Consolidation with 90 Yttrium-ibritumomab tiuxetan after bendamustine and rituximab for relapsed follicular lymphoma.

Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with 90 Yttrium-ibritumomab tiuxetan (90 Y-IT) after re-induction therapy with BR in patients with previously treated FL. This study included adult patients with relapsed FL who had undergone one or two prior therapies. Re-induction therapy with BR was administered every 4 weeks up to 4-6 cycles. If patients achieved at least partial response, 90 Y-IT was administered as consolidation therapy. The primary endpoint was 2-year progression-free survival (PFS) after consolidation. A total of 24 FL patients (median age 60 years) who had undergone one (n = 17) or two (n = 7) prior treatments received BR. After BR therapy, 22 patients proceeded to consolidation with 90 Y-IT, resulting in an overall 88% response rate to the protocol treatment. Within a median observation period of 46.8 months, the estimated 2-year PFS rate after the consolidation among the 22 patients receiving 90 Y-IT was 59% (95% confidence interval [CI], 38%-77%). Patients whose remission after previous treatment had lasted ≥2 years had a significantly higher 2-year PFS rate than patients whose remission after previous treatment had been <2 years (68% vs. 33%, Wilcoxon p = 0.0211). Major adverse events during the protocol treatment and within 2 years after the consolidation were hematological toxicities, but they were generally acceptable. Consequently, the estimated 2-year overall survival after the consolidation was 95% (95% CI, 74%-99%). In conclusion, in a subset of patients with previously treated FL, 90 Y-IT consolidation after BR re-induction conferred a durable remission, indicating that consolidation therapy using 90 Y-IT may be a novel therapeutic option for patients with relapsed FL (UMIN000008793).

Selective TACE with irinotecan-loaded 40 µm microspheres and FOLFIRI for colorectal liver metastases: phase I dose escalation pharmacokinetic study.

BACKGROUND: Efficacy of treatments for colorectal liver metastases after failure of first-line chemotherapy is limited. The aim of this study was to prospectively evaluate the feasibility, tolerability, and pharmacokinetics of selective transarterial chemoembolization (TACE) with irinotecan-loaded 40 µm microspheres combined with systemic FOLFIRI for colorectal liver metastases refractory to oxaliplatin regimen. METHODS: The dose escalation study was conducted in three patient groups with different amounts of irinotecan loaded (50, 75 and 100 mg per mL-microspheres). Selective catheterization was performed to embolize subsegments or segments of located tumors using TACE navigation system. FOLFIRI was administrated 7 days after TACE. Plasma concentration was measured before and time points after administration. RESULTS: Nine patients successfully underwent a total of 22 TACE procedures. Dose-limiting toxicity did not appear at any level. The overall response rate was 55.6%. The median progression free and overall survival were 8.1 and 18.2 months, respectively. The AUC and Cmax of plasma SN-38 per 1 mg injected irinotecan dose were significantly higher in irinotecan-loaded microspheres compared with FOLFIRI (P = 0.009 and P <  0.001, respectively). CONCLUSION: Selective TACE using 40 µm irinotecan-loaded microspheres combined with systemic FOLFIRI was feasible and safe even when a high dose of irinotecan was loaded. Irinotecan-loaded microspheres resulted in a higher plasma concentration and AUC of SN-38 than treatment with FOLFIRI. Further large scale trials to evaluate the efficacy are mandatory. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, Registration number; UMIN000015367 ; Registered date; 08,10,2014.

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand. PATIENTS AND METHODS: The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of ≥65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP. RESULTS: A total of 836 patients with a median age of 74 years (range, 65-96 years) were analyzed. In the SoLT-J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n = 281). CONCLUSION: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. The Oncologist 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.

Aortitis after administration of pegfilgrastim to a healthy donor for peripheral blood stem cell collection.

A 45-year-old man who was a sibling donor for allogeneic peripheral blood stem cell transplantation (allo-PBSCT) was administered 7.2 mg of pegfilgrastim for stem cell collection. Peripheral blood stem cells were collected 4 days after administration of pegfilgrastim (Day 4) and 4.32 × 106 /kg of CD34-positive cells per recipient body weight were obtained. Fever of 38 ℃ or higher and left submandibular pain appeared on Day 6. Ultrasonography and contrast-enhanced computed tomography (CT) showed wall thickening of the carotid artery and the abdominal aorta. We carefully excluded the possibilities of cardiovascular and autoimmune diseases by thorough examination, and ultimately diagnosed pegfilgrastim-induced aortitis. The patient's fever resolved rapidly after treatment with prednisolone (PSL) 1 mg/kg. We began to taper PSL after eight days. Sixty-one days after starting PSL, we confirmed that abdominal aortic wall thickening had improved by contrast-enhanced CT. We continued to taper off PSL and stopped 141 days later with no relapse thereafter. This is the first case report of pegfilgrastim-induced aortitis in an allo-PBSCT donor. Careful monitoring is warranted when administering pegfilgrastim to donors even without past medical history.

Anaplastic thyroid cancer with long-term survival with lenvatinib therapy and preservation of laryngeal function after one-stage reconstruction: A case report.

Laryngotracheal reconstruction is performed to treat locally advanced thyroid carcinoma invading the larynx and/or trachea. The reconstructive technique varies. The present report describes the case of a 71-year-old female patient who underwent surgery for thyroid carcinoma involving the larynx. Reconstructive surgical techniques were employed to maintain laryngeal structure and function. An anterolateral thigh flap with free rib cartilage grafts was used to compensate for laryngeal defects. Although a temporary tracheal stoma was constructed, it closed spontaneously after decannulation. Therefore, one-stage laryngeal reconstruction was accomplished. Post-operative histopathological examination revealed focal anaplastic changes in the lesion, which mainly consisted of papillary components. Post-operative positron emission tomography/computed tomography indicated early recurrence in the left side of the neck. Therefore, lenvatinib was started as adjuvant therapy. Complete response was observed with lenvatinib therapy. The patient was alive and had good laryngeal function 26 months after the operation. One-stage laryngeal reconstruction can reduce burden and improve quality of life in patients with thyroid carcinoma involving the larynx. Lenvatinib may be useful for treating early recurrence of anaplastic thyroid carcinoma after reconstructive surgery with a free flap.

Effects of ultrasound on apoptosis induced by anti-CD20 antibody in CD20-positive B lymphoma cells.

AIM: The present study was conducted to examine the thermal and non-thermal effects of ultrasound on apoptosis induced by anti-CD20 monoclonal antibody (rituximab). MATERIALS AND METHODS: SU-DHL-4 cells, a CD20-positive cell line derived from B cell lymphomas with a BCL2 gene rearrangement, were exposed to continuous 1 MHz ultrasound for therapeutic use under an air- or CO(2)-saturated condition to control cavitation. Early apoptosis (EA) and secondary necrosis (SN) were examined by flow cytometry. Cavitation was determined by detecting the hydroxyl radicals derived from pyrolysis of water molecules using electron paramagnetic resonance-spin trapping. To assess thermal effects, cells were treated in a temperature-controlled water bath. RESULTS: There was a significant additive increase in EA and EA+SN observed in cells treated with rituximab combined with heat at 42 degrees C or non-thermal ultrasound at 0.5 W/cm(2) under an air-saturated condition, where heat or ultrasound induced some cell death. A significant synergistic increase in EA and EA+SN was observed in cells treated with rituximab and ultrasound at 2.5 W/cm(2) under CO(2)-saturated conditions, where inertial cavitations were completely suppressed. No enhancement was observed at a temperature less than 40 degrees C or ultrasound at 0.5 W/cm(2) under CO(2)-saturated conditions. CONCLUSION: These results suggest that the immuno-therapeutic application of ultrasound at relatively high-intensities combined with rituximab thus produces synergistic effects under conditions where the non-thermal and non-cavitational effects are predominant.

Adjuvant Hepatic Arterial Infusion Chemotherapy After Resection for Pancreatic Cancer Using Coaxial Catheter-Port System Compared with Conventional System.

PURPOSE: Previous reports have shown the effectiveness of adjuvant hepatic arterial infusion chemotherapy (HAIC) in pancreatic cancer. However, percutaneous catheter placement is technically difficult after pancreatic surgery. The purpose of this study was to evaluate the feasibility and outcome of HAIC using a coaxial technique compared with conventional technique for postoperative pancreatic cancer. MATERIALS AND METHODS: 93 consecutive patients who received percutaneous catheter-port system placement after pancreatectomy were enrolled. In 58 patients from March 2006 to August 2010 (Group A), a conventional technique with a 5-Fr indwelling catheter was used and in 35 patients from September 2010 to September 2012 (Group B), a coaxial technique with a 2.7-Fr coaxial catheter was used. RESULTS: The overall technical success rates were 97.1 % in Group B and 86.2 % in Group A. In cases with arterial tortuousness and stenosis, the success rate was significantly higher in Group B (91.7 vs. 53.8 %; P = 0.046). Fluoroscopic and total procedure times were significantly shorter in Group B: 14.7 versus 26.7 min (P = 0.001) and 64.8 versus 80.7 min (P = 0.0051), respectively. No differences were seen in the complication rate. The 1 year liver metastasis rates were 9.9 % using the conventional system and 9.1 % using the coaxial system (P = 0.678). The overall median survival time was 44 months. There was no difference in the survival period between two systems (P = 0.312). CONCLUSIONS: The coaxial technique is useful for catheter placement after pancreatectomy, achieving a high success rate and reducing fluoroscopic and procedure times, while maintaining the safety and efficacy for adjuvant HAIC in pancreatic cancer.

A retrospective study of patients with follicular lymphoma (FL): identification of in situ FL or FL-like B cells of uncertain significance in lymph nodes resected at the time of previous surgery for carcinomas.

BACKGROUND AND AIMS: In situ follicular lymphoma (iFL)/intrafollicular neoplasia and follicular lymphoma (FL)-like B cells of uncertain significance represent proliferation of Bcl-2/t(14;18)-positive B cells solely in the germinal centres. The condition is interpreted as an early event in the multi-step lymphomagenesis of FL. The aim of this study is to examine the issue more specifically. METHODS: We reviewed medical history of FL patients in whom thoracoabdominal surgery with lymphadenectomy had been performed for management of carcinomas. These previously resected lymph nodes as well as the current FL nodes were analysed by immunohistochemistry, fluorescent in situ hybridisation, and PCR amplification with direct sequencing. RESULTS: We studied four such FL patients from a total of 150 patients with FL; all had iFL in the previously resected lymph nodes. Clonal relation was verified and suggested in one case each. The time from lymphadenectomy to the diagnosis of FL was 23-120 months. There appeared to be a reverse correlation between the rate of Bcl-2-positive follicle proliferation and the time from surgery to diagnosis of FL. CONCLUSIONS: Although the rate for development of FL in individuals having iFL has been reported to be low from prospective studies, the present data indicate that follow-up studies for a longer period is necessary; the rate of Bcl-2-positive follicle proliferation could be a factor to predict development of FL in prospective studies. Such a retrospective study may contribute to elucidate mechanism(s) involved in lymphomagenesis of FL.

Low-intensity ultrasound enhances the anticancer activity of cetuximab in human head and neck cancer cells.

The potential clinical use of ultrasound in inducing cell apoptosis and enhancing the effects of anticancer drugs in the treatment of cancers has previously been investigated. In this study, the combined effects of low-intensity ultrasound (LIU) and cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, on cell killing and induction of apoptosis in HSC-3 and HSC-4 head and neck cancer cells, and its mechanisms were investigated. Experiments were divided into 4 groups: non-treated (CNTRL), cetuximab-treated (CETU), ultrasound-treated (UST) and the combination of cetuximab and US-treated (COMB). Cell viability was assessed by trypan blue staining assay and induction of apoptosis was detected by fluorescein isothiocyanate (FITC)-Annexin V and propidium iodide (PI) staining assay at 24 h after cetuximab and/or US treatment. To elucidate the effect of cetuximab and US on EGFR signaling and apoptosis in head and neck cancer cells after the treatments, the expression of EGFR, phospho-EGFR, and the activation of caspase-3 were evaluated with western blotting. More cell killing features were evident in the COMB group in HSC-3 and HSC-4 cells compared with the other groups. No differences in EGFR expression among the CETU, UST and COMB groups was observed, while the expression of phospho-EGFR in the CETU group was downregulated compared with that in the CNTRL group. Phospho-EGFR expression was much more downregulated in the COMB group compared with that in the other groups. In addition, the activation of caspase-3 in the UST group was upregulated compared with that in the CNTRL group. Caspase-3 activation was much more upregulated in the COMB group than that in the other groups. These data indicated that LIU was able to enhance the anticancer effect of cetuximab in HSC-3 and HSC-4 head and neck cancer cells.

Influence of living style and situation on the compliance of taking antihypertensive agents in patients with essential hypertension.

BACKGROUND: As the reason for insufficient control of blood pressure (BP), poor compliance of taking antihypertensive agents is an important issue. In Japan, no prospective study on the compliance of antihypertensive agents has been done. In this study we prospectively investigated the details of the relationship between the compliance of taking antihypertensive agents and living style and situation in hypertensive patients. METHODS: We prospectively examined 121 outpatients with essential hypertension treated with antihypertensive agents for 12 months. Using an oral interview based on the questionnaire sheet, the factors about living style and situations which worsen the compliance were assessed. Also we evaluated the relationship of BP control and season, which was compared between patients with poor compliance and those with good compliance. RESULTS: As for the background of the poor compliance, many factors related to the patients' living style and situation were clarified. On average for 12 months the levels of the compliance and BP showed a significant negative correlation and BP was significantly higher in patients with poor compliance than those with good compliance. However, in the summer season BP did not differ between patients with poor and good compliance, CONCLUSION: Many factors regarding the patients' living style and situation were related to poor compliance. The development of strategy that changes these factors is a future task for improving compliance. This study may also imply that unnecessary antihypertensive agents are prescribed in some patients with poor compliance in the summer season. Determination of the suitable prescription by which to attain optimal individual patients' compliance is important in the treatment of hypertensive patients.