Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma

A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal‐naïve patients with relapsed or refractory multiple myeloma (RRMM). Patients ≥20 and <80 years old with a documented diagnosis of symptomatic multiple myeloma (MM) who received one or more prior therapies were randomized to receive BD (Bor 1.3 mg/m²) or TD (Thal 200 mg/d). In both arms, 8 cycles of induction (3‐week cycle) were followed by maintenance phase (5‐week cycle) until disease progression, unacceptable toxicity, or patient refusal. The primary end‐point was 1‐year progression‐free survival (PFS). Forty‐four patients were randomized and assigned to receive BD and TD (n = 22, each group). At a median follow‐up of 34.3 months, the 1‐year PFS in the BD and TD arms were 45.5% (95% confidence interval (CI), 24.4%‐64.3%) and 31.8% (95% CI, 14.2%‐51.1%), respectively, and the overall response rates were 77.3% and 40.9%, respectively. The 3‐year overall survival (OS) was 70.0% (95% CI, 44.9%‐85.4%) in the BD, and 48.8% (95% CI, 25.1%‐69.0%) in the TD arm. Among grade 3/4 adverse events, thrombocytopenia (54.5% vs 0.0%) and sensory peripheral neuropathy (22.7% vs 9.1%) were more frequent in BD when compared with the TD arm. Patients treated with BD had better outcomes than those treated with TD with regard to 1‐year PFS and 3‐year OS. Thus, BD was prioritized over TD for further investigations in Bor and Thal‐naïve RRMM patients. (Clinical trial registration no. UMIN000003135.)     

Educational Approaches That Enhance Online Clinical Clerkship during the COVID-19 Pandemic

Objective This cross-sectional national study determined which educational approaches are associated with the effectiveness of online clerkship for medical students. Method A survey was conducted for medical students at 78 medical schools in Japan from May 29 to June 14, 2020. It comprised the following aspects: (a) participants'' profiles, (b) number of opportunities to learn from each educational approach (lecture, medical quiz, assignment, oral presentation, observation of a physician''s practice, clinical skill practice, participation in interprofessional meetings, and interactive discussions with physicians) in online clerkship, (c) frequency of technical problems, and (d) educational outcome measurement (satisfaction, motivation, knowledge acquisition, skill acquisition, change in self-study time, and understanding of the importance of medical care team). Results Of the 2,640 respondents, 2,594 (98.3%) agreed to cooperate. Ultimately, 1,711 matched our inclusion criteria. All educational approaches but assignments were positively associated with satisfaction and motivation. All educational approaches excluding assignment submission and interprofessional meeting were positively associated with knowledge acquisition. Observation, practice, and interprofessional meeting were positively associated with skill acquisition. Only assignment submission was positively associated with the change in self-study time. Educational approaches excluding medical quizzes were positively associated with understanding the importance of the medical care team. Technical problems were negatively associated with motivation, knowledge acquisition, and skill acquisition. Conclusions Educators should implement various educational approaches, especially observation and practice, even in online clinical clerkship. They also need to minimize the technical problems associated with the Internet, as they reduce the effectiveness of online clerkship.     

Grafting of choroid plexus ependymal cells promotes the growth of regenerating axons in the dorsal funiculus of rat spinal cord: a preliminary report

Nerve regeneration in the central nervous system has been studied by grafting various tissues and cells. In the present study, we demonstrated that choroid plexus ependymal cells can promote nerve regeneration when grafted into spinal cord lesions. The choroid plexus was excised from the fourth ventricle of adult rats (Wistar), minced into small fragments, and grafted into the dorsal funiculus at the C2 level in adult rat spinal cord from the same strain. Electron microscopy and fluorescence histochemistry showed that ependymal cells of the grafted choroid plexus intimately interacted with growing axons, serving to support the massive growth of regenerating axons. CGRP-positive fibers closely interacted with grafted ependymal cells. HRP injection at the sciatic nerve showed that numerous HRP-labeled regenerating fibers from the fasciculus gracilis extended into the graft 7 days after grafting. This regenerating axons from the fasciculus gracilis was maintained for at least 10 months, with some axons elongating rostrally into the dorsal funiculus. Evoked potentials of long duration were recorded at a level ca. 5 mm rostral to the lesion in the rats 8 to 10 months after grafting. These findings indicate that choroid plexus ependymal cells have the ability to facilitate axonal growth in vivo, suggesting that they may be a promising candidate as graft for the promotion of nerve regeneration in the spinal cord.     

Study of p53 in Elderly Patients with Myelodysplastic Syndromes by Immunohistochemistry and DNA Analysis

We analyzed the tumor suppressor gene product, p53, in elderly patients with myelodysplastic syndromes (MDS) and in overt leukemia patients after transformation from MDS using immunohistochemical techniques. We examined 52 MDS patients (mean age 79 years, range 68 to 96) from the time of initial diagnosis to death or development of overt leukemia. p53 protein was detected by immunohistochemistry (IHC) in 8/52 patients (15%) at initial diagnosis: 1/26 with refractory anemia (RA), 0/4 with RA with ringed sideroblasts, 3/11 with RA with an excess of blasts (RAEB), 3/8 with RAEB in transformation, and 1/3 with chronic myelomonocytic leukemia. We also analyzed gene mutations in patients with positive IHC. p53 mutations were detected in 3/8 (38%) patients. IHC-positive patients had a significantly higher incidence of leukemic transformation and the presence of a complex karyotype with monosomy 17. IHC-positive cells included blasts as well as mature myeloid cells, erythroblasts, and megakaryocytes. Scrutiny of our data in combination with previous data revealed that patients with positive IHC in multilineage cells were older than those in whom positivity was noted mostly in myeloblasts. This suggests that p53 IHC positivity with a multilineage pattern may be a characteristic of MDS in older patients.     

Complete cure of established murine hepatocellular carcinoma is achievable by repeated injections of retroviruses carrying the herpes simplex virus thymidine kinase gene.

Although xenotransplantation of retrovirus-producing cells into a tumor has been shown to be effective for the treatment of cancer, injections of recombinant retroviruses are much more feasible for clinical applications. We established a clone producing retroviruses carrying the herpes simplex virus thymidine kinase (HSVtk) gene with titers of up to 4 x 10(7) colony-forming units/ml, and examined the effectiveness of in vivo gene therapy against cancer. Syngeneic mice were inoculated subcutaneously with murine hepatocellular carcinoma (HCC) cells, BNL1ME A.7R.1, and the treatment was initiated after tumors were established. When mice were given an intratumoral injection of HSVtk-carrying retroviruses or their producing cells followed by ganciclovir (GCV) treatment, significantly prolonged survival periods were observed. When mice were treated with repeated intratumoral injections of HSVtk-carrying retrovirus-producing cells, significant antitumor responses and some cures were induced by GCV treatment. Furthermore, repeated intratumoral injections of HSVtk-carrying retroviruses and GCV treatment resulted in complete regression of established HCC tumors in all animals used in the experiment. Mice that completely eradicated tumors exhibited protective immunity against wild-type HCC tumors. These results suggest that repeated injections of HSVtk-carrying retroviruses followed by GCV treatment is a potent modality for the treatment of solid tumors.     

89Sr bremsstrahlung single photon emission computed tomography using a gamma camera for bone metastases

Objective

Strontium-89 chloride (⁸⁹Sr) bremsstrahlung single photon emission computed tomography (SPECT) imaging was evaluated for detecting more detailed whole body ⁸⁹Sr distribution.

Methods

⁸⁹Sr bremsstrahlung whole body planar and merged SPECT images were acquired using two-detector SPECT system. Energy window A (100 keV ± 50 %) for planar imaging and energy window A plus adjacent energy window B (300 keV ± 50 %) for SPECT imaging were set on the continuous spectrum. Thirteen patients with multiple bone metastases were evaluated. Bone metastases can be detected with ^99mTc-HMDP whole body planar and merged SPECT images and compared with ⁸⁹Sr bremsstrahlung whole body planar and merged SPECT images. Based on the location of metastatic lesions seen as hot spots on ^99mTc-HMDP images as a reference, the hot spots on ⁸⁹Sr bremsstrahlung images were divided into the same bone parts as ^99mTc-HMDP images (a total of 35 parts in the whole body), and the number of hot spots were counted. We also evaluated the incidence of extra-osseous uptakes in the intestine on ⁸⁹Sr bremsstrahlung whole body planar images.

Results

A total of 195 bone metastatic lesions were detected in both ^99mTc-HMDP whole body planar and merged SPECT images. Detection of hot spot lesions in ⁸⁹Sr merged SPECT images (127 of 195; 66 %) was more frequent than in ⁸⁹Sr whole body planar images (108 of 195; 56 %), based on metastatic bone lesions in ^99mTc-HMDP whole body planar and merged SPECT images. A large intestinal ⁸⁹Sr accumulation was detected in 5 of the 13 patients (38 %).

Conclusions

⁸⁹Sr bremsstrahlung-merged SPECT imaging could be more useful for detailed detection of whole body ⁸⁹Sr distribution than planar imaging. Intestinal ⁸⁹Sr accumulation due to ⁸⁹Sr physiologic excretion was detected in feces for 4 days after tracer injection.     

An elderly autopsy case of chronic myelomonocytic leukemia with infiltration of a giant liver cyst and multiple organs

A 78-year-old man was referred to his local hospital at the beginning of July 2006 with low grade fever and cough, and was admitted on August 22 with pneumonia. Hematology tests on admission revealed leukocytosis, anemia, and thrombocytopenia, so he was subsequently transferred to our hospital on August 24. A diagnosis of chronic myelomonocytic leukemia (CMML) was made from the hematological findings and he was given hydroxycarbamide from September 7. Seventeen days later, abdominal CT revealed hemorrhage into a giant liver cyst, as well as both intraabdominal and intrathoracic hemorrhage. He died of hemorrhagic shock on September 25. Autopsy showed extensive infiltration of myelomonocytic leukemic cells into the walls of the liver cyst, as well as the pleura and multiple other organs. In summary, we report an elderly autopsy case of CMML with infiltration of a giant liver cyst and multiple organs.