Multicenter prospective phase II trial of concurrent chemoradiotherapy with weekly low-dose carboplatin for cisplatin-ineligible patients with advanced head and neck squamous cell carcinoma.

BACKGROUND: The optimal chemotherapy regimen in concurrent chemoradiotherapy (CCRT) for cisplatin-ineligible head and neck squamous cell carcinoma (HNSCC) has not been established. We aimed to evaluate the feasibility, efficacy, and safety of CCRT with weekly low-dose carboplatin for the treatment of advanced HNSCC in patients who are cisplatin-ineligible. METHODS: This prospective phase II study enrolled adult patients (age ≥ 20 years) with HNSCC receiving whole-neck irradiation including bilateral levels II-IV and who were aged (≥ 75-year-old patients with 40 mL/min estimated glomerular filtration rate [eGFR] or better) or had renal dysfunction (< 75-year-old patients with 30-60 mL/min eGFR). Carboplatin was administered weekly (area under the plasma concentration-time curve = 2.0) for up to seven cycles during concurrent radiotherapy (70 Gy/35 Fr). The primary endpoint was the completion rate of CCRT. Secondary endpoints included overall response rate and incidence of adverse events. RESULTS: Among the 30 patients enrolled, 28 were men. The median age was 73.5 years. Seventeen patients were < 75 years whereas 13 were ≥ 75 years old. The completion rate of CCRT was 90%. The overall response rate was 90%. Grade 3 adverse events that occurred in 10% or more patients were oral/pharyngeal mucositis (47%), leukocytopenia (20%), and neutropenia (10%). Grade 4 adverse events occurred in one patient (elevation of alanine aminotransferase level). No treatment-related deaths occurred. CONCLUSION: CCRT with weekly low-dose carboplatin is a promising treatment option, with favorable feasibility, efficacy, and acceptable toxicity, for patients who are cisplatin-ineligible with advanced HNSCC. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031190028.

Plus moist HS-W®: a new nasal packing material for the middle meatus in endoscopic sinus surgery.

PURPOSE: Removal of the current calcium alginate packing materials to the middle meatus in endoscopic sinus surgery (ESS) is usually accompanied by discomfort or pain owing to the hard and brittle nature of these materials. Plus moist HS-W® is a new calcium alginate packing material released in 2022 developed to overcome this issue by changing the uronic acid component. We aimed to compare the discomfort/pain during the removal of Plus moist HS-W® with Kaltostat®, as well as their suitability as packing materials in ESS. METHODS: Kaltostat® and Plus moist HS-W® were used as packing materials in 22 and 21 patients who underwent ESS in 2021 and 2022, respectively. Patients were asked to rate the pain during the packing removal 10 days after ESS using the Numerical Rating Scale (NRS). The ratio of residual packing materials, number of suctions (insertions/extractions of the suction cannula), and time required to remove packing materials were measured. Postoperative complications such as hemorrhage, local infection, lateralization of the middle turbinate, and synechia of the middle meatus were also evaluated. RESULTS: The Plus moist HS-W® group exhibited significantly lower NRS pain scores, a lower ratio of residual packing materials, a reduced number of suctions, and a shorter time required to remove the packing. No obvious postoperative complications occurred in both groups except for one suspicious case of a slight infection in the Kaltostat® group. CONCLUSION: Compared with Kaltostat®, Plus moist HS-W®, characterized by better gelatinization than Kaltostat®, benefits patients by minimizing discomfort/pain during removal. LEVEL OF EVIDENCE: Level 3.

Synthesis of 7-Deaza-cyclic Adenosine-5'-diphosphate-carbocyclic-ribose and Its 7-Bromo Derivative as Intracellular Ca(2+)-Mobilizing Agents.

Cyclic ADP-carbocyclic-ribose (cADPcR, 3) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. We became interested in the biological activity of the 7-deaza analogues of cADPcR, i.e., 7-deaza-cADPcR (7) and its 7-bromo derivative, i.e., 7-deaza-7-Br-cADPcR (8), because 7-deazaadenosine is an efficient bioisostere of adenosine. The synthesis of 7 and 8 required us to construct the key N1-carbocyclic-ribosyl-7-deazaadenosine structure. Therefore, we developed a general method for preparing N1-substituted 7-deazaadenosines by condensing a 2,3-disubstituted pyrrole nucleoside with amines. Using this method, we prepared the N1-carbocyclic ribosyl 7-deazaadenosine derivative 10a, from which we then synthesized the target 7-deaza-cADPcR (7) via an Ag(+)-promoted intramolecular condensation to construct the 18-membered pyrophosphate ring structure. The corresponding 7-bromo derivative 8, which was the first analogue of cADPR with a substitution at the 7-position, was similarly synthesized. Biological evaluation for Ca(2+)-mobilizing activity in the sea urchin egg homogenate system indicated that 7-deaza-cADPcR (7) and 7-deaza-7-Br-cADPcR (8) acted as a full agonist and a partial agonist, respectively.

Architecture of brush-on-brush copolymers by photoinduced ATRP approach.

We established a preparation method of brush-on-brush copolymers by grafting from photoinduced ATRP of multifunctional polystyrene having N,N-diethyldithiocarbamate (DC) pendant groups with stearyl methacrylate (STM). We studied the solution properties of brush-on-brush copolymers from the view point of crowding effect of PSTM brush side chains. It was speculated from angular dependence on dynamic light scattering (DLS) that the brush-on-brush copolymer (BB1:PSTM brushes were grafted at regular intervals of 1/4 styrene units on the backbone) with large aspect ratio took a geometrical anisotropic conformation such as a cylinder due to crowding of brush side chains. In fact, transmission electron microscopy (TEM) photograph of such brush-on-brush showed a rigid rod-like morphology.

Identification of risk factors for lymph node metastasis of colorectal cancer.

BACKGROUND/AIMS: Although lymph node metastasis is widely considered to be the potent prognostic factor in colorectal cancer patients, the clinical risk factors for lymph node metastasis in these patients have been scarcely analyzed. METHODOLOGY: The clinical records of 2125 patients who underwent colonoscopy and were diagnosed with colorectal cancer were reviewed. RESULTS: Multivariate analysis revealed that an increase in T stage (odds ratio (OR); 2.54, 95% confidence interval (CI) 2.17-2.98), and tumors with high grade pathology (OR; 1.63, 95% CI 1.10-2.41) were identified as the independent predictive factors for the presence of lymph node metastasis. On the other hand, the presence of synchronous adenomas (OR; 0.78, 95% CI 0.65-0.95) was a predictor for being free of lymph node metastasis. Stratification of the risk according to age and gender revealed that a tumor located in the right colon indicated significant risk for patients less than 50 years old (OR; 2.23, 95% CI 1.01-4.95), whereas tumors with high grade pathology indicated a significant risk only in female patients (OR; 1.74, 95% CI 1.01-3.00). CONCLUSIONS: The significant risk factors for lymph node metastasis were elucidated, and may facilitate surgeons in deciding the best surgical procedure to implement and pathologists in treating resected specimens.

Synthesis of 8-Substituted Analogues of Cyclic ADP-4-Thioribose and Their Unexpected Identification as Ca2+-Mobilizing Full Agonists.

A series of 8-substituted analogues of cyclic ADP-4-thioribose (cADPtR, 3), which is a stable equivalent of Ca2+-mobilizing second messenger cyclic ADP-ribose (cADPR, 1), were designed as potential pharmacological tools for studies on cADPR-modulated Ca2+ signaling pathways. These 8-amino analogue (8-NH2-cADPtR, 4), 8-azido analogue (8-N3-cADPtR, 5), and 8-chloro analogue (8-Cl-cADPtR, 6) were efficiently synthesized, where the stereoselective N1-ß-thioribosyladenine ring closure reaction via an α/ß-equilibrium of the 1-aminothioribose derivative and construction of the characteristic 18-membered pyrophosphate ring by Ag+-promoted activation of a phenyl phosphorothioate type substrate were the two key steps. Although 8-NH2-cADPR (2) is a well-known potent antagonist against cADPR-inducing Ca2+-release, the 4-thioribose congener 8-NH2-cADPtR turned out unexpectedly to be a full agonist in sea urchin egg homogenate evaluation system. This important finding suggested that the ring-oxygen in the N1-ribose of cADPR analogues is essential for the antagonistic activity in the Ca2+-signaling pathway, which can contribute to clarify the structure-agonist/antagonist activity relationship.

Photosensitive neurogenic heart of the isopod crustacean Ligia exotica.

The heart of animals is regulated through the central nervous system in response to external sensory stimuli. We found, however, that the adult neurogenic heart of the isopod crustacean Ligia exotica has photosensitivity. The beat frequency of the isolated heart decreased in response to a light stimulus. Magnitude of the response was stimulus intensity dependent and the heartbeat frequency decreased to less than 80% of the dark value during illumination of the white light with an intensity of 6.0 mW cm-2. The spectral sensitivity curve of the heart photoresponse peaked at a wavelength around 520 nm. In response to 530 nm monochromatic light, the relationship between light intensity and response magnitude was linear and the threshold intensity was 7.26 x 1012 quanta cm-2 s-1. Bursting activity of the cardiac ganglion, which is located in the heart and acts as the cardiac pacemaker deceased in frequency in response to illumination by white light. This fact suggests that the heart photoresponse of L. exotica results from the photosensitivity of the cardiac ganglion neurons. The photoresponse of the heart therefore contributes to regulation of cardiac output in addition to other regulatory systems.

Design, Synthesis, and Identification of 4″α-Azidoethyl-cyclic ADP-Carbocyclic-ribose as a Highly Potent Analogue of Cyclic ADP-Ribose, a Ca(2+)-Mobilizing Second Messenger.

Cyclic adenosine diphosphate-carbocyclic-ribose (cADPcR, 2) is a stable equivalent of cyclic adenosine diphosphate-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. On the basis of the structure-activity relationship of cADPR-related compounds and three-dimensional structural modeling of cADPcR, we designed and synthesized cyclic-ADP-4″α-azidoethyl carbocyclic-ribose (N3-cADPcR, 3) to demonstrate that it has a highly potent Ca(2+)-mobilizing activity (EC50 = 24 nM). N3-cADPcR will be a useful precursor for the preparation of biological tools effective to investigate cADPR-mediated signaling pathways.

Dual effects of dopamine on the adult heart of the isopod crustacean Ligia exotica.

In the adult heart of the isopod crustacean Ligia exotica, the cardiac ganglion acts as the primary pacemaker with the myocardium having a latent pacemaker property. We show several lines of evidence that dopamine modulates the heartbeat of adult L. exotica affecting both pacemaker sites in the heart. Dopamine caused positive chronotropic (frequency increase) and inotropic (amplitude increase) effects on the heartbeat in a concentration dependent manner. The time courses of these effects were considerably different and the inotropic effect appeared later and lasted longer than the chronotropic effect. Dopamine rapidly increased the frequency of the bursting activity in the cardiac ganglion neurons and each impulse burst of the cardiac ganglion was always followed by a heartbeat. Moreover, dopamine slowly increased the amplitude and duration of the action potential plateau (plateau potential) of the myocardium. When the myocardial pacemaker activity was induced by application of tetrodotoxin, which suppresses cardiac ganglion activity, dopamine slowly increased the amplitude and duration of the myocardial plateau potential while decreasing its frequency. These results suggest that dopamine modulates the heartbeat in adult L. exotica producing a dual effect on the two pacemaker sites in the heart, the cardiac ganglion and myocardium.

Design, Synthesis, and Chemical and Biological Properties of Cyclic ADP-4-Thioribose as a Stable Equivalent of Cyclic ADP-Ribose.

Here we describe the successful synthesis of cyclic ADP-4-thioribose (cADPtR, 3), designed as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, in which the key N1-ß-thioribosyladenosine structure was stereoselectively constructed by condensation between the imidazole nucleoside derivative 8 and the 4-thioribosylamine 7 via equilibrium in 7 between the α-anomer (7α) and the ß-anomer (7ß) during the reaction course. cADPtR is, unlike cADPR, chemically and biologically stable, while it effectively mobilizes intracellular Ca2+ like cADPR in various biological systems, such as sea urchin homogenate, NG108-15 neuronal cells, and Jurkat T-lymphocytes. Thus, cADPtR is a stable equivalent of cADPR, which can be useful as a biological tool for investigating cADPR-mediated Ca2+-mobilizing pathways.

A case of hemoglobin Hiroshima (ß146 histidine to aspartic acid) with compensatory erythremia and undetectable HbA1c.

Hemoglobin (Hb) Hiroshima is an Hb variant that travels rapidly on electrophoresis and shows a fourfold increase in oxygen affinity and a decreased Bohr effect. We encountered a 40-year-old male patient with erythremia and an undetectable HbA(1c) level. The presence of an abnormal hemoglobin molecule was suggested by the results of high-performance liquid chromatography analysis. Subsequent gene analysis by direct sequencing confirmed Hb Hiroshima (ß146 histidine → aspartic acid). Caution should be exercised when diagnosing erythremia.