Search

Follicular lymphoma (FL) is one of the most common lymphoma. Occasionally, FL is associated with tumoral epidural compression and management of these patients remain poorly codified. This study aims to report incidence, clinical characteristics, management and outcomes of patients with FL and tumoral epidural compression. Observational, retrospective cohort study of adult patients with FL and epidural tumor compression, treated in a French Institute over the last 20 years (2000–2021). Between 2000 and 2021, 1382 patients with FL were followed by the haematological department. Of them, 22 (1.6%) patients (16 men and 6 women) had follicular lymphoma with epidural tumor compression. At epidural tumor compression occurrence, 8/22 (36%) patients had a neurological clinical deficit (motor, sensory or sphincter function) and 14/22 (64%) had tumor pain. All patients were treated with immuno-chemotherapy; the main regimen being used was R-CHOP plus high dose IV methotrexate in 16/22 (73%) patients. Radiotherapy for tumor epidural compression was performed in 19/22 (86%) patients. With a median follow-up of 60 months (range = [1–216]), 5 year local tumor relapse free survival was achieved in 65% (95% CI 47–90%) of patients. The median PFS was of 36 months (95% CI 24–NA) and 5 years OS estimate was 79% (95% CI 62–100%). Two patients developed a relapse at a second epidural site. FL with tumoral epidural compression reached 1.6% of all FL patients. Management based on immuno-chemotherapy with radiotherapy appeared to produce comparable outcomes with the general FL population. [ABSTRACT FROM AUTHOR]

There has been no comprehensive analysis of the age-specific efficacy of G-CSF to prevent febrile neutropenia (FN). We evaluated factors associated with FN occurrence according to patient age in rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R–CHOP) treatment. We retrospectively reviewed diffuse large B-cell lymphoma (DLBCL) patients aged ≥50 years, who underwent the first R–CHOP cycle between July 2010 and March 2017, using a Japanese inpatient database. Multivariable logistic regression analysis was performed to identify the factors associated with FN. A total of 16,399 patients with untreated DLBCL were identified. Primary prophylaxis with pegfilgrastim was significantly associated with the lower occurrence of FN (odds ratio: 0.71 [95% confidence interval: 0.51–0.99]). Subgroup analysis according to age was then performed. Although there was no significance, primary prophylaxis with pegfilgrastim tended to have a lower odds ratio for the occurrence of FN in patients aged 50–60 years (0.86 [0.39–1.89]) and 61–70 years (0.64 [0.36–1.13]). In patients aged 71–80 years, primary prophylaxis with pegfilgrastim was significantly associated with reduced FN occurrence (0.46 [0.26–0.80]). Notably, in patients aged >80 years, the use of pegfilgrastim tended to be associated with a rather higher occurrence of FN (1.55 [0.84–2.87]). Preventing effect of G-CSF may be limited in patients aged >80 years. [ABSTRACT FROM AUTHOR]

Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. In this retrospective study, we identified 1088 patients with grade I–IIIA FL; of whom, 238 patients with stage II–IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy. • Early progression after first-line treatment in follicular lymphoma is a marker of poor prognosis. • Positron-emission tomography (PET) staging possibly identifies patients with highest risk of poor outcomes. • PET staging reduces the prognostic impact of early progression likely by excluding patients with early transformation. • Patients with early progression and early transformation have the highest risk of poor outcomes. [ABSTRACT FROM AUTHOR]

With modern treatments, mantle cell lymphoma (MCL) patients more frequently experience long-lasting remission resulting in a growing population of long-term survivors. Follow-up care includes identification and management of treatment-related late-effects, such as secondary malignancies (SM). We conducted a population-based study to describe the burden of SM in MCL patients. All patients with a primary diagnosis of MCL, aged ≥ 18 years and diagnosed between 2000 and 2017 in Sweden were included along with up to 10 individually matched population comparators. Follow-up was from twelve months after diagnosis/matching until death, emigration, or December 2019, whichever occurred first. Rates of SM among patients and comparators were estimated using the Anderson-Gill method (accounting for repeated events) and presented as hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age at diagnosis, calendar year, sex, and the number of previous events. Overall, 1 452 patients and 13 992 comparators were followed for 6.6 years on average. Among patients, 230 (16%) developed at least one SM, and 264 SM were observed. Relative to comparators, patients had a higher rate of SM, HR adj = 1.6 (95%CI:1.4–1.8), and higher rates were observed across all primary treatment groups: the Nordic-MCL2 protocol, R-CHOP, R-bendamustine, ibrutinib, lenalidomide, and R-CHOP/Cytarabine. Compared to Nordic-MCL2, treatment with R-bendamustine was independently associated with an increased risk of SM, HR adj = 2.0 (95%CI:1.3–3.2). Risk groups among patients were those with a higher age at diagnosis (p < 0.001), males (p = 0.006), and having a family history of lymphoma (p = 0.009). Patients had preferably higher risk of melanoma, other neoplasms of the skin and other hematopoietic and lymphoid malignancies. MCL survivors have an increased risk of SM, particularly if treated with R-bendamustine. The intensive treatments needed for long-term remissions are a concern, and transition to treatment protocols with sustained efficacy but with a lower risk of SM is needed. • Mantle cell lymphoma patients had 60% increased rate of secondary malignancies. • R-bendamustine treated patients had higher risk compared with Nordic-MCL2. • Risk factors included high age, male sex, and family history of lymphoma. • Rates were increased of skin cancer and other hematopoietic malignassncies. [ABSTRACT FROM AUTHOR]

Abstract Diffuse large B-cell lymphoma (DLBCL) is a group of lymphomas comprising heterogeneous molecular and biological subtypes, reflected in a broad range of clinical outcomes. With the standard R-CHOP regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab administered every 21 days, the treatment failure rate remains unacceptably high in certain DLBCL subsets. Here we review possible avenues for optimizing initial therapy. The role of functional imaging and biological features, such as double-hit lymphomas, defined by the dual translocation of MYC and BCL2, and dual protein-expresser lymphomas, defined by the overexpression of MYC and BCL2, activated B-cell (ABC)-like DLBCL, to better define these high-risk patient subsets, and their use to guide and personalize treatment decisions are discussed. Secondly, the implications of varying dose-intensification of the various agents administered, and the link to imaging are reviewed. Thirdly, the results of the addition of novel drugs to standard R-CHOP will be analyzed, when added at induction or in maintenance. Finally, with CNS relapse in DLBCL representing a major and devastating unmet medical need, an overview and future directions for CNS prophylaxis is presented. Highlights • Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL). • R-CHOP administered every 21 days, today remains the standard therapy for DLBCL patients. • Functional imaging is a promising tool for optimizing initial therapy. • The discovery of novel biological features has encouraged the combination of new drugs to R-CHOP, either during induction or in maintenance. • CNS relapse is still a major unmet medical need. However, recently the high-risk population has better defined using the CNS-IPI score. [ABSTRACT FROM AUTHOR]

Background Optimal treatment strategy for the oldest patients with diffuse large B-cell lymphoma (DLBCL) remains controversial, as this group often is precluded from clinical trials, and population-based studies are limited. Methods All Danish DLBCL-patients ≥75 years diagnosed from 2003 to 2012 were identified, using the Danish National Lymphoma Registry (LYFO). Information regarding baseline characteristics, treatment, comorbidities and outcomes was retrieved from LYFO, the Danish National health registries and medical records. Patients were stratified by age (75–79; 80–84 and 85 + years), comorbidity score and treatment modality (standard treatment [R-CHOP/CHOP-like], less intensive regimens or palliative treatment). Findings A total of 1011 patients were included. Standard treatment was initiated in 64%, ranging from 83% among patients aged 75–79 years to 32% among patient aged 85 + years. With standard treatment, median overall survival (OS) estimates were 4·6, 2·6, and 1·9 years for the age groups 75–79, 80–84 and 85+ years. Among patient aged 75–79 and 80–84 years, OS was superior with standard treatment, although high comorbidity scores attenuated this association. Among patients aged 85+ years, survival was not influenced by treatment intensity. Patients ≥80 years had similar OS regardless of intended (R-)CHOP dosing, whereas patients of 75–79 years scheduled for full dose had higher OS. Standard treatment was not associated with increased hospitalisation. Interpretation Standard treatment is feasible with good outcomes in a large proportion of elderly DLBCL-patients. Planned dose reduction in patients aged ≥80 years had no negative impact on OS. [ABSTRACT FROM AUTHOR]

Background: The first-line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been carried out over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and methods: Reports of phase III trials evaluating the addition of molecularly targeted agents or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phases I and II trials which preceded these phase III trials were also reviewed. Results: Among six phase III trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary end point. The other five trials did not show an improved outcome with the addition of the new agent. The preceding phases I and II trials were very heterogeneous in their end points and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase III trials. Conclusion: The standard of care for DLBCL is still R-CHOP. Phase I/II trials failed to predict the results of subsequent phase III trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase II trials evaluating new agents in DLBCL needs to be better defined in the future. [ABSTRACT FROM AUTHOR]

The current first line treatment of a patient with mantle cell lymphoma (MCL) is often considered as too toxic for elderly patients. The elderly, however, comprise the majority of the patients with MCL. The results of several recent studies have shown that the outcome of this patient group is not as dismal as in the past. Indeed, if patients are not considered frail, and can tolerate rituximab and moderate intensive chemotherapy such as R-CHOP followed by rituximab maintenance or R-bendamustine, a 4-year overall survival of >80% can be achieved. In this chapter the developments of the regimens, resulting in the standard treatment options for these patients, are discussed. [ABSTRACT FROM AUTHOR]

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 (N¼217) and RICOVER-60 (N¼204) 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 (P¼0.05) 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 (HR¼1.96; 95% CI: 1.22–3.16; P¼0.01) and DHL (HR¼2.21; 95% CI: 1.18–4.11; P¼0.01) 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). [ABSTRACT FROM AUTHOR]

Background: The optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies, assess the impact of maintenance rituximab and patterns of treatment failure. Patients and Methods: We retrospectively analyzed patients with treatment-naive advanced-stage, grade 1-2 FL treated at our center from 2004 - 2014. We included 356 patients treated on clinical trials or standard-of-care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n=119); R-CHOP with maintenance (R-CHOP+M, n=65); bendamustine/rituximab (BR, n=45); BR with maintenance (BR+M, n=35); R² (n=94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment. Results: After a median follow-up of 4 years (range 0.2-15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR +M and 87% (78% to 93%) for R². Patients treated with R-chemotherapy had more high-risk features than patients treated with R² but, by adjusted multivariate analysis, treatment with R² [hazard ratio (HR) 0.39 (0.17-0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21-0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57-16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84-42.93)] increased risk of death. Conclusion: Induction therapy with R² may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival. [ABSTRACT FROM AUTHOR]

In the past decade, patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. Standard treatment is now changing as a result of deeper understanding of underlying biologic differences of such lymphomas. One of the most powerful predictors of an adverse outcome on R-CHOP therapy is the presence of a MYC gene rearrangement ( MYC + lymphoma). Determination of MYC gene rearrangement by FISH (fluorescent in situ hybridisation) has recently become a standard diagnostic procedure. In this paper, an overview of current literature on MYC function and MYC + lymphoma patient outcome is presented. Furthermore, we present 26 patients from our tertiary referral centre who were diagnosed with MYC + lymphoma between 2009 and 2014. In our patient series, we confirm the dismal prognosis of MYC + lymphoma patients. Intensification of classical chemotherapy does not lead to better overall survival, justifying new treatment modalities. First line therapy should be more specifically targeted against MYC and the genes and proteins that are deregulated by MYC. To this end, the first clinical trial in which MYC + patients will be offered targeted treatment has recently been launched. [ABSTRACT FROM AUTHOR]

Purpose: To determine the prognostic performance of tumor necrosis at FDG-PET in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy.Materials and Methods: 108 patients with newly diagnosed DLBCL who underwent FDG-PET before R-CHOP therapy were retrospectively included. Lymphomatous sites at FDG-PET were assessed for the presence of a photopenic area, in keeping with tumor necrosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of tumor necrosis and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) with progression-free survival (PFS) and overall survival (OS).Results: On univariate Cox regression analysis, both tumor necrosis and higher NCCN-IPI risk groups were significantly associated with PFS (P=0.024 and P<0.001, respectively) and OS (P=0.034 and P<0.001, respectively). On multivariate Cox regression analysis, both tumor necrosis and the NCCN-IPI were independent significant predictors for PFS (P=0.007, hazard ratio: 2.723 [95% confidence interval: 1.324-5.597] and P<0.001, hazard ratio: 2.952 [95% confidence interval: 1.876-4.646], respectively) and OS (P=0.009, hazard ratio: 2.794 [95% confidence interval: 1.305-5.985] and P<0.001, hazard ratio: 2.813 [95% confidence interval: 1.724-4.587], respectively).Conclusion: Tumor necrosis at FDG-PET is an NCCN-IPI-independent predictor of outcome in DLBCL. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is nowadays a curable disease with the frontline treatment R-CHOP, but 30-40% of patients are still unresponsive or relapse thereafter. In the recent era several upcoming new options are improving the therapeutic landscape for relapsed/refractory (R/R) DLBCL setting, first of all anti-CD19 chimeric antigen receptor T-cells (CAR-T) that already represent a standard of care as third-line therapy and are rapidly moving as second-line treatment for those who are refractory or early relapse after R-CHOP. Among these new therapies, the combinations polatuzumab plus rituximab and bendamustine, tafasitamab plus lenalidomide for transplant ineligible patients, and CD3xCD20 bispecific antibodies are the most relevant, but several other agents and strategies are on the way. On the other hand, in the last 20 years, several efforts have been spent in the attempt to ameliorate the outcome over R-CHOP for the frontline treatment of DLBCL shortening the interval between the cycles or intensifying treatment or adding novel drugs to R-CHOP without success, so far. Recent studies combining the anti-CD79b antibody-drug conjugate polatuzumab vedotin plus R-CHP and the anti-BCL2 agent venetoclax plus R-CHOP showed promising results. Preliminary data of new upcoming strategies characterized by a tailored therapy based on different molecular subtypes of DLBCL are encouraging, showing a benefit over the standard R-CHOP. In this manuscript, the literature data on the landscape of new therapies available and upcoming for both frontline and R/R settings of DLBCL will be critically reviewed. [ABSTRACT FROM AUTHOR]

Useful prognostic markers for patients with diffuse large B cell lymphoma (DLBCL) have been reported. To identify which biomarker best predicts the prognosis of patients with DLBCL, we performed a retrospective study that included 319 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy between 2003 and 2012. We assessed the prognostic significance of six biomarkers [lactate dehydrogenase, soluble interleukin-2 receptor, thymidine kinase activity, beta-2 microglobulin (B2M), C-reactive protein, and ferritin] and representative clinical characteristics using progression-free survival (PFS) as the endpoint. The study group included 181 men and 138 women with a median age of 63 years (range, 22–89 years). In a multivariate analysis, the serum B2M level most strongly correlated with PFS (hazard ratio, 2.11; P = 0.04). In a univariate analysis, patients with serum B2M levels >1.75 μg/mL ( n = 210) had a worse 3-year PFS rate (71.2%) than those with B2M levels < 1.75 μg/mL ( n = 109; 90.0%). Therefore, serum B2M level at the time of diagnosis is a useful prognostic indicator in DLBCL patients receiving R-CHOP. [ABSTRACT FROM AUTHOR]

Summary Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by reactivation of a latent JC polyoma virus. The first cases of PML were described 50 years ago in patients with lymphoma. PML typically occurs in immunocompromised individuals, particularly those infected with HIV. We present a 52-year-old male with lymphoma who was treated with R-CHOP (R: Rituximab; C: Cyclophosphamide; H: Doxorubicin; O: Vincristine; P: Prednisone). After six cycles of therapy, the patients developed tonic–clonic seizure. MRI of the brain showed multiple brain lesions. The pathology of a brain biopsy was diagnostic for PML. We review radiographic and histopathological features of the disease. The literature on PML and its association with immunosuppressant agents is reviewed, and the impact of rituximab and other biological agents in the setting is highlighted. [ABSTRACT FROM AUTHOR]

Aim: We aimed to investigate the impact of chemotherapy on 18F-FDG uptake in the liver and mediastinal blood pool (MBP) among patients with non-Hodgkin's lymphoma. Methods: Twenty-three patients with NHL underwent baseline, interim, and postchemotherapy 18F-FDG PET/CT. SUVmax and SUVmean values of the liver and MBP at imaging time were compared statistically. Results: We did not find any significant differences between the liver and mediastinum SUVmean and SUVmax values (P> .05). Conclusions: Our study demonstrates that the 18F-FDG uptake in the liver and MBP are not significantly affected by R-CHOP chemotherapy in patients with NHL. [ABSTRACT FROM AUTHOR]

Irradiation therapy alone is a standard strategy for limited-stage FL, leading to a 10-year progression-free survival (PFS) rate of 30–50%. However, we have been administering R-CHOP therapy alone to patients with limited-stage FL. A total of 35 patients with newly diagnosed FL received R-CHOP therapy with curative intent between 2002 and 2009. The median age of the 35 patients was 61 years; 7 patients had in CS 1 FL, and 28 patients, CS 2 FL. The median number of R-CHOP cycles was 6. On completion of the R-CHOP therapy, 33 patients achieved complete response and 1 showed partial response (PR). The patient showing PR after the completion of R-CHOP was administered additional irradiation. The remaining 1 patient was not evaluated because of discontinuation of hospital visit. In all the 35 patients, the 5-year PFS rate was 70%, and the 5-year overall survival rate was 92%. In the 15 patients with a PFS > 5 years, only 1 patient showed disease progression. The outcome of R-CHOP therapy alone in patients with limited-stage FL was at least equivalent to the reported outcome of irradiation therapy alone. R-CHOP therapy could be an alternative to irradiation therapy in limited-stage FL patients. [ABSTRACT FROM AUTHOR]

The first-line standard treatment for diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). It is associated with cardiotoxicity, which is why new treatment strategies are needed. Liposomial doxorubicin has been proven to reduce these side-effects, but until now a direct comparison regarding efficacy has not yet been published. We retrospectively assessed 364 consecutive DLBCL patients who underwent either R-CHOP (218; 60%) or R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; 146; 40%) in first line and compared outcome and survival. We provide evidence that both regimens induce a high and comparable number of complete remissions and that both are able to cure patients with DLBCL. Confirmatory data are needed. [ABSTRACT FROM AUTHOR]

Abstract: Background: Few data on patterns of care and outcomes are available for elderly patients with diffuse large B-cell lymphoma (DLBCL) outside of clinical trials. Methods: We identified patients with DLBCL older than 60years from a regional cancer registry between 2000 and 2010. Based on registry data and chart review, 128 patients from the oncology network of Eastern Switzerland were analysed for patient characteristics, treatment and outcomes of DLBCL. Three age groups were compared: 60–69, 70–79 and over 80years old. Results: Median age was 73years (range: 60 to 95years). 52/121 treated patients received 6cycles of R-CHOP/CHOP, of those 30 (58%), 18 (35%) and 4 (7%) patients were 60–69years, 70–79years or older than 80years respectively, with a significant difference by age group, p =0.001. Median OS of patients 60–69, 70–79, and 80years and older receiving 6cycles of R-CHOP/CHOP were: 54months, 31months and 24months respectively. In comparison, patients receiving other than 6cycles of R-CHOP/CHOP treatment regimens had a median OS of 22months, 17months and 6months, respectively. In the multivariable analysis other than 6cycles of R-CHOP/CHOP were significantly associated with poor survival. The risk of dying increased by a mean of 6% for each year of age from age 60years onwards. Conclusion: In conclusion, treatment regimens other than 6cycles of R-CHOP/CHOP were significant predictors for survival in our oncology network. The possibility of using R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL. [Copyright &y& Elsevier]

Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 25% of all NHL cases. Primary appendiceal lymphomas (PAL) presenting as acute appendicitis are very rare, occurring in only 0.015% of all cases of gastrointestinal lymphoma. A 57-year-old man who was initially presented as acute appendicitis and subsequently underwent interval laparoscopic appendectomy. Pathological examination revealed diffuse large B cell lymphoma with cut end involvement. Whole-body positron emission tomography (PET) scan revealed enlarged right palatine tonsil and raised a suspicion of lymphoma involvement in two right cervical lymph nodes (level II and III); biopsy, however, showed that the lymph nodes were benign, with non-specific cellular changes. Bone marrow biopsy of the iliac crest also did not show lymphoma involvement. Subsequently, a diagnosis of primary appendiceal diffuse large B cell lymphoma (Ann Arbor Stage II) was established. After six courses of definite chemotherapy with cyclophosphamide, doxorubicin HCl, vincristine, and rituximab (R-CHOP), PET/CT showed complete remission of the prior FDG-avid malignancy of appendiceal DLBCL. The patient continued to be stable with no recurrence for fifteen months of regular outpatient department follow-ups. PAL is rare, and it clinically manifests the signs and symptoms of acute appendicitis. Specific characteristics of lymphoma in CT scans may lead to a more confirmative diagnosis. PET/CT is important for staging the lymphoma. Patients with PAL should be managed with surgical resection followed by R-CHOP-21 for 6 cycles regardless of whether they have localized disease or disseminated disease. • A rare case of appendiceal diffuse large B-cell lymphoma treated by laparoscopic appendectomy followed by chemotherapy with complete remission for fifteen months of follow-ups. • An inflamed appendix usually expanded less than 15 mm in diameter in by computed tomography scan. • PET/CT is important for staging lymphoma. • Patients with primary appendiceal lymphoma should be managed with surgical resection followed by R-CHOP-21 for six cycles regardless localized disease or disseminated disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Little is known on racial differences in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this retrospective study is to compare characteristics, prognostic factors and outcomes of Asian and Western patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Methods: Patient-level data was collected from 8 centers. All patients were diagnosed with DLBCL and treated with R-CHOP. Patients were divided into Asian and Western, according to the country of report. Comparisons and univariate/multivariate survival analyses were performed. Results: 712 patients, 455 Asian and 257 Western patients were included. Westerners were more likely to present with elevated LDH (64% vs. 48%, p <0.01) and advanced stage (58% vs. 49%, p <0.01). After a median follow-up of 36 months, there was no difference in progression-free (PFS; p =0.33) or overall survival (OS; p =0.69). There were no PFS or OS differences between races when evaluating separately each age-adjusted International Prognostic Index category. In the multivariate analyses, performance status and stage were associated with PFS and OS in both races. Conclusions: There are no differences in prognostic factors, PFS and OS between Asian and Western patients with DLBCL treated with R-CHOP. [Copyright &y& Elsevier]

Background: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). Patients and methods: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. Results: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. Conclusions: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation. [ABSTRACT FROM PUBLISHER]

Purpose: For patients with recurrent or refractory large B-cell non-Hodgkin''s lymphoma, high-dose chemotherapy and autologous stem cell transplant (ASCT) is the treatment of choice. We evaluated the role of involved field radiation therapy (IFRT) post-ASCT for patients initially induced with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or, more recently, rituximab-CHOP (R-CHOP). Materials and Methods: Between May 1992 and April 2005, 176 patients underwent ASCT for recurrent or refractory large B-cell non-Hodgkin''s lymphoma; 164 patients were evaluable for endpoint analysis. Fifty percent of the CHOP group (n = 131), and 39% of the R-CHOP group (n = 33), received IFRT. Follow-up from the time of transplant was a median/mean of 1.7/3 years (range, 0.03-13 years). Results: The 5-year overall survival (OS) and disease-specific survival (DSS) improved with IFRT in both the R-CHOP (p = 0.006 and 0.02, respectively) and CHOP (p = 0.02 and p = 0.04, respectively) groups. IFRT was associated with a 10% (p = 0.17) reduction in local failure, alone or with a distant site. On univariate analysis, IFRT was associated with superior OS (hazard ratio [HR] = 0.50 [95% CI 0.32, 0.78]; p = 0.002) and DSS (HR = 0.53 [95% CI 0.33, 0.86]; p = 0.009). Presence of B symptoms was adverse (p = 0.03). On multivariate analysis, only IFRT was associated with significant improvement in OS (HR = 0.35 [0.18, 0.68]; p = 0.002) and DSS (HR = 0.39 [95% CI 0.18, 0.84]; p = 0.01). Conclusions: Recognizing that positive and negative patient selection bias exists for the use of IFRT post-ASCT, patients initially treated with CHOP or R-CHOP and who undergo ASCT for recurrent or refractory disease may benefit from subsequent IFRT presumably due to enhanced local control that can translate into a survival advantage. [Copyright &y& Elsevier]

Background: The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the risk of central nervous system (CNS) relapse in the R-CHOP in a population-based cohort of patients with DLBCL. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Rituximab, a chimeric antibody targeted to the human CD20 molecule, is a major component of the R-CHOP protocol used to treat patients with diffuse large B cell lymphoma (DLBCL). It is also a very expensive drug. Though the response rate of R-CHOP is higher than that of CHOP alone, patients may still experience a poor response. One possible mechanism that may mediate the poor response to R-CHOP is poor binding of the drug to the CD20 molecule, perhaps due to mutations or polymorphisms of the CD20 gene that affect its structure. To test this hypothesis and perhaps define a new predictor of R-CHOP response, our pilot study evaluated the CD20 gene sequence from patients exhibiting a poor outcome to R-CHOP. Methods: Eleven patients with DLBCL who exhibited a recurrence of their disease and/or died within 24 months of R-CHOP treatment were categorized as showing poor progression-free survival (poor outcomes). Paraffin-embedded tissue specimens from the original tumors were evaluated for mutations or polymorphisms of the CD20 gene. Furthermore, sections from these patients and as well as from matched control patients who were categorized as good outcome patients (no progression of their disease within 36 months) were stained with anti-CD20 antibody and compared for CD20 protein expression. Results: DNA sequence analyses revealed that no mutations were observed in DNA from the coding region of the CD20 gene in any of the initial tumors from 11 patients who showed poor outcomes with R-CHOP therapy. One case showed a synonymous single nucleotide polymorphism in exon 2 (C216T; rs2070770; Ile≫Ile). No significant differences in CD20 expression was observed between good and poor outcome patients with R-CHOP. Conclusions: Our results do not support association of CD20 mutations in specimens of the initial tumor or structural polymorphisms of the CD20 gene with patients who exhibited poor outcomes to R-CHOP. [Copyright &y& Elsevier]

Objective: The objective of this study was to provide a detailed comparative microcosting analysis for two cancer treatment pathways to contribute evidence for resource allocation and operational decision-making in a Canadian cancer care context. Methods: We estimated direct medical costs (in 2004 CAN$) of the entire pathway of care for diffuse large B-cell lymphoma (DLBCL) patients in a large Canadian cancer treatment center. Patient samples were defined as those who received R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; n = 85) or CHOP (i.e., without rituximab; n = 86) as first-line treatment. All subsequent treatments including palliative care for these patient samples were assessed. Hospitalization costs and unit costs of medical resources were collected from integrated medical organizations. Individual patient resource consumption was assessed via medical chart review. Results: For first-line treatment, drug cost was the largest contributor to total cost, followed by hospitalization cost. Rituximab was the largest contributor to mean cost differences between R-CHOP and CHOP treatments. For treatments subsequent to first-line treatment, no significant cost differences were found. Hospitalization and transplantation costs were the two largest constituents of total costs subsequent to first-line treatment, followed by drug cost. Patients with advanced stage disease cost significantly more than patients with limited stage disease. Conclusion: This is the first detailed microcosting study that has employed consistent local data to estimate total medical costs for DLBCL patients in Canada. This information is useful for resource allocation planning and operational decisions, because it provides more substantive, relevant evidence as compared to aggregated, literature or extrapolated information. [ABSTRACT FROM AUTHOR]

• The introduction of rituximab to the CHOP improved PFS and OS in DLBCL. • In the pre-rituximab period, it was shown that bulky mass has poor prognosis. • The effect of bulky disease under R-CHOP therapy remained uncertain. • Bulky disease does not seem to affect remission status. • Overall survival was not influenced by bulky disease. The introduction of rituximab to the CHOP protocol has demonstrated an improvement in PFS and OS in DLBCL patients with both early and advanced stages. Most studies in the pre-rituximab period indicated that bulky disease has an unfavorable impact on clinical outcomes of DLBCL. The effect of bulky mass on the outcome of DLBCL patients undergoing R-CHOP therapy remained uncertain. One-hundred-twelve newly diagnosed DLBCL patients aged 18 and older were enrolled in the study. Patients were divided into groups-based presence of bulky disease. 56 patients with bulky disease and their age, gender, ECOG score, Ann Arbor stage, immunohistochemical origin, treatment, radiotherapy and comorbidity 1:1 matched 56 control patients with non-bulky disease included. Overall response rate at end of treatment was similar among groups (p = 0.1). Patients with bulky disease and non-bulky disease were comparable regarding overall survival (p = 0,9). All cohort investigated for predictors for survival, after multivariate analysis, ECOG score, Ann arbor stage, IPI score and LDH level were found significant. Here, we found no impact of bulky disease on remission and survival. We believe, with increasing available data, poor prognostic value of bulky disease will be weakening in the rituximab era. [ABSTRACT FROM AUTHOR]

Background Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and comprises approximately 5-10% of all lymphomas. However, in Korea, MCL accounts for just 2% of B-cell lymphomas. In addition to the paucity of the disease, due to lack of feasibility of novel agents for this disease, clinical outcomes of the novel agents have yet to be defined in Korea. Methods We performed a retrospective study of MCL patients treated with ibrutinib in Korea. The primary endpoint of the analysis was progression free survival (PFS) out of ibrutinib treatment. Results Between 2013 to 2019, a total of 75 cases were eligible for analysis. Median age at diagnosis was 69 (range, 40 – 90) and 61 patients (81%) were male. Most patients had an advanced disease at diagnosis (II 10, III 10, IV 55). The received induction regimens were as follows, R-CHOP (N = 48); R-HyperCVAD/MA (N = 10); R-bendamustine (N = 5); VR-CAP (N = 3); others (N = 9) At time of ibrutinib treatment, median age was 71 (range, 41-92), and the median number of prior treatments was 1 (range, 1 – 6). Eleven patients (15%) had received salvage autologous stem cell transplantation. Complete and partial responses were achieved in 31 (41%) and 22 patients (29%), respectively. At a median follow-up duration of 30.5 months (95% CI 25.9 – 35.1), the estimated median PFS was 18.6 months (95% CI 11.0 – 26.2). Those who were classified as low- or intermediated-risk MIPI score at the time of ibrutinib start (24.4 vs. 9.9 months, p = 0.031) demonstrated superior PFS, and patients with tumor size < 5 cm (25.5 vs. 9.4 months, p = 0.092) demonstrated trends for prolonged PFS. Among elderly patients (≥ 65 yrs), those who had received ibrutinib as the first salvage treatment showed significantly prolonged PFS compared to those who had received ibrutinib as the later line of treatment (24.4 vs. 5.8 months, p = 0.015). Conclusions The response rate as well as the PFS data of the current study is similar to those of the Western reports. The current study provided additional evidence to support the use of ibrutinib in relapsed or refractory MCL, especially as the early salvage treatment. The compliance and safety data will be presented in the meeting. Funding Janssen, Korea. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Mantle cell lymphoma (MLC) is nowadays an aggressive and incurable Non-Hodgkin's lymphoma, characterized by multiple relapses.The persistent activation of B-cell receptor pathway is critical for pathogenesis. Ibrutinib is a potent covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits B-cell antigen receptor signaling downstream of BTK and changed for better how MCL is treated in relapsed/refractory setting. However, resistance is common and response limited. Methods Retrospective analysis and follow-up of all MCL patients treated with Ibrutinib in a Onco-Hematology Department. Results Eleven patients were identified, with a median age of 68 years [58-78], the majority of them were males (83.3%). At diagnosis, 9% were in stage III of Ann Arbor while 81.8% were in stage IV. The median MIPI (MCL International Prognostic Index) was 5.5 [4-8]. These patients were exposed to a median of 3 treatments [3-5]. The majority of them performed as 1ºline treatment R-FCM (18.2%) or R-CHOP (54.5%); as 2ºline R-CHOP (45.5%), as 3ºline Ibrutinib (63.6%), as 4ºline PEPC (60%) and as 5ºline Ibrutinib (100%). Ibrutinib therapy was prescribed as a 2ºline in 9.1% of the patients, as a 3ºline in 63.6%, as 4ºline in 40% and as a 5ºline in 100%. Ibrutinib achieved a complete response rate in 9.1%, a partial response in 45.5% (response rate, RR, of 54.5%), disease progression in 36.4%, stable disease in 9,1%. At the end of the study, 5 patients were alive and still doing Ibrutinib (4 of them in full dose 560 mg/day). The median progression free survival (PFS) was 3 months [1-26]. Overall survival was not reached (3 patients died with disease progression). Conclusions Although a larger sample and a longer follow-up are needed, these data showed worse results when compared to previous phase 2 trials demonstrating a 68% response rate (RR), including for high-risk patients and heavily pretreated. Most recently, a pooled analysis of the three open-label studies of ibrutinib in MCL, PCYC-1104, SPARK, and RAY revealed an ORR of 68%, 63% and 72%. Ibrutinib may be changing the natural history of MCL as many other agents still under development. Enrollment in clinical trials is crucial not only for discovery of new agents and testing combinations but also to understand the natural history of relapsed MCL. Legal entity responsible for the study Onco-Hematology Service of Instituto Português de Oncologia do Porto, F.G. E.P.E. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Introduction There is limited evidence regarding the impact of updated Charlson comorbidity index (CCI) on survival in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. Methods We retrospectively reviewed 125 patients with newly diagnosed DLBCL receiving R-CHOP as a first-line immunochemotherapy who were admitted to Nagoya City West Medical Center between May 2011 and December 2018. We evaluated the association between their survival and the 5 following baseline indexes: CCI, age-adjusted CCI, updated CCI, Barthel index and mini-nutritional assessment (MNA-SF). Result Baseline characteristics of the 125 patients with newly diagnosed DLBCL were as follows: median age was 75 years; 84% was >60 years; 70% had high LDH (> upper limit of normal); 33% had ECOG-PS ≥2; Ann Arbor stage of I, II, III, IV was 14%, 21%, 18% and 48%, respectively; 39% had extranodal site ≥2; 11% had high BNP levels (BNP≥100 pg/mL). None of CCI, age-adjusted CCI and updated CCI was associated with the survival, although both a lower Barthel index and malnutrition were significantly associated with shorter overall survival. The patients with high BNP levels had worse prognosis compared to those with low levels. Multivariate analysis revealed that age >60 years, extranodal site ≥2 and malnutrition (MNA-SF ≤7) were independent risk factors for survival (adjusted hazard ratios, 2.9, 2.2 and 2.0, respectively; p < 0.05). Conclusion In our cohort, none of CCI, age-adjusted CCI and updated CCI had impact on survival in patient with DLBCL receiving R-CHOP treatment, whereas malnutrition (MNA-SF ≤7) had negative impact on survival in those patients. Well-designed clinical trials are warranted to identify not only lymphoma-related factors but also host factors for survival. [ABSTRACT FROM AUTHOR]

Background No comprehensive analysis has evaluated the appropriate relative dose intensity (RDI) of R-CHOP treatment in elderly patients. This study aimed to clarify the relationships between the RDI of R-CHOP treatment and susceptibility of febrile neutropenia (FN) using a national inpatient database in Japan. Methods We identified patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who received the first R-CHOP treatment between July 2007 and March 2017 from the Japanese Diagnosis Procedure Combination Database. RDI was calculated according to a comparison between the actual cyclophosphamide dose and the 100%-dose cyclophosphamide. Multivariable logistic regression analysis was performed to identify factors associated with the incidence of febrile neutropenia (FN). Results FN occurred in 1,465 of the 18,095 (8.1%) patients, at a median of 10 days (IQR, 8-12) from the initiation of the chemotherapy. Compared with the >100% RDI group, multivariate analyses showed that each low-RDI group (80%≤RDI<100%, 60%≤RDI<80%, and 40%≤RDI<60%) presented a significantly decreased FN susceptibility (odds ratio; 0.84 [95% confidence interval; 0.73-0.97], 0.75 [0.60-0.95], 0.84 [0.42-0.79], respectively). In patients who were 50-60 or 61-70 years old, the associated low-RDI groups did not show decreased FN susceptibility. On the contrary, in patients who were 71-80 years old, the two low-RDI groups (60%≤RDI<80% and 40%≤RDI<60% groups) showed significantly decreased FN susceptibility (0.68 [0.50-0.92], 0.48 [0.30-0.78], respectively), while the 80%≤RDI<100% group did not show a significant FN susceptibility reduction. In the patients who were over 80 years old, all low-RDI groups showed significantly reduced FN susceptibility (80%≤RDI<100%: 0.33 [0.17-0.64], 60%≤RDI<80%: 0.45 [0.23-0.88], 40%≤RDI<60%: 0.37; [0.19-0.72]). Conclusions Our study suggests that low-RDI R-CHOP treatment decreases the susceptibility of FN in patients who are over 70 years of age. [ABSTRACT FROM AUTHOR]

Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL. • DLBCLs expressing LMO2 protein have deficient homologous recombination DNA repair • LMO2 interacts with and requires 53BP1 to inhibit homologous recombination • LMO2 expression sensitizes tumor cells to PARP1/2 inhibitors (PARPi) • PARPi and chemotherapy synergistically inhibit the growth of LMO2-positive tumors Parvin et al. show that LMO2 inhibits BRCA1 recruitment to DNA double-strand breaks (DSB) by interacting with 53BP1. Thus, diffuse large B cell lymphomas expressing LMO2 are functionally deficient in homologous recombination-mediated DSB repair and are sensitive to poly(ADP-ribose) polymerase inhibitors. [ABSTRACT FROM AUTHOR]

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDHlow lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDHlow B cells and improve GAPDHlow B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDHhigh B cell lymphomas. Ultimately, we selected four GAPDHlow DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors. • GAPDH is a clinical biomarker of DLBCL response to R-CHOP • GAPDH expression predicts B cell lymphoma metabolic status • GAPDHlow B cell lymphomas are sensitive to mitochondrial metabolism inhibitors • DLBCL-GAPDH low R-CHOP refractory patients respond to specific metabolic inhibitors About 40% of diffuse large B cell lymphoma (DLBCL) patients are refractory to the combined immuno-chemotherapy (R-CHOP) standard of care. DLBCL is metabolically heterogeneous, and Chiche et al. show that low levels of GAPDH, which predict poor R-CHOP response, are associated with OxPhos metabolism, mTORC1 signaling, and glutaminolysis. Disruptors of these pathways improved GAPDH low DLBCL response in mice and patients. [ABSTRACT FROM AUTHOR]