Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial).

BACKGROUND: Locally advanced pancreatic ductal adenocarcinoma (PDAC), accounting for about 30% of PDAC patients, is difficult to cure by radical resection or systemic chemotherapy alone. A multidisciplinary strategy is required and our TT-LAP trial aims to evaluate whether triple-modal treatment with proton beam therapy (PBT), hyperthermia, and gemcitabine plus nab-paclitaxel is a safe and synergistically effective treatment for patients with locally advanced PDAC. METHODS: This trial is an interventional, open-label, non-randomized, single-center, single-arm phase I/II clinical trial organized and sponsored by the University of Tsukuba. Eligible patients who are diagnosed with locally advanced pancreatic cancer, including both borderline resectable (BR) and unresectable locally advanced (UR-LA) patients, and selected according to the inclusion and exclusion criteria will receive triple-modal treatment consisting of chemotherapy, hyperthermia, and proton beam radiation. Treatment induction will include 2 cycles of chemotherapy (gemcitabine plus nab-paclitaxel), proton beam therapy, and 6 total sessions of hyperthermia therapy. The initial 5 patients will move to phase II after adverse events are verified by a monitoring committee and safety is ensured. The primary endpoint is 2-year survival rate while secondary endpoints include adverse event rate, treatment completion rate, response rate, progression-free survival, overall survival, resection rate, pathologic response rate, and R0 (no pathologic cancer remnants) rate. The target sample size is set at 30 cases. DISCUSSION: The TT-LAP trial is the first to evaluate the safety and effectiveness (phases1/2) of triple-modal treatment comprised of proton beam therapy, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer. ETHICS AND DISSEMINATION: This protocol was approved by the Tsukuba University Clinical Research Review Board (reference number TCRB22-007). Results will be analyzed after study recruitment and follow-up are completed. Results will be presented at international meetings of interest in pancreatic cancer plus gastrointestinal, hepatobiliary, and pancreatic surgeries and published in peer-reviewed journals. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031220160. Registered 24 th June 2022, https://jrct.niph.go.jp/en-latest-detail/jRCTs031220160 .

A Heat Dissipation Study of Iron Oxide Nanoparticles Embedded an Agar Phantom for the Purpose of Magnetic Fluid Hyperthermia.

Magnetic nanoparticles have recently been the subject of intensive research for biomedical applications. In particular, injecting colloidal magnetic nanoparticles into the cancerous tissues and heating them by heat dissipation from magnetic nanoparticles with applying an alternating magnetic field have been expected as a new cancer treatment (magnetic fluid hyperthermia). In this study, iron oxide nanoparticles were dispersed in an agar phantom in order to use them to mimic tumor tissue that is surrounded by normal tissue. Their heat transfer properties were investigated to study magnetic fluid hyperthermia. Magnetite nanoparticles with a median diameter of 13.8 nm fixed in an agar matrix showed a specific absorption rate of 5.6 W/g in a field of 5.0 kA/m, and a concentration of 5 wt.% was sufficient to increase the temperature above the temperature required for magnetic hyperthermia treatment. The simulated temperature profile inside the phantom shows reasonable agreement with the temperature distribution obtained by experiments. These results offer a guide for preventing the overheating of normal tissues during hyperthermia treatment.

[Hyperuricemia and acute kidney injury following kidney transplantation : a case report].

We report a case of hyperuricemia and acute kidney injury associated with mizoribine (MZR). A 15- year-old male with congenital renal hypoplasia underwent kidney transplantation. We used tacrolimus extended release (0.15 mg/kg/day), mizoribine (MZR) (12 mg/kg/day), prednisolone and basiliximab as immunosuppressants. On the 35th post operative day, he complained of acute right chest pain, right inguinal pain and dyspnea. Serum uric acid and creatinine were elevated. Accordingly, we changed MZR to mycophenolate mofetil, and added allopurinol and potassium citrate. Gradually, the symptoms disappeared and renal function was improved. In this case, prolonged MZR metabolism, hyperuricemia and progressive renal dysfunction may have formed a vicious cycle. In conclusion, monitoring of serum uric acid level is necessary, especially when using a high dose MZR.

Pulmonary artery mapping for differential diagnosis of left-sided atrial tachycardia.

BACKGROUND: Distinguishing left-and right-sided atrial tachycardia (AT) is often challenging. The coronary sinus (CS) provides information only concerning the anterior left atrium (LA). Potentials recorded in the pulmonary artery (PA) have been substituted for those of the upper posterior LA because of their anatomical relationship. METHODS AND RESULTS: Three patterns were designed, using potentials in the PA, right atrium (RA) and CS, to predict the side of AT. Two patterns were for left-sided AT and 1 pattern was for right-sided AT. Ten left-sided and 11 right-sided ATs were investigated regardless of mechanism. Electrode catheters were inserted in the RA, His bundle region, and CS, and an ablation catheter was inserted into the left and/or right PA. The sequences from these catheters were analyzed before detailed electroanatomical mapping. Patterns were obtained for 20 of 21 ATs. The mechanism was focal in 16 ATs and macroreentry in 5. The method predicted left-sided AT with a sensitivity of 78%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 84%, and an accuracy of 90%. CONCLUSIONS: The use of potentials in PA combined with conventional RA and CS electrograms is useful for distinguishing left-sided AT from right-sided AT, regardless of mechanism.

Blind cavefish and heat shock protein chaperones: a novel role for hsp90alpha in lens apoptosis.

Lens apoptosis plays a central role in cavefish eye degeneration. Heat shock proteins (hsps) can regulate apoptosis; therefore, we examined the relationship between constitutive hsp70 and hsp90 expression and lens apoptosis. The model system is Astyanax mexicanus, a teleost species consisting of an eyed surface-dwelling (surface fish) form and numerous blind cave-dwelling (cavefish) forms. Optic primordia are formed in the cavefish embryo but they subsequently undergo lens apoptosis, arrest in development and degenerate. Astyanax hsp90 and hsp70 DNAs were isolated to use as probes to compare gene expression during surface fish and cavefish development. Hsp90beta, which encodes one of two hsp90 isoforms, was not expressed in the surface fish or cavefish lens, whereas hsp70 was expressed in the lens of both forms, suggesting that neither is directly involved in lens apoptosis. In contrast, hsp90alpha, the other hsp90 isoform, was expressed in the cavefish but not the surface fish lens. Hsp90alpha expression peaked shortly before the beginning of lens apoptosis in three convergent cavefish populations, suggesting a close relationship with lens apoptosis. The absence of hsp90beta in the lens allowed us to use geldanamycin and radicicol, specific inhibitors of hsp90 chaperone function, to determine whether lens cell death requires hsp90alpha expression. Both inhibitors blocked TUNEL labeling in the cavefish lens, suggesting that hsp90alpha is required for apoptosis. In contrast to their effects on the lens, these inhibitors induced TUNEL labeling in the surface epidermis, presumably due to effects on hsp90beta function, implying that the two-hsp90 isoforms may have contrasting roles in cell survival. We conclude that hsp90alpha plays a novel role in lens apoptosis and cavefish eye degeneration.