R‐High‐CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY

Although induction immunochemotherapy including high‐dose cytarabine and rituximab followed by high‐dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R‐High‐CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20‐65 years. Patients received 1 cycle of R‐High‐CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R‐High‐CHOP/CHASER. Primary endpoint was 2‐year progression‐free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38‐65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty‐five patients completed ASCT. Two‐year PFS was 77% (80% CI 68‐84), which met the primary endpoint. Five‐year PFS and overall survival were 52% (95% CI 34‐68%) and 71% (95% CI 51‐84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R‐High‐CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.     

WT1 peptide‐based immunotherapy for advanced thymic epithelial malignancies

Thymic epithelial tumors are rare malignancies, and no optimal therapeutic regimen has been defined for patients with advanced disease. Patients with advanced thymic epithelial tumors, which were resistant or intolerable to prior therapies, were eligible for this study. Patients received 9 mer‐WT1‐derived peptide emulsified with Montanide ISA51 adjuvant via intradermal administration once a week as a monotherapy. After the 3‐month‐protocol treatment, the treatment was continued mostly at intervals of 2–4 weeks until disease progression or intolerable adverse events occurred. Of the 15 patients enrolled, 11 had thymic carcinoma (TC) and 4 had invasive thymoma (IT). Median period from diagnosis to the start of treatment was 13.3 and 65.5 months for TC and IT, respectively. No patients achieved a complete or partial response. Of the 8 evaluable TC patients, 6 (75.0%) had stable disease (SD) and 2 had progressive disease (PD). Of the 4 evaluable IT patients, 3 (75.0%) had SD and 1 (25.0%) had PD. Median period of monotherapy treatment was 133 and 683 days in TC and IT patients, respectively. No severe adverse events occurred during the 3‐month‐protocol treatment. As adverse events in long responders, thymoma‐related autoimmune complications, pure red cell aplasia and myasthenia gravis occurred in two IT patients. Cerebellar hemorrhage developed in a TC patient complicated with Von Willebrand disease. Induction of WT1‐specific immune responses was observed in the majority of the patients. WT1 peptide vaccine immunotherapy may have antitumor potential against thymic malignancies.     

Comparison of human papillomavirus genotyping and cytology triage,COMPACT Study: Design,methods and baseline results in 14 642 women

Although cytology‐based screening programs have significantly reduced mortality and morbidity from cervical cancer, the global consensus is that primary human papillomavirus (HPV) testing for cervical screening increases detection of high‐grade cervical intraepithelial neoplasia (CIN) and invasive cancer. However, the optimal triage strategy for HPV‐positive women to avoid over‐referral to colposcopy may be setting specific. As Japan requires data that have been generated domestically to modify screening guidelines, we conducted a 3‐year prospective study, COMparison of HPV genotyping And Cytology Triage (COMPACT), to evaluate the potential role of HPV16/18 partial genotyping and cytology for primary HPV screening. In total, 14 642 women aged 20 to 69 years undergoing routine screening at 3 centers in Hokkaido were enrolled. Conventional cytology and HPV testing were carried out. Women with abnormal cytology or HPV16/18 positivity underwent colposcopy. Those with 12 other high‐risk (hr) HPV types underwent repeat cytology after 6 months. Primary study endpoints were detection of high‐grade cervical disease defined as CIN2/CIN3 or greater as determined by consensus pathology. Prevalence of cytological abnormalities was 2.4%. hrHPV, HPV 16, and HPV 18 were detected in 4.6%, 0.9%, and 0.3% of women, respectively. HPV16/18 were detected in all (8/8) invasive cervical cancers and in all (2/2) adenocarcinomas in situ. Both cytological abnormalities and hrHPV positivity declined with increasing age. This is the first Japanese study to investigate the role of partial genotyping and cytology in an HPV‐based screening program. Results should help policy‐makers develop guidelines for future cervical screening programs and management of cervical abnormalities based on HPV genotype.     

Detection of Apoptosis and Expression of Apoptosis-associated Proteins as Early Predictors of Prognosis after Irradiation Therapy in Stage IIIb Uterine Cervical Cancer

We investigated the proportion of apoptotic cells and the expression of apoptosis-associated proteins after the delivery of the first week of irradiation for stage IIIb uterine cervical cancer. Thirty patients with stage IIIb squamous cell carcinoma of the uterine cervix who received only irradiation therapy were registered in this study. Specimens were obtained before irradiation therapy and at the end of the first week of irradiation. The apoptotic index (AI) of each tissue specimen was calculated by counting the apoptotic cells and expressed as a percentage. Immunohistochemical evaluation for apoptosis-related proteins, p53, Bcl-2, Bax, caspase-1 and caspase-3 was also performed. The AI was 0.8±0.9% (mean±SD) before irradiation and 1.7±1.3% at the end of the first week of irradiation. We observed that the patients who survived more than 5 years had AI levels of 2.1±1.3% at the end of their first week of therapy. This rate was significantly higher than the rate of 1.1±0.8% ( P =0.02) of the patients who died within 5 years. When the cut-off value of the AI was set at 1.7%, the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of patients' prognosis after irradiation therapy were 73.4%, 72.4%, 82.4%, and 61.5%, respectively. In 17 of the AI-positive cases, expressions of Bax ( P =0.006), caspase-1 ( P =0.045), and caspase-3 ( P =0.013) at the end of the first week were significantly higher than before irradiation. The proportion of apoptotic cells and the expression of apoptosis-associated proteins, Bax, caspase-1, and caspase-3, at the end of the first week of irradiation could be useful predictors of the prognosis in stage IIIb squamous cell carcinoma of the uterine cervix treated by irradiation therapy.     

Reduction of Postincisional Allodynia by Subcutaneous Bupivacaine: Findings with a New Model in the Hairy Skin of the Rat

Background: An incision of hairy skin of the rat's back provides a new model for postincisional pain to determine the importance of cutaneous anesthesia.

Methods: Male Sprague-Dawley rats were anesthetized with sevoflurane and given a 0.6-ml subcutaneous injection of bupi-vacaine (0.25%) under the incision site or the medial lumbar dorsum or at the nuchal midline, 30 min before a 1.0-cm skin incision. Mechanical stimuli (von Frey hairs, 18-250 mN) were applied to measure nociception, indicated by twitching of local subcutaneous muscles, the cutaneus trunci muscle reflex. A graded response score, averaging the twitches weighted by their vigor, or a population response score, measuring the fraction of rats that showed any response, was assessed for 3 days before and over 7 days after incision. von Frey hairs were applied 0.5 cm from the incision to test primary hyperalgesia and 2.0 cm contralateral to the incision for secondary hyperalgesia.

Results: Incision induced responses to stimuli that had no effect on intact skin (allodynia) and also enhanced responses to forces that normally gave less than the full reflex (hyperalgesia). Hyperalgesia was present 30 min after surgery, peaked at 3-6 h, and persisted through the week; allodynia had a similar onset but was briefer. Both changes were transiently reversed by subcutaneous morphine (2.5 mg/kg intraperitoneal). Subcutaneous bupivacaine (0.25%), injected preoperatively at the incision site and anesthetizing skin for 2-3 h, suppressed primary allodynia for 1 week but had no effect on hyperalgesia. Secondary allodynia was obliterated, and secondary hyperalgesia attenuated by this treatment. Bupivacaine injected subcutaneously at the nuchal midline before surgery was also effective in abbreviating primary and secondary allodynia, with no signs of sedation, ataxia, or preconvulsive behavior.