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.     

Associations between early tumor shrinkage and depth of response and clinical outcomes in patients treated with 1st-line chemotherapy for advanced gastric cancer

Background

Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy.

Methods

We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (±4) weeks for ETS and at the smallest observed volume for DpR.

Results

Eligible patients were sorted into HER2⁺ (n = 100) and HER2^? (n = 186) groups. Median follow-up was 14.8 months. The overall response rate and disease control rates were 64 and 87% in the HER2⁺ group and 53.2 and 86.0% in the HER2^? group. Respective median PFS and OS were HER2⁺: 7.9 and 20.8 months and HER2^?: 6.6 and 13.8 months. The respective ETS rate and median DpR were HER2⁺: 70 and 44% and HER2^?: 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2⁺ group (OS: P < 0.0001; PFS: P < 0.0001). In multivariate analysis, ETS was an independent predictor for OS in the HER2⁺ group and for PFS in both groups.

Conclusion

These results indicate that ETS may be an early-on treatment predictor of the efficacy of HER2⁺ advanced gastric cancer treated with first-line chemotherapy that includes trastuzumab.

     

Relationship of p21 (waf1/cip1) and differentiation in chondrosarcoma cells

The histological grade of chondrosarcoma correlates well with their clinical behavior and with the patient's survival duration. We have previously demonstrated that p21 was expressed in the hypertrophic chondrocytes of the growth plate. To assess the relationship of p21 (waf1/cip1) to cell differentiation in chondrosarcoma, we examined the p21 expression in 14 cases of chondrosarcoma immunohistochemically and the induction of p21 by insulin-like growth factor-I (IGF-I) during cell differentiation in SW1353 chondrosarcoma cells. p21 immunoreactivity was seen in well-differentiated chondrosarcoma cells and was mutually exclusive with MIB1 reactivity in grade-1 chondrosarcoma. In vitro, the proteoglycan synthesis of SW1353 cells was increased by IGF-I in a dose-dependent manner. However, cell proliferation was not markedly stimulated. Overexpressions of p21 mRNA and p21 protein in SW1353 cells were induced by IGF-I 100 ng/ml. Our results suggested that the p21 expression was directly related to tumor differentiation and that the p21 expression was an important mediator for IGF-I in chondrosarcoma cells.     

Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant

Background

Oncogenic mutations in BRAF genes are found in approximately 5–10% of colorectal cancers. The majority of BRAF mutations are located within exons 11–15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation.

Methods

HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis.

Results

The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance.

Conclusions

We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.

     

Interaction between low dose-rate irradiation, mild hyperthermia and low-dose caffeine in a human lung cancer cell line.

PURPOSE: To investigate cell killing by means of low dose-rate irradiation (LDRI) combined with concurrent mild hyperthermia and to determine the effect of low-dose caffeine on this combination treatment. MATERIALS AND METHODS: Human lung adenocarcinoma cells, LK87, were treated with LDRI (50 cGy/h) in combination with mild hyperthermia at 41 degrees C and low-dose caffeine (1 mM). Cell survival was estimated by clonogenic assay. Flow-cytometry was performed with PI staining using FACScan. Heat-shock protein (HSP72/73) was measured by the Western blotting method. All treatments were simultaneously performed for up to 48 h (24 Gy). RESULTS: LDRI cytotoxicities were enhanced by hyperthermia at 41 degrees C. D0 calculated from the dose-response curve for LDRI combined with 41 degrees C was 3.46 Gy whereas it was 6.55 Gy for LDRI alone. The survival curve for LDRI +41 degrees C demonstrated no chronic thermotolerance up to 48 h. For LDRI + simultaneous low-dose caffeine, cell killing was also enhanced, where D0 was 3.38 Gy at 37 degrees C. Radiosensitization caused by caffeine was enhanced by combination with simultaneous mild hyperthermia at 41 degrees C, where D0=1.78 Gy. Cell cycle analysis demonstrated remarkable G2 and mild G1 arrest for LDRI alone, but only G1 arrest was observed for LDRI combined with 41 degrees C and for LDRI combined with caffeine. Strong and early G1 arrest was observed in the treatment with LDRI + caffeine at 41 degrees C. The amount of HSP72/73 in the combination of LDRI with caffeine at 41 degrees C was less than that at 41 degrees C alone. CONCLUSION: LDRI cytotoxicity was enhanced by non-lethal hyperthermia. Low dose caffeine produced further cell killing in the combination of LDRI with mild hyperthermia.     

Ten‐year follow‐up study of Japanese patients with obsessive–compulsive disorder

Aim

Obsessive–compulsive disorder (OCD) is a well‐known chronic illness. This study retrospectively investigated 10‐year outcomes and associated clinical factors in Japanese OCD patients. We focused on the impact of several sociocultural factors, including medical expenses and insurance systems specific to each country, on the differences or biases in follow‐up procedures of OCD.

Methods

Seventy‐nine patients diagnosed with OCD who received a standardized combination of treatments for 10 continuous years were divided into three groups according to their improvement rates on the Yale–Brown Obsessive–Compulsive Scale after 10 years of treatment.

Results

A survival analysis revealed that the rate of patients achieving full remission increased every year. Following 10 years of treatment, 56% of OCD patients experienced ‘full remission’ for at least 1 year. Consequently, 48% exhibited full remission, and 37% exhibited partial remission at the end‐point of this study. We identified several factors that were predictive of poorer outcomes, including lower Global Assessment of Functioning Scale scores and the presence of hoarding symptoms or involvement behaviors. In addition, improvement rates after 1 year significantly predicted better 10‐year outcomes.

Conclusion

Our findings highlight the transcultural nature of long‐term outcomes of OCD treatment, which appear to be independent of sociocultural differences.

     

Bortezomib induces apoptosis in T lymphoma cells and natural killer lymphoma cells independent of Epstein-Barr virus infection

Epstein-Barr virus (EBV), which infects not only B cells, but also T cells and natural killer (NK) cells, is associated with multiple lymphoid malignancies. Recently, the proteasome inhibitor bortezomib was reported to induce apoptosis of EBV-transformed B cells. We evaluated the killing effect of this proteasome inhibitor on EBV-associated T lymphoma cells and NK lymphoma cells. First, we found that bortezomib treatment decreased the viability of multiple T and NK cell lines. No significant difference was observed between EBV-positive and EBV-negative cell lines. The decreased viability in response to bortezomib treatment was abrogated by a pan-caspase inhibitor. The induction of apoptosis was confirmed by flow cytometric assessment of annexin V staining. Additionally, cleavage of caspases and polyadenosine diphosphate-ribose polymerase, increased expression of phosphorylated IκB, and decreased expression of inhibitor of apoptotic proteins were detected by immunoblotting in bortezomib-treated cell lines. We found that bortezomib induced lytic infection in EBV-positive T cell lines, although the existence of EBV did not modulate the killing effect of bortezomib. Finally, we administered bortezomib to peripheral blood mononuclear cells from five patients with EBV-associated lymphoproliferative diseases. Bortezomib had a greater killing effect on EBV-infected cells. These results indicate that bortezomib killed T or NK lymphoma cells by inducing apoptosis, regardless of the presence or absence of EBV.     

Inheritance of an autosomal recessive disorder, Gitelman's syndrome, across two generations in one family

Gitelman's syndrome (GS) is an autosomal recessive disorder; it is rarely inherited over several generations. A 16-year-old boy showed hypokalemia and hypocalciuria. Clinically, he was diagnosed as GS because of diuretic responsiveness to furosemide but not thiazide. Genetic testing disclosed he was a compound heterozygote (T180K/V677M) for the SLC12A3 gene. Unexpectedly, the patient's father also showed hypokalemia and hypocalciuria. The genetic analysis showed he had an L849H mutation in addition to T180K. The present pedigree showed an extremely rare case. Diuretic tests are useful diagnostic methods, and genetic testing is necessary for precise evaluation of complicated cases as in this family.