The Incidence and Its Associated Factors Relevant to Brain Radionecrosis That Requires Intervention Following Single or Fractionated Stereotactic Radiosurgery Using Vero4DRT for Brain Metastases.

PURPOSE: Several factors, including the surrounding brain volume receiving specific doses, have hitherto been reported to correlate with brain radionecrosis (BR) after single or fractionated stereotactic radiosurgery (sSRS or fSRS) for brain metastases (BMs); however, those, especially for fSRS, have not yet been fully elucidated. Furthermore, the clinical outcome data of patients with BM treated with SRS using Vero4DRT are extremely limited. Therefore, this study aimed to demonstrate the incidence of BR requiring intervention (BRRI) and its highly correlated factors. MATERIALS AND METHODS: Patients with BMs treated with sSRS or fSRS using Vero4DRT at Toyohashi Municipal Hospital between July 2017 and June 2021 were retrospectively reviewed, of whom patients were available for at least 20 weeks of magnetic resonance imaging follow-up from SRS were included, and analyzed. The prescribed dose fractionation schemes to the planning target volume (PTV) boundary included 24 Gy (sSRS), 35 Gy (5 fractions [fr]), 42 Gy (10 fr), and 30 Gy (3 fr), according to the tumor volume and location. The volume of the surrounding normal brain receiving 84 Gy (V84 Gy, biologically effective dose [BED2] based on a linear-quadratic model with an alpha/beta ratio of 2, single-dose equivalent [SDE] to 12 Gy), V112 Gy (BED2, SDE to 14 Gy) for all lesions, and all irradiated volume, including gross tumor volume (GTV) receiving 81.6 Gy (81.6 Gy vol., BED2) for fSRS were calculated, for which cerebrospinal fluid and bone volumes were cautiously excluded. The diagnosis of tumor progression or BR dominance was based on serial T1/T2 matching. RESULTS: Sixty patients with 120 lesions (65 treated with sSRS and 55 treated with fSRS) were included in the final analysis, with a median follow-up period of 65 weeks. The local control rate at one year was 87.5%. The cumulative incidence of BRRI within two years was 11.5%. The risk of symptomatic BR was significantly higher for V84 Gy >10 cc (p <0.001) and V112 Gy >5 cc (p = 0.021). In the fSRS group, the cumulative incidence of Grade 3 BR and those requiring resection was significantly higher for 81.6 Gy vol. >14 cc (p = 0.003 and p = 0.004, respectively). The coexistence of viable tumor tissue and BR could not be ruled out for enlarging lesions after the nadir response, especially for fSRS, due to a lower BED10 to GTV margin (<80 Gy, BED10). CONCLUSIONS: Stereotactic irradiation with Vero4DRT provided efficacy and safety comparable to previous linear accelerator series, and most of the dose-volume thresholds for BRRI presented in this study were notably lower than those reported in previous studies. This study suggests that the indication of single and up to 5 frSRS should be limited to far smaller tumors than previously acknowledged to ensure long-term safety and efficacy.

The clinical utility of serum free light chain and heavy/light chain assays in monitoring disease activity in patients with IgG myeloma after achieving a deep response.

Heavy/light chain (HLC) assay will enable us to evaluate the changes in the concentrations of iHLC and uHLC separately and to better identify whether the change observed is clonal or reactive. It would therefore aid in decision making for earlier implementation or discontinuation of treatment for patients with intact immunoglobulin multiple myeloma (MM).

Critical evaluation of a prospective study of concurrent chemoradiotherapy with S-1 for early glottic carcinoma.

AIM: To improve the outcomes of radiotherapy alone for T2 glottic carcinoma (GC), we initiated a prospective study of concurrent chemoradiotherapy with S-1 for patients with early GC, primarily T2 cases. We report the efficacy and safety of this protocol. PATIENTS AND METHODS: Eligible patients had T1b or T2 glottic squamous cell carcinomas. Patients received S-1 (55.3 mg/m(2)/day, once daily) and radiotherapy (2 Gy/day, five days/week, to a total of 30 fractions). RESULTS: Thirteen patients were eligible. Complete responses were observed in all 13 patients (100%). At a median follow-up duration of 53 months (range=23-68 months), the 3-year local control and overall survival rates were both 100%. Grade 3 dermatitis occurred in only one patient. CONCLUSION: This chemoradiotherapy protocol is well -tolerated and effective in patients with early glottic carcinoma. Furthermore, due to its once-daily administration, this protocol is considered to be easier than usual chemoradiotherapy, and makes outpatient-treatment possible.

Durable hematological response and improvement of nephrotic syndrome on thalidomide therapy in a patient with refractory light chain deposition disease.

Light chain deposition disease (LCDD) is a rare disease for which an optimal treatment is not yet available. Here, we report the clinical course of a 32-year-old woman with LCDD who was successfully treated with thalidomide. She presented with nephrotic syndrome. Based on the renal biopsy findings and the presence of monoclonal immunoglobulin light chains in her serum and urine, LCDD was diagnosed. Prednisolone and cytotoxic chemotherapy used for multiple myeloma proved ineffective. We initiated administration of thalidomide (100 mg daily) and dexamethasone (20 mg for 4 days per month). After 8 months of treatment, she achieved complete hematological remission, defined as the disappearance of monoclonal protein and a normalized free light chain ratio, which led to improvement of her renal insufficiency. She has shown sustained hematological and organ response for 31 months with thalidomide therapy. Thus, thalidomide therapy seems to be a promising approach to the treatment of LCDD.

Chiral Brønsted acid catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with α,ß-unsaturated ketones: short access to optically active 2- and 3-substituted indole derivatives.

The asymmetric Friedel-Crafts alkylation reaction of indoles with α,ß-unsaturated ketones catalyzed by chiral phosphoric acid is reported. A wide range of indoles and 4,7-dihydroindoles were allowed to react with α,ß-unsaturated ketones to give the corresponding 1,4-adducts in good to high chemical yields and with excellent enantioselectivities.

Radiotherapy with or without chemotherapy for patients with T1-T2 glottic carcinoma: retrospective analysis.

BACKGROUND: To assess the results for local control (LC) and survival in patients with early-stage glottic cancer (GC) who were treated by radiotherapy (RT) with or without chemotherapy. METHODS: Fifty-eight patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 2001 and 2006 were analyzed retrospectively. Potential prognostic factors for LC were evaluated by univariate analysis. RESULTS: The 5-year LC rate in all patients was 84.3%. The overall 5-year LC rates for patients with T1a, Tb, and T2 GC were 85.9%, 83%, and 85%, respectively. Of the 58 patients, eight developed recurrent disease at the primary site, and one had lymph node recurrences on the neck. In the final analysis, the total laryngectomy-free survival rate was 93% at five years, and the ultimate LC rates for T1a, Tb, and T2 were 100%, 90.9%, and 95.2%, respectively. In a univariate analysis of 55 patients, there was no statistical significance between the LC rate for RT alone and that for chemoradiation. Only two patients died of laryngeal carcinoma, and one died of intercurrent disease. Fifty-five patients were living disease-free at the end of the study period. The 5-year overall survival (OS) rate for all patients was 88.1%, and the 5-year OS rates for T1a, Tb, and T2 were 91.6%, 77.8%, and 89.9%, respectively. CONCLUSIONS: The retrospective analysis showed a high rate of LC and larynx preservation in patients with T1-T2 GC by means of RT with or without chemotherapy. There was, however, no statistical difference in LC rates for the two types of therapy.

[Clinical usefulness of serum free light chain measurement in monoclonal gammopathy].

Recently, a highly sensitive assay (FREELITE) capable of measuring serum immunoglobulin-free light chains (FLC) was developed. An abnormal kappa/lambda ratio supports the presence of clonal plasma cell expansion. Using this assay, we measured serum and urine samples of 178 healthy volunteers, 184 patients with polyclonal gamma-globulinemia and 150 patients with monoclonal gamma-globulinemia. The diagnostic sensitivity of the FLC assays for monoclonal gammopathies was 88.0% and the specificity for healthy volunteers and polyclonal gammopathies was 96.1%. The minimal detection sensitivity of this assay for serum FLC was 0.3 mg/l and was greater than 100-fold more sensitive than serum protein electrophoresis (SPE). The combination of FLC with SPE and immunoelectrophoresis identified 99% of patients with monoclonal gammopathies. Effective treatment often leads to a more rapid reduction of the involved FLC level relative to the intact immunoglobulin or total light chain concentration because the half-life of FLC is <6 hours. These observations suggest that FREELITE is useful for diagnosis, disease monitoring and assessment of response to treatment in patients with monoclonal gammopathies such as multiple myeloma and AL amyloidosis.

Chiral Brønsted acid catalyzed enantioselective Mannich-type reaction.

Mannich-type reaction of ketene silyl acetals with aldimines proceeded catalytically by means of a phosphoric acid diester, derived from (R)-BINOL, as a chiral Brønsted acid to afford beta-amino esters with good diastereoselectivity in favor of the syn isomer and high enantioselectivity (up to 96% ee). The highest enantioselectivity was achieved by the phosphoric acid diester bearing 4-nitrophenyl groups on the 3,3'-positions of BINOL. The N-2-hydroxyphenyl group of aldimine was found to be essential for the present Mannich-type reaction. In combination with these experimental investigations, two possible monocoordination and dicoordination pathways were explored using density functional theory calculations (BHandHLYP/6-31G*). The present reaction proceeds via a dicoordination pathway through the zwitterionic and nine-membered cyclic transition state (TS) consisting of the aldimine and the phosphoric acid. The re-facial selectivity was also well-rationalized theoretically. The nine-membered cyclic structure and aromatic stacking interaction between the 4-nitrophenyl group and N-aryl group would fix the geometry of aldimine on the transition state, and the si-facial attacking TS is less favored by the steric hindrance of the 3,3'-aryl substituents.

[Evaluation of the clinical relevance of serum measurements of free-light chains in patients with multiple myeloma].

Measurement of serum free-light chains (FLCs) was performed using a recently developed immunoassay in 180 healthy individuals, 16 patients with multiple myeloma, and each 1 patient with Waldenström's macroglobulinemia, primary amyloidosis, or MGUS (monoclonal gammopathy of undetermined significance) to evaluate the clinical relevance of FLCs in the diagnosis and disease monitoring. Serum FLC levels of each patient were elevated compared with the levels of healthy individuals. The changes in FLC levels after treatment and at the time of relapse occurred earlier than those in serum immunoglobulin levels due to the short half-life of FLCs. Serum FLC levels were elevated in patients with Bence Jones type myeloma in spite of negative urinary immunoelectrophoresis. The serum FLC assay is a sensitive and useful tool for the diagnosis and monitoring of multiple myeloma and other B-cell proliferative disorders.

Chiral Brønsted acid catalyzed enantioselective hydrophosphonylation of imines: asymmetric synthesis of alpha-amino phosphonates.

[reaction: see text] A cyclic phosphoric acid derivative, derived from (R)-BINOL, was used as a chiral Brønsted acid (10 mol %) in hydrophosphonylation of aldimines with diisopropyl phosphite at room temperature. Alpha-amino phosphonates were obtained with good to high enantioselectivities.