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Background: KW-2478 is a novel non-ansamycin Hsp90 inhibitor with modest single-agent activity in relapsed/refractory myeloma but which shows synergistic antimyeloma activity with bortezomib (BTZ) in preclinical studies. This study determined the safety, preliminary clinical activity, and pharmacokinetics of KW-2478, an Hsp90 inhibitor, in combination with BTZ in patients with relapsed/refractory multiple myeloma (MM). Methods: Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II. Results: The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m −2 plus BTZ 1.3 mg m −2 on days 1, 4, 8, and 11 every 3 weeks. In the efficacy evaluable phase I/II population treated at the RP2D ( n =79), the objective response rate was 39.2% (95% confidence interval: 28.4–50.9%), clinical benefit rate 51.9% (40.4–63.3%), median progression-free survival 6.7 (5.9-not reached (NR)) months, and median duration of response 5.5 (4.9-NR) months. In the phase I/II safety population ( n =95), the most frequently observed treatment-related grade 3/4 adverse events were diarrhoea, fatigue, and neutropenia (each in 7.4% of patients), and nausea and thrombocytopenia (each in 5.3%). Conclusions: KW-2478 plus BTZ was well tolerated with no apparent overlapping toxicity in patients with relapsed/refractory MM. The antimyeloma activity of KW-2478 in combination with BTZ as scheduled in this trial appeared relatively modest; however, the good tolerability of the combination would support further exploration of alternate dosing schedules and combinations.

Background The coronavirus disease 2019 (COVID-19) pandemic was reported to have increased depression among university students which was associated with impairments in their campus lives. This study examined changes in depressive states among Japanese university students during the COVID-19 pandemic. Methods A secondary data analysis from a factorial randomized controlled trial involving smartphone-based cognitive-behavioral therapy was performed. Six cohorts ( N  = 1626) underwent an 8-week intervention during the spring or autumn of 2019–2021, with a 9-month follow-up. We evaluated participants’ depressive states weekly using the Patient Health Questionnaire-9 (PHQ-9) during the intervention, with monthly evaluations thereafter. The follow-up periods included Japan’s four states of emergency (SOEs) to control COVID-19. Hypothesizing that SOEs caused a sudden worsening of depressive states, Study 1 compared the cohorts’ PHQ-9 scores, and Study 2 employed time series analysis with a mixed-effects model to estimate identified changes in PHQ-9 scores. Results Although no changes in depressive states were observed in relation to the SOEs, Study 1 identified sudden increases in PHQ-9 scores at the 28-week evaluation point, which corresponded to the beginning of the new academic year for the three autumn cohorts. In contrast, the three spring cohorts did not exhibit similar changes. Study 2 showed that, for all three autumn cohorts ( n  = 522), the 0.60-point change was significant (95% CI 0.42–0.78; p  < .001) at 28 weeks; that is, when their timeline was interrupted. Conclusions While the results do not indicate any notable impact of the SOEs, they highlight the influence of the new academic year on university students’ mental health during COVID-19. Trial registration UMIN, CTR-000031307. Registered on February 14, 2018.

Because of the increased incidence of early gastric cancer in Japan, minimally invasive laparoscopic approaches to gastric malignancies have been under development since 1991. Laparoscopic local resection of the stomach, i.e., laparoscopic wedge resection (LWR) and intragastric mucosal resection (IGMR), is used to treat mucosal cancer without lymph node metastasis. Laparoscopy-assisted distal gastrectomy (LADG) is used to treat early gastric cancer with risk factors for regional lymph node metastasis. A survey conducted by the Japan Society for Endoscopic Surgery showed that 1428 LWRs, 260 IGMRs, and 2600 LADGs were performed between 1991 and 2001 in departments of endoscopic surgery in Japan. Laparoscopic gastrectomy for gastric cancer is still under development in Japan. According to short-term results reported by a small group of surgeons, laparoscopic approaches to gastric cancer provide for minimal invasion, early recovery, and decreased morbidity and mortality. If the advantages can be confirmed in one or more multicenter randomized control studies of the long-term outcome of patients undergoing laparoscopic gastrectomy for gastric cancer, the procedure should come into wide acceptance and use.

The three-dimensional dynamics and morphology of the human embryonic brain have not been previously analyzed using modern imaging techniques. The morphogenesis of the cerebral vesicles and ventricles was analyzed using images derived from human embryo specimens from the Kyoto Collection, which were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. A total of 101 embryos between Carnegie stages (CS) 13 and 23, without apparent morphological damage or torsion in the brain ventricles and axes, were studied. To estimate the uneven development of the cerebral vesicles, the volumes of the whole embryo and brain, prosencephalon, mesencephalon, and rhombencephalon with their respective ventricles were measured using image analyzing Amira™ software. The brain volume, excluding the ventricles (brain tissue), was 1.15±0.43mm3 (mean±SD) at CS13 and increased exponentially to 189.10±36.91mm3 at CS23, a 164.4-fold increase, which is consistent with the observed morphological changes. The mean volume of the prosencephalon was 0.26±0.15mm3 at CS13. The volume increased exponentially until CS23, when it reached 110.99±27.58mm3. The mean volumes of the mesencephalon and rhombencephalon were 0.20±0.07mm3 and 0.69±0.23mm3 at CS13, respectively; the volumes reached 21.86±3.30mm3 and 56.45±7.64mm3 at CS23, respectively. The ratio of the cerebellum to the rhombencephalon was approximately 7.2% at CS20, and increased to 12.8% at CS23. The ratio of the volume of the cerebral vesicles to that of the whole embryo remained nearly constant between CS15 and CS23 (11.6–15.5%). The non-uniform thickness of the brain tissue during development, which may indicate the differentiation of the brain, was visualized with surface color mapping by thickness. At CS23, the basal regions of the prosencephalon and rhombencephalon were thicker than the corresponding dorsal regions. The brain was further studied by the serial digital subtraction of layers of tissue from both the external and internal surfaces to visualize the core region (COR) of the thickening brain tissue. The COR, associated with the development of nuclei, became apparent after CS16; this was particularly visible in the prosencephalon. The anatomical positions of the COR were mostly consistent with the formation of the basal ganglia, thalamus, and pyramidal tract. This was confirmed through comparisons with serial histological sections of the human embryonic brain. The approach used in this study may be suitable as a convenient alternative method for estimating the development and differentiation of the neural ganglia and tracts. These findings contribute to a better understanding of brain and cerebral ventricle development. [Display omitted] •Three-dimensional morphogenesis of the human embryonic brain was presented from MRI.•The volume of three brain vesicles and ventricles were measured at 101 embryos.•The brain volume exponentially increased 164.4-fold from Carnegie stage 13 to 23.•The volume ratio of the brain to whole embryo remained nearly constant.•The non-uniform thickness of the brain tissue during development was 3D visualized.

The sentinel node (SN) concept has attracted considerable attention recently for the treatment of patients with early gastric cancer (EGC). This study evaluated the feasibility of laparoscopic SN navigation achieved by means of an infrared ray electronic endoscopy (IREE) system with indocyanine green (ICG) injection in patients with EGC. Laparoscopic SN navigation was performed for 16 patients with preoperatively diagnosed EGC. After identification of SNs, routine laparoscopically assisted distal gastrectomy with lymphadenectomy was performed. Lymph nodes were examined histologically for metastasis by hematoxylin and eosin staining on one section of each node. One or more SNs and lymphatic basins were detected in all 16 patients. The average number of SNs detected was 2.9. Lymph node metastasis was found in 2 of the 16 patients (13%). In one of these two patients, lymph node metastasis was found in SNs. In the other patient, metastasis was found in a non-SN rather than a SN, but in the same lymphatic basin. The accuracy of this detection method was 94%, and there was one false-negative case. No adverse events occurred after injection of ICG. Laparoscopic SN navigation by means of IREE combined with ICG injection is feasible for patients undergoing laparoscopic surgery for EGC.

Laparoscopy-assisted distal gastrectomy (LAG) is gaining acceptance for treating early gastric cancer. However, the long-term quality of life after LAG for gastric cancer is unknown. This study compared the long-term quality of life after LAG versus open distal gastrectomy (ODG) for early gastric cancer. This study included 53 patients who underwent LAG and 37 patients who underwent ODG for treatment of early gastric cancer. Quality of life was evaluated on the basis of a 22-item questionnaire that addressed food tolerance and mental and physical conditions, scored on a scale of 1-3. The mean follow-up periods after LAG and ODG were 99.3 and 97.0 months, respectively. Although the majority of patients who had undergone LAG were consuming a normal diet and had weight loss of less than 5 kg, all 22 items and the total score of the LAG group were comparable to those of the ODG group. However, the incidence of postoperative intestinal obstruction was significantly lower in the LAG group than in the ODG group (1% vs. 13%, p < 0.05). LAG is equivalent to ODG with respect to long-term quality of life and is associated with a reduced incidence of postoperative intestinal obstruction.

Intravenous iron administration induces oxidation of serum albumin in hemodialysis patients. Intravenous iron administration (IVIR) is effective for correcting anemia in hemodialysis (HD) patients. However, it may also enhance the generation of hydroxyl radicals. Recently, plasma proteins have been demonstrated to be extremely susceptible to oxidative stress. Therefore, we investigated the effect of IVIR on the oxidative status of albumin, a major plasma protein, in HD patients. Eleven hemodialysis (HD) patients were treated with 40 mg of saccharated ferric oxide intravenously after every dialysis session for four weeks, and 11 age-/gender-matched HD patients were treated with vehicle. We performed high performance liquid chromatography (HPLC) analysis of serum albumin and determined the levels of reduced and oxidized albumin. Carbonyl formation of plasma proteins were also measured using an anti-2,4 dinitrophenylhydrazine antibody in patients with or without IVIR. IVIR resulted in an increase in both disulfide form (f(HNA-1)) and oxidized form (f(HNA-2)) of albumin in HD patients (36.0 ± 6.03 vs. 41.7 ± 6.27; 5.46 ± 1.50 vs. 8.7 ± 2.22, respectively, P < 0.05). The findings here also show that IVIR substantially increased plasma protein carbonyl content by oxidizing albumin. In addition, we found a strong correlationbetween plasma carbonyl content and the levels of oxidized albumin (f(HNA-1) and f(HNA-2)) in HD patients (R = 0.674 and R = 0.724, respectively, P < 0.01). The results of this study indicate that the HPLC analysis of serum albumin represents a potentially useful method for the quantitative and qualitative evaluation of oxidative stress in HD patients, and strongly suggest the possibility that oxidative stress, generated by IVIR, enhances the oxidation of albumin in those patients.

An obturator hernia occurs through the pelvic obturator canal, a rigid ring made up of the underside of the superior pubic ramus and the obturator fascia. Obturator hernias have been associated with a high mortality due to the difficulty in diagnosis and the population in which it occurs. We examined four patients diagnosed with incarcerated obturator hernia, and showed that the strangulated intestine was not necrotic. We flexed the diseased leg calmly and repeatedly with slight rotation toward the outside and slight adduction toward the inside at supine position. The pain vanished suddenly during this maneuver. After this maneuver, the patients were able to undergo elective surgery after a certain interval. We discuss the possible use of this maneuver to release an incarcerated obturator hernia.

Background The efficacy and safety outcomes of laparoscopy-assisted distal gastrectomy (LADG) with D2 lymph node dissection for locally advanced gastric cancer remain unclear. Therefore, we conducted a randomized, controlled phase II trial to confirm the feasibility of LADG in terms of technical safety, and short-term surgical outcomes were investigated. Methods Eligibility criteria included pre-operatively diagnosed advanced gastric cancer that could be treated by distal gastrectomy with D2 lymph node dissection; MP, SS, and SE without involvement of other organs; and N0–2 and M0. Patients aged 20–80 years were pre-operatively randomized. Results In total, 180 patients were registered and randomized to the open (89 patients) and laparoscopic arms (91 patients). Among 91 patients in the laparoscopic arm, 86 underwent laparoscopic gastrectomy according to the study protocol. Regarding the primary endpoint of the phase II trial, the proportion of patients with either anastomotic leakage or pancreatic fistula was 4.7 % (4/86). The grade 3 or higher morbidity rate, including systemic and local complications, was 5.8 %. Conversion to open surgery was required for 1 patient (1.2 %), without any intra-operative complication. The post-operative mortality rate was 0, and no patient required readmission for surgical complications within 6 months after initial discharge. Conclusions The technical safety of LADG with D2 lymph node dissection for locally advanced gastric cancer was demonstrated. A phase III trial to confirm the non-inferiority of this procedure to open gastrectomy in terms of long-term outcomes is ongoing. Registered Number: UMIN 000003420 ( www.umin.ac.jp/ctr/ ).

Laparoscopic surgery provides for a less invasive procedure than open surgery in patients with gastric cancer, but the immune responses after laparoscopic surgery for early gastric cancer remain unknown. Peripheral blood mononuclear cells from 20 patients with early gastric cancer who underwent laparoscopy-assisted distal gastrectomy (LADG) or open distal gastrectomy (ODG) were obtained; the cell surface molecules and intracellular cytokines (IFN-gamma and IL-4) were measured by flow cytometry. The populations of T lymphocytes after LADG, including CD3-, 4-, 8-, 57-, and HLA-DR-positive lymphocytes, showed patterns similar to those after ODG. The production of IFN-gamma as Th1 cell function decreased significantly on the third postoperative day after ODG but increased after LADG. The production of IL-4, representing Th2 cell function, increased postoperatively after ODG but not after LADG. When compared with ODG, LADG contributes to the preservation of postsurgical Th1 cell-mediated immune function.