemcitabine, dexamethasone, cisplatin (GDP) or dexamethasone, cytarabine, cisplatin (DHAP); 177 patients (28.6%) enrolled were >60.0 years of age (range, 60-74) and 442 were ≤60.0 years of age. After two to three cycles, responding patients proceeded to ASCT. Intention-to-treat analysis was used to compare response rate, transplantation rate, event-free survival (EFS) and overall survival (OS) between patients aged ≤60.0 and >60.0 years. Results: Patient characteristics were comparable between the two cohorts, except a larger proportion of older patients had high International Prognostic Index risk scores. Response to salvage therapy was 48.6% for patients aged >60.0 versus 43.0% for those aged ≤60.0 (P = 0.21). Transplantation rates were also similar: 50.3% versus 49.8% (P = 0.87) for older versus younger patients. Rates of febrile neutropenia and adverse events requiring hospitalization were comparable for older and younger patients (30.5% versus 22.9% and 37.9% versus 32.1%, respectively). With a median follow-up of 53 months, there was no difference in 4-year OS (36% and 40% for patients aged >60.0 and ≤60.0 years, P = 0.42), or 4-year EFS (20% versus 28%, P = 0.43). Mortality from salvage therapy was 8/174 (4.60%) and 5/436 (1.15%), and 100-day mortality post-ASCT was 7/88 (8.06%) and 4/219 (1.85%). Conclusion: This subgroup analysis suggests that older patients derive similar benefit from salvage therapy and ASCT to younger patients, with acceptable toxicity. ClinicalTrials.gov Identifier: NCT00078949.

An open-label expanded-access trial of bendamustine in patients with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT.

BACKGROUND: Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). METHODS: The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m(2) over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m(2) over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles. RESULTS: Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)-mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl). CONCLUSIONS: The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.

The role of body mass index in survival outcome for lymphoma patients: US intergroup experience.

BACKGROUND: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. RESULTS: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). CONCLUSION: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.

An individual patient-data comparison of combined modality therapy and ABVD alone for patients with limited-stage Hodgkin lymphoma.

BACKGROUND: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. PATIENTS AND METHODS: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. RESULTS: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44). CONCLUSIONS: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. CLINICAL TRIALS: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Outcome of patients with transformed indolent non-Hodgkin lymphoma referred for autologous stem-cell transplantation.

BACKGROUND: The proportion of potentially eligible patients with transformed indolent non-Hodgkin lymphoma who undergo autologous stem-cell transplantation (ASCT) is unknown. There are limited data describing their outcome in the rituximab era. PATIENTS AND METHODS: We reviewed 105 consecutive patients with biopsy-proven transformation referred to Princess Margaret Hospital for consideration of ASCT during 1996-2009. Patients received anthracycline or platinum-based chemotherapy with or without rituximab. Responders proceeded to stem-cell mobilization and ASCT. RESULTS: The median age at transformation was 54 (range 30-65) years. Patients received a median of two chemotherapy regimens for transformation, including rituximab in 39%. Fifty patients (48%) proceeded with ASCT and 55 (52%) did not, mainly due to progressive disease (n = 42). Three-year overall (OS) and progression-free survival (PFS) post-ASCT were 54% and 42%, respectively. Patients receiving rituximab with chemotherapy before transplant had a 3-year post-ASCT OS of 71% versus 47% in those who received chemotherapy alone (P = 0.046). Patients transplanted after 2004 had a 3-year post-ASCT OS of 69% versus 39% in those receiving ASCT earlier (P = 0.009). CONCLUSIONS: About half of transplant-eligible patients with transformation are able to undergo ASCT. Outcomes following ASCT appear to have improved over recent years, although the role of rituximab in this patient population requires further evaluation.

Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points.

BACKGROUND: The correlation between efficacy end points in randomized controlled trials (RCTs) of systemic therapy for non-Hodgkin's lymphoma (NHL) was investigated to identify an appropriate surrogate end point for overall survival (OS). METHODS: RCTs of previously untreated NHL published from 1990 to 2009 were identified. Associations between absolute differences in efficacy end points were determined using nonparametric Spearman's rank correlation coefficients (r(s)). RESULTS: Thirty-eight RCTs representing 85 treatment arms for aggressive NHL and 20 RCTs representing 42 arms for indolent NHL were included. For aggressive NHL, differences in 3-year progression-free survival (PFS)/event-free survival (EFS) were high correlated with differences in 5-year OS {r(s) of 0.90 [95% confidence interval (CI) 0.73-0.96]} and linear regression determined that a 10% improvement in 3-year EFS or PFS would predict for a 7% ± 1% improvement in 5-year OS. For indolent histology disease, differences in complete response were strongly correlated with differences in 3-year EFS [r(s) 0.86 (95% CI 0.35-0.97)], but there was no correlation between 3-year time-to-event end points and 5-year OS. CONCLUSIONS: Improvements in 3-year EFS/PFS are highly correlated with improvements in 5-year OS in aggressive NHL and should be explored as a candidate surrogate end point. Definition of these relationships may inform future clinical trial design and interpretation of interim trial data.

High-dose chemotherapy and auto-SCT in elderly patients with Hodgkin's lymphoma.

Our purpose was to assess efficacy and toxicity of high-dose chemotherapy (HDCT) and ASCT in patients with relapsed and refractory Hodgkin's lymphoma (HL) aged 60 years and older and compare the results with a group of younger HL patients treated in a similar manner. We identified 15 consecutive patients, with HL aged 60 years and older who underwent HDCT (etoposide 60 mg/kg+ melphalan 160 mg/m(2)) and ASCT at our institution from May 2001 to March 2008. The results were compared with a cohort of 157 younger HL patients treated in a similar manner from January 1999 to December 2006. After a median follow-up of 2.5 years, PFS at 3 years after ASCT was 73% (95% confidence interval (CI) 37-90) for the older group and 56% (95% CI 46-64) for the younger group (P=0.45); OS after ASCT was 88% (95% CI 39-98) for the older group and 84% (95% CI 75-90) for the younger group (P=0.80). No transplant-related deaths were seen. Our study suggests that ASCT is feasible for selected elderly patients with HL, giving similar results to younger patients in terms of survival and toxicity.

Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma.

BACKGROUND: Ocrelizumab is a humanized anti-CD20 antibody with increased antibody-dependent cellular cytotoxicity compared with rituximab. This phase I/II study evaluated its safety and efficacy in patients with relapsed/refractory follicular lymphoma (FL) after prior rituximab therapy. DESIGN AND METHODS: Forty-seven patients were treated in three dose cohorts and received eight infusions every 3 weeks: cohort A, 200 mg/m(2) (n = 15); cohort B, 375 mg/m(2) (n = 16); cohort C, first dose 375 mg/m(2), seven subsequent doses of 750 mg/m(2) (n = 16). Patients were assessed for safety, efficacy, pharmacodynamics and pharmacokinetics. RESULTS: The median patient age was 58 years, the majority had Ann Arbor stage III/IV disease and had received a median of 2 (range 1-6) prior regimens. Ocrelizumab was well tolerated with grade 3/4 toxicity occurring in 9% of patients. The most common toxicity was infusion-related reactions (74% patients), all grade 1/2 except one grade 3 event. The objective response rate was 38% and was similar in patients with low-affinity and high-affinity variants of the Fcgamma receptor IIIa (FcgammaRIIIa). With follow-up of approximately 28 months, the median progression-free survival was 11.4 months. CONCLUSION: Ocrelizumab demonstrated activity in patients with relapsed/refractory FL following prior rituximab treatment, with safety similar to rituximab although adverse events appeared milder.

Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma.

We enrolled 23 patients with relapsed follicular lymphoma (FL) in a prospective single-arm study of auto-SCT combined with in vivo rituximab graft purging and post transplant rituximab maintenance. Minimal residual disease was monitored with quantitative PCR testing. With a median follow-up of 74.2 months, neither median overall survival (OS) nor PFS has been reached. Here, 5-year OS and 5-year PFS are 78% (95% confidence interval (CI) 61-95%) and 59% (95% CI 38-80%), respectively. Time to progression (TTP) with the experimental regimen was significantly improved compared with TTP with the last prior treatment (P<0.001). Durable molecular remissions occurred in 11 of 13 assessable patients. PFS was significantly longer in patients who achieved a molecular remission by 3 months post-auto-SCT (P=0.001). Prolonged hypogammaglobulinemia occurred in most patients; however, no increase in major infections was observed.

Predictors of mortality in patients undergoing autologous hematopoietic cell transplantation admitted to the intensive care unit.

Between January 2001 and July 2006, 1013 patients received autologous hematopoietic cell transplants (AHCT) at Canada's largest transplant center. In this retrospective cohort study of AHCT patients admitted to the intensive care unit (ICU), we describe the outcomes following ICU admission and the variables measured in the first 24 h of ICU admission associated with overall ICU mortality. Results indicate a 3.3% ICU admission rate (n=34) with 13 deaths (1% overall mortality rate, 38% in ICU mortality rate). The worst outcome was in AL amyloid patients of whom 28% were admitted to the ICU, with an ICU mortality rate of 55%. The Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score in the first 24 h were statistically associated with mortality by univariate analysis. Other variables measured at 24 h and associated with ICU mortality included multiorgan failure, mechanical ventilation, inotropic support >4 h and Gram-negative sepsis. Our data indicate that ICU admission in the autotransplant population is rare and that it is influenced by underlying diagnosis, with AL amyloid patients having the highest risk. Our observations may assist clinical decision-making regarding the continuation of intensive care delivered 24 h after ICU admission.

Utility of subsequent conventional dose chemotherapy in relapsed/refractory transplant-eligible patients with diffuse large B-cell lymphoma failing platinum-based salvage chemotherapy.

Up to 60% of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) do not respond to second-line (salvage) chemotherapy and hence are not offered autologous hematopoietic cell transplantation (AHCT). The utility of further salvage chemotherapy in an attempt to proceed with AHCT remains undefined. The authors reviewed 201 patients with DLBCL relapsed/refractory to anthracycline-based chemotherapy who received first-line salvage chemotherapy containing cis-platinum. Of the 120 non-responders to first-line platinum-based salvage chemotherapy, 73 received second-line salvage chemotherapy. The response rate to second-line salvage chemotherapy was 14%. Factors predicting lack of response were progression on primary therapy (p = 0.007), abnormal lactate dehydrogenase findings (p = 0.0027) and tumor bulk (p = 0.013) at second progression. Eight patients who responded received AHCT and appeared to have comparable survival to those transplanted after one salvage regimen. The authors conclude that the utility of second-line salvage chemotherapy is low, and that it is best reserved for patients demonstrating initial anthracycline sensitivity and low tumor burden.

G-CSF-stimulated BM progenitor cells supplement suboptimal peripheral blood hematopoietic progenitor cell collections for auto transplantation.

Peripheral blood hematopoietic progenitor cells (PBHC) are the standard source of support for high-dose chemotherapy because of faster recovery of marrow function. Unfortunately, a proportion of patients are unable to mobilize adequate progenitors to proceed to autologous hematopoietic cell transplant (AHCT). Granulocyte-CSF-stimulated BM-derived hematopoietic progenitor cells (BMHC) may circumvent this problem. From 1999 to 2006, 52 patients (cases) with AML, Hodgkin (HL) or non-Hodgkin's lymphoma (NHL) in whom PBHC mobilization failed underwent a G-CSF-stimulated bone marrow harvest and proceeded to AHCT. Their outcome was compared with 422 patients (controls) with AML, HL and NHL undergoing AHCT using only PBHC. Twenty-three patients received BMHC alone and 29 patients received a combination of PBHC and BMHC. Median engraftment time for neutrophils (>0.5 x 10(9)/l) and platelets (>20 x 10(9)/l) were 14 and 27 days, but significantly longer when compared with controls (11 days, 11 days, P<0.0001). Patients receiving both PBHC and BMHC had faster engraftment, when compared with those receiving BMHC alone (P<0.001). In conclusion, performing an AHCT using G-CSF-stimulated BMHC in patients failing PBHC collection is feasible with faster engraftment seen in patients receiving both BMHC and PBHC over BMHC alone.

The relationship between absolute lymphocyte count with PFS in patients with Hodgkin's lymphoma undergoing autologous hematopoietic cell transplant.

Previous reports in Hodgkin's lymphoma (HL) patients undergoing autologous hematopoietic cell transplantation (AHCT) have demonstrated a significant association between the absolute lymphocyte count at day 15 (ALC-15) with survival. To evaluate this finding further, we analyzed 146 patients with relapsed/refractory HL who underwent AHCT to evaluate the relationship between lymphocyte counts at apheresis and at two time points (days 15 and 90) after AHCT with PFS. We found no association between the ALC-15 and the ALC-90 with PFS. We found lymphocyte counts at apheresis and disease sensitive to salvage chemotherapy were predictive of PFS. In conclusion, our study does provide some support for the theory that the immune system may be important in disease control but further and more detailed studies in this area are required.

Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma.

BACKGROUND: Vorinostat has demonstrated activity in refractory cutaneous T-cell lymphoma. In a phase I trial, an encouraging activity in diffuse large-B-cell lymphoma (DLBCL) was noted. PATIENTS AND METHODS: We carried out a phase II trial (NCT00097929) of oral vorinostat 300 mg b.i.d. (14 days/3 weeks or 3 days/week) in patients with measurable, relapsed DLBCL who had received two or more systemic therapies. Response rate and duration (DOR), time to progression (TTP) and safety were assessed. RESULTS: Eighteen patients were enrolled (median age: 66 years; median prior therapies: 2). Seven received 300 mg b.i.d. 14 days/3 weeks, but four had grade 3 or 4 toxicity (dose-limiting toxicity, DLT). The schedule was amended to 300 mg b.i.d. 3 days/week), and none had DLT. One achieved a complete response (TtR = 85 days; DOR =or >468 days) and one had stable disease (301 days). Sixteen discontinued for progressive disease; median TTP was 44 days. Median number of cycles was 2 (1 to >19). Common drug-related adverse experiences (AEs; mostly grade 1/2) were diarrhea, fatigue, nausea, anemia and vomiting. Three patients had dose reduction; none discontinued for drug-related AEs. Drug-related AE >or=grade 3 included thrombocytopenia (16.7%) and asthenia (11.1%). CONCLUSION: Vorinostat was well tolerated at 300 mg b.i.d. 3 days/week or 200 mg b.i.d. 14 days/3 weeks but had limited activity against relapsed DLBCL.

Screening mammography for young women treated with supradiaphragmatic radiation for Hodgkin's lymphoma.

BACKGROUND: Female survivors of Hodgkin's lymphoma (HL) treated with supradiaphragmatic radiation therapy (SRT) are at increased risk of breast cancer (BC), but there is little data on the optimal screening strategy. PATIENT AND METHODS: We report a prospective surveillance study of women treated for HL with SRT before age 30 participating in a high-risk screening clinic. Starting 8 years after treatment, women received annual mammography and clinical follow-up from 1997 to 2006. Method of detection and characteristics of BCs were identified. RESULTS: In all, 115 female HL survivors attended at least one clinic; 100 participated in annual surveillance. The majority had mammography alone; adjunctive magnetic resonance imaging (MRI) was used more frequently in women with high breast density (P = 0.025). Median age at first mammogram was 36 years and decreased with more recent year of diagnosis. Twelve of the 100 participating women (12%) were diagnosed with BC after a median of 5 years of surveillance (range, 1-9). Seven BCs presented as palpable masses [six invasive, one ductal carcinoma in situ (DCIS)], five were detected by mammography (one invasive, four DCIS). CONCLUSIONS: Despite earlier initiation of mammographic screening, most BCs were detected clinically and had unfavorable pathologic characteristics. Evaluation of more intensive screening and the contribution of MRI for earlier detection is warranted.

A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.