Late-Onset Neutropenia in Patients Treated with Rituximab for Non-Hodgkin’s Lymphoma

Late-onset grade 4 neutropenia occurred in 3 (5.6%) of 54 non-Hodgkin's lymphoma patients treated with rituximab between September 2001 and March 2004. Neutropenia appeared 5 to 25 weeks after administration of cytotoxic agents in combination with rituximab and recurred 4 and 17 weeks after the first onset in 2 patients. Five episodes occurred in a total of 332 cycles of rituximab therapy. Bone marrow findings at the time of late-onset neutropenia showed neutrophil maturation arrest with or without reversible myeloid dysplasia in 3 episodes and selective depletion of the myeloid series in 1 episode. Neither circulating immune complexes nor antineutrophil antibodies were detected during the 3 episodes that we evaluated. Bone marrow cells stained CD8- and CD57-. Late-onset neutropenia resolved 5 to 7 days after granulocyte colony-stimulating factor therapy was started. Further studies are needed to determine how rituximab functions and to identify appropriate countermeasures.     

Non-Hodgkin’s Lymphoma Developing in a Pacemaker Pocket

A 29-year-old man developed diffuse large B-cell lymphoma in a subpectoral pacemaker pocket that 6 years previously had been created in the chest for a titanium-covered pulse generator. The patient had an 8-cm-diameter dark red tumor with necrotic tissue on a keloidal surgical scar in the left side of the chest. Left axillary lymphadenopathy also was present. Laboratory studies showed an increased level of soluble interleukin 2 receptor and a normal level of lactose dehydrogenase. A biopsy specimen showed a diffuse large B-cell phenotype and monoclonal immunoglobulin H gene rearrangement. A gallium scintigraphy study showed abnormal accumulation in the left chest and left axilla. On the basis of these findings, we diagnosed diffuse large B-cell lymphoma, stage II. The patient received THP-COP chemotherapy (pirarubicin, cyclophosphamide, vincristine, and prednisolone) and radiotherapy, achieved complete remission, and was free of disease for 16 months after treatment. This case suggests that there was a relationship between the development of non-Hodgkin's lymphoma and the presence of chronic inflammation in the pulse generator pocket.     

Non-Hodgkin’s Lymphoma in a Patient with Probable Hereditary Nonpolyposis Colon Cancer

PURPOSE: Hereditary nonpolyposis colorectal cancer kindreds are frequently associated with cancers in various organs, including endometrium, stomach, and ovary. However, hematologic malignancy has rarely been reported in association with this cancer syndrome. We present here the case of a probable hereditary nonpolyposis colon cancer patient in whom non-Hodgkin's lymphoma developed after curative resection of colon cancer. Our experience with this rare case encouraged us to review the literature for reports indicating a possible relationship between these diseases. RESULTS: A 52-year-old male whose family history was consistent with the criteria for hereditary nonpolyposis colon cancer underwent right hemicolectomy for ascending colon cancer. Histologically the tumor consisted of adenocarcinoma that was moderately differentiated with mucinous foci and that invaded beyond the muscularis propria. Neither metastasis nor lymphoma was found in paracolonic lymph nodes. Eight months after surgery, the patient developed non-Hodgkin's lymphoma of T-cell origin involving the ileum and lungs. Both colon cancer and lymphoma frequently showed microsatellite DNA instability, sharing alteration in a locus of chromosome 7 (D7S501). CONCLUSION: A possible association of hematologic malignancy with hereditary nonpolyposis colon cancer reported in the literature, together with a report that MSH2-deficient mice are susceptible to malignant lymphoma, strongly supports the finding that this patient's lymphoma was related to hereditary nonpolyposis colon cancer. Overall, this case manifested a distinct clinical course similar to that observed in an animal model that is deficient in DNA mismatch repair machinery, thus providing scientific and clinical implications for understanding the molecular basis of these tumors and for critical management of hereditary nonpolyposis colorectal cancer patients, respectively.     

Acute Spontaneous Tumor-Lysis Syndrome in a Pregnant Woman with Non-Hodgkin’s Lymphoma

Both non-Hodgkin's lymphoma (NHL) in pregnancy and acute spontaneous tumor-lysis (ASTL) syndrome are rare. Here we present a 32-year-old Egyptian woman in the 27th week of pregnancy, who was admitted with epistaxis, lethargy, vomiting and dehydration. This patient developed ASTL syndrome secondary to undiagnosed NHL, but was not on any medication associated with the syndrome. At 28 weeks, she gave birth to a healthy baby who, unfortunately, died within a few days. To our knowledge, this is the first case of ASTL syndrome in a pregnant woman.     

Non-Hodgkin’s Lymphoma among Patients Infected with Human Immunodeficiency Virus: The Experience of a Single Center in Brazil

The relative risk of non-Hodgkin’s lymphoma (NHL) among patients infected with human immunodeficiency virus (HIV) is elevated compared with the general population. We describe a retrospective study of 78 HIV-infected patients with NHL treated between 1999 and 2006 at the Infectology Institute, a reference center for HIV treatment in São Paulo, Brazil. All patients were treated with standard CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). An evaluation of treatment response was available for 48 (61.5%) of the patients who completed initial treatment.Twenty-three patients (47.9%) achieved a complete response (CR), 3 (6.3%) achieved a partial response, and 22 (45.8%) failed to respond to treatment. Of the 30 patients (38.5%) who were not available for response evaluation, 23 died of sepsis during treatment, 5 abandoned treatment, and 2 are still under treatment. After a median follow-up of 3 years, the overall survival rate for all patients is 20.5%. A univariate analysis showed a significant CR rate in patients with respect to the following factors: no acquired immunodeficiency syndrome (AIDS) diagnosis prior to the lymphoma, disease stage of I to II, and an International Prognostic Index (IPI) of low or low-intermediate risk. A multivariate analysis indicated that only a previous AIDS diagnosis and the IPI were significantly related to the CR rate. A median disease-free survival (DFS) time for the patients who achieved a CR was not reached, with a mean survival time of 73 months and a 3-year DFS rate of 77.5%. Our results provide additional information regarding HIV-related lymphoma in Brazil.     

Treatment of Indolent Non-Hodgkin’s Lymphoma with Cladribine as Single-Agent Therapy and in Combination with Mitoxantrone

The term indolent in describing a non-Hodgkin's lymphoma (NHL) generally refers to a group of B-cell NHLs composed of predominantly small cells that make up several categories, including follicular lymphoma, small lymphocytic lymphoma, and lymphoma of mucosa-associated lymphoid tissue. Most patients with follicular lymphoma respond to therapy, and the average survival time in large series is approximately 10 years. Patients who achieve a complete remission with initial treatment have an approximately 25% chance of remaining free of disease for 10 years. However, this means that more than 80% of patients will require salvage therapy. Cladribine is a newer purine analogue and is of particular interest because it is resistant to deamination by adenosine deaminase. It is cytotoxic to both proliferating and resting lymphocytes, making it an attractive agent for the treatment of indolent NHL. In this review article, we summarize the current treatment approaches for indolent NHL and the results of cladribine monotherapy studies in Japan and cladribine studies in Germany that have focused on a combination therapy with mitoxantrone. Cladribine is a potent inhibitor of DNA repair. The combination of a DNA-damaging agent with an inhibitor of DNA repair constitutes the rationale for combining cladribine with mitoxantrone. A German study has demonstrated that the combination of reduced-dose cladribine and mitoxantrone is a highly active regimen with favorable toxicity profiles. Cladribine is highly effective as a single agent and in combination with mitoxantrone in the treatment of indolent NHL, and its availability broadens the range of therapeutic options for indolent NHL.     

Low-dose Granulocyte Colony-Stimulating Factor Overcomes Neutropenia in the Treatment of Non-Hodgkin’s Lymphoma with Higher Cost-Effectiveness

To facilitate more economical medical care, we carried out a prospective study of whether a THP-COP regimen (cyclophosphamide, pirarubicin, vincristine, and prednisolone) with low-dose granulocyte colony-stimulating factor (G-CSF) would effectively treat non-Hodgkin's lymphoma (NHL). From April 2003 through March 2004, we enrolled 19 consecutive patients with newly diagnosed NHL treated at our hospital. The patients were divided into young and elderly groups. Each patient underwent chemotherapy with 8 courses of a THP-COP regimen with a 50-microg dose of lenograstim. Age- and sex-matched historical control patients (n = 141) received NHL diagnoses between 1998 and 2003. Each patient in the control group underwent the same chemotherapy and received a 100-microg dose of lenograstim. The mean (+/-SD) total amounts of G-CSF per cycle of chemotherapy were 332 +/- 103 microg (young patients) and 345 +/- 128 microg (elderly patients) in the low-dose group and 594 +/- 439 microg (young) and 730 +/- 551 microg (elderly) in the control group. The duration of fever in 1 cycle of chemotherapy was 0.3 +/- 1.0 days (young) and 0.1 +/- 0.8 days (elderly) in the low-dose group and 0.5 +/- 1.3 days (young) and 0.8 +/- 2.0 days (elderly) in the control group. A THP-COP regimen with low-dose G-CSF could be administered to NHL patients with safety. Administration of a 50-microg dose of lenograstim is sufficient and recommended for the treatment of NHL.     

Prospective Randomized Trial of Argon Plasma Coagulation Ablation Versus Endoscopic Surveillance of Barrett’s Esophagus in Patients Treated with Antisecretory Medication

Argon plasma coagulation (APC) has been used to ablate Barrett’s esophagus, however, its role in the management of non-dysplastic Barrett’s esophagus is uncertain. The purpose of this study is to determine the efficacy of endoscopic argon plasma coagulation (APC) for ablation of Barrett’s esophagus in a prospective randomized controlled trial in two university teaching hospitals. Fifty-seven patients using proton pump inhibitor (PPI) medication and with Barrett’s esophagus were randomized to undergo either ablation using endoscopic argon plasma coagulation (APC) or ongoing surveillance. Fifty-one patients underwent endoscopy at 12 months. Endoscopic argon plasma coagulation (APC) versus surveillance endoscopy was studied. Endoscopy and histopathological appearances of Barrett’s esophagus at 12 months follow-up was also studied. Initially, at least 95% ablation of the metaplastic mucosa was achieved in 25 of the 26 treated patients. At 12 months, 14 of 23 APC patients had at least 95% regression, and nine of 23 had complete regression of Barrett’s esophagus. No surveillance patient had more than 95% regression. The length of Barrett’s esophagus shortened significantly after APC (mean 3.0 vs. 0.5 cm). Significant regression of Barrett’s esophagus follows ablation with APC, although complete regression was achieved in less than half. The role of APC ablation of non-dysplastic Barrett’s esophagus remains uncertain.     

A Randomized Multicenter Trial of Paricalcitol versus Calcitriol for Secondary Hyperparathyroidism in Stages 3–4 CKD

Background and objectives

Calcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%–60%.

Design, setting, participants, & measurements

Patients with stages 3–4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 μg/d of calcitriol or 1 μg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%–60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups.

Results

Forty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (−52% with paricalcitol and −46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405; P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3–0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups.

Conclusions

These results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3–4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.     

Effects of Transdermal Tulobuterol in Pediatric Asthma Patients on Long-Term Leukotriene Receptor Antagonist Therapy: Results of a Randomized,Open-Label,Multicenter Clinical Trial in Japanese Children Aged 4–12 Years

BackgroundFew studies have examined the efficacy or safety of a transdermal β2 agonist as add-on medicationto long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients.MethodsIn this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2 mg daily) or oral sustained-release theophylline (usual dose, 4-5 mg_kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events.ResultsThirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group.ConclusionsThese results suggest that short-term use of a transdermal β2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy.     

Advanced Stage Is the Most Important Prognostic Factor for Survival in Patients with Systemic Acquired Immunodeficiency Syndrome-Related Non-Hodgkin’s Lymphoma Treated with CHOP and Highly Active Antiretroviral Therapy

In the era of highly active antiretroviral therapy (HAART), the prognosis for acquired immunodeficiency syndrome-related lymphomas (ARL) seems to be similar to that for aggressive B-cell lymphomas in human immunodeficiency virus (HIV)-negative patients. This improvement in prognosis might lead to a modification of the classic prognostic factors for ARL. We evaluated the prognostic factors for response and survival in a series of HIV-infected patients with systemic non-Hodgkin's lymphoma (NHL) in the HAART era. Forty patients with systemic NHL treated with a CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) and HAART were studied. The main clinicopathologic and laboratory parameters were recorded in each case. Patients were scheduled to receive cycles of CHOP therapy, and all received granulocyte colony-stimulating factor. In addition, 9 patients received rituximab (375 mg/m2). The complete remission (CR) rate was 62.5% (n = 25). No prognostic factors influencing CR attainment were found. The 5-year disease-free survival (DFS) probability (95% confidence interval [CI]) was 73% (54%-92%). The median overall survival (OS) time was 69.17 months, and the 5-year OS rate (95% CI) was 51% (35%-67%). A disease stage of III to IV was the only parameter with prognostic influence on DFS. The factors influencing OS were an International Prognostic Index >2, an Eastern Cooperative Ecology Group (ECOG) score >2, and a disease stage of III to IV. Patients with an advanced stage had a lower OS probability in a multivariate analysis (odds ratio, 4.24; 95% CI, 1.24- 14.57). Advanced stage was the main prognostic factor predicting survival in ARL treated with CHOP and HAART.     

Biweekly CHOP or THP-COP regimens in the treatment of newly diagnosed aggressive non-Hodgkin’s lymphoma

Purpose To compare the efficacy and safety of a biweekly CHOP regimen consisting of cyclophosphamide (CPA), doxorubicin (DOX), vincristine (VCR), and prednisolone (PSL) and those of a biweekly THP-COP regimen containing pirarubicin (THP), an anthracyclin with less cardiotoxicity than DOX.Methods A prospective, randomized phase II study with 80 patients (40 receiving CHOP or THP-COP) less than 70 years of age with previously untreated aggressive non-Hodgkins lymphoma (NHL). The regimens consisted of DOX or THP 50 mg/m², CPA 750 mg/m², VCR 1.4 mg/m², and PSL 100 mg/body administered for 5 days every 2 weeks for eight cycles.Results No significant differences in known prognostic factors were found between the two groups. Complete remission rate was 72.5% (72.5% for CHOP, 72.5% for THP-COP). The 5-year overall survival rate was 49.2% (43.7% for CHOP, 54.0% for THP-COP). When the patients were divided into groups with favorable or poor prognostic factors according to the International Prognostic Index, survival of the former group (L/LI) was superior to that of the later group (HI/H), regardless of chemotherapy regimen (P<0.001). Although grade 3 cardiotoxicity occurred in one patient in the CHOP group, no fatal toxic reactions occurred in either group. The THP-COP produced results equivalent to those of CHOP regarding efficacy and safety in aggressive NHL patients less than 70 years of age.Conclusions Although both regimens effectively treated those patients with favorable prognostic factors, neither was satisfactory for treating those with poor prognostic factors.     

CD64 Surface Expression on Neutrophils and Monocytes Is Significantly Up-Regulated after Stimulation with Granulocyte Colony-Stimulating Factor during CHOP Chemotherapy for Patients with Non-Hodgkin’s Lymphoma

The present study was performed to examine whether the expression of CD64 Fc gamma receptor type I (FcgammaRI) on both neutrophils and monocytes can be modulated by multiple daily administrations of granulocyte colony-stimulating factor (G-CSF) to patients with non-Hodgkin's lymphoma in neutropenia caused by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. The expression of CD64 was determined by flow cytometric analysis at the following time points: before chemotherapy, at the nadir of the neutrophil count, at the fifth day after the start of G-CSF administration, and at more than 8 days after the start of G-CSF administration. CD64 expression was enhanced in patients given G-CSF during CHOP treatment, whereas CD64 expression remained unchanged in patients not given G-CSF CD64 expression levels on both neutrophils and monocytes were significantly up-regulated by the daily administration of G-CSF and reached peak levels at day 5 (P = .0007). Thereafter, expression on both cell types remained at almost the same levels as on day 5 for the rest of the treatment course, even though G-CSF therapy continued for 3 to 5 more days. Interestingly, CD64 expression on monocytes was already increased significantly (P = .0001) at the nadir of the neutrophil count relative to the baseline before chemotherapy and then was additionally up-regulated by day 5 after the start of G-CSF injections (P = .019). In antibody-dependent cellular cytotoxicity assays, we found that rituximab-mediated cell lysis was significantly enhanced at day 5 after the start of G-CSF treatment (P = .01). In conclusion, this study shows that multiple doses of G-CSF administered to lymphoma patients with neutropenia due to CHOP chemotherapy can enhance CD64 expression on both neutrophils and monocytes. Peak CD64 levels are reached at day 5 of G-CSF treatment, resulting in an activation of the rituximab-mediated antitumor ability of these effector cells. This finding may be useful in determining the optimal timing of administration for an antibody such as rituximab in a chemotherapeutic strategy designed to exert a maximal effect against tumor cells.     

Mechanical Bowel Preparation or Not? Outcome of a Multicenter, Randomized Trial in Elective Open Colon Surgery

PURPOSE Mechanical bowel preparation is common practice in elective colon surgery. In recent literature the value of this procedure is under discussion. To verify the value of mechanical bowel preparation in elective open colon surgery, a randomized clinical trial was conducted.METHODS During a prospective, multicenter, randomized study, 250 patients undergoing elective open colon surgery were randomized between receiving mechanical bowel preparation with polyethylene glycol (PEG group, 125 patients) and having a normal meal preoperatively (normal meal preoperatively group, 125 patients). Outcome parameters were wound infection with bacterial results of intraoperative swabs and anastomotic leak.RESULTS In the polyethylene glycol group there were a total of nine wound infections (7.2 percent) and seven anastomotic leaks (5.6 percent) compared with seven wound infections (5.6 percent) (P = 0.61) and six anastomotic leaks (4.8 percent) (P = 0.78) in the normal meal preoperatively group. Bacterial results showed 52 percent sterile subcutis swabs in the PEG group and 63 percent sterile subcutis swabs in the normal meal preoperatively group (P = 0.11).CONCLUSION In the pres-ent study we could not detect a difference in outcome parameters between patients receiving mechanical bowel preparation in elective open colon surgery and patients without preoperative treatment of the bowel. The present study, although underpowered, did not show a difference in the primary outcome of bacterial wound cultures between patients receiving preoperative mechanical bowel preparation and patients receiving no preoperative bowel treatment. We conclude that there may be no need to continue the use of mechanical bowel preparation in elective open colon surgery.Presented at the Fourth Belgian Surgical Week, May 2 to 4, 2003, Oostende, Belgium, and at the Dutch Surgical Week, May 15 to 16, 2003, Veldhoven, The Netherlands.Reprints are not available     

Endoscopic Mucosal Resection Results in Change of Histologic Diagnosis in Barrett’s Esophagus Patients with Visible and Flat Neoplasia: A Multicenter Cohort Study

Background

There are limited data on the effect of endoscopic mucosal resection (EMR) on changes of histopathologic diagnosis for Barrett’s esophagus (BE) patients undergoing endoscopic eradication therapy (EET); especially those without visible lesions.

Aim

To compare the frequency of changes of diagnosis by EMR compared with pre-EMR biopsy diagnosis for patients with and without visible lesions.

Methods

In this multicenter outcomes project, patients with Barrett’s-related neoplasia undergoing EET at three tertiary-care centers were included. Patients undergoing biopsies followed by EMR within six months were included. The main outcome measures were frequency of overall change of histopathologic diagnosis, change based on pre-EMR biopsy diagnosis, and change based on the presence of visible lesions.

Results

One-hundred and thirty-eight BE patients (low-grade dysplasia (LGD) 15 (10.9 %), high-grade dysplasia (HGD) 87 (63 %), esophageal adenocarcinoma (EAC) 36 (26.1 %)) were included; 114 (82.6 %) patients had visible lesions. EMR resulted in a change of diagnosis for 43 (31.1 %) patients (upgrade 14 (10.1 %); downgrade 29 (21 %)). For HGD patients, EMR downstaged dysplasia grade for 17 (19.5 %) cases and upstaged it to EAC for nine (10.3 %) cases. There was a change of diagnosis for 26 (29.9 %) HGD patients, irrespective of the presence or absence of visible lesions (p = 0.76). For EAC patients, EMR downstaged dysplasia grade in 10 (27.8 %) cases. There was a change of diagnosis for 10 (27.8 %) EAC patients, irrespective of the presence or absence of endoscopically visible lesions (p = 0.48).

Conclusions

EMR results in a change of diagnosis for approximately 30 % of BE patients with early neoplasia (with and without visible lesions) referred for EET.     

St. John’s Wort in Patients Non-responders to Clopidogrel Undergoing Percutaneous Coronary Intervention: a Single-Center Randomized Open-Label Trial (St. John’s Trial)

We assessed if St. John’s Wort (SJW) improves platelet response in patients (pts) resistant to clopidogrel after percutaneous coronary intervention (PCI). Stable angina pts non-responders to 600 mg clopidogrel (P2Y12 reaction units (PRU) >240) were randomized (2:1) to SJW (n?=?15) or placebo (n?=?8). SJW (300 mg × 3/day) was administrated for 2 weeks after PCI. Platelet reactivity was assessed by VerifyNowTM before (BL), 2 (T1), and 4 weeks (T2) after PCI. PRU significantly changed during protocol in SJW (BL (316?±?60) vs. T1 (170?±?87) vs. T2 (220?±?96), p?<?0.0001) and placebo group (BL (288?±?36) vs. T1 (236?±?31) vs. T2 (236?±?62), p?=?0.046). Yet, PRU changes from BL were higher at T1 in SJW than in placebo group (Δ%, ?47?±?24 vs. ?16?±?15, p?=?0.0033), with no differences at T2 between the groups (Δ%, ?30?±?29 vs. ?17?±?24, p?=?0.30). Residual platelet reactivity improved with SJW during the first month post-PCI.