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 .

Effectiveness of tenofovir alafenamide for chronic hepatitis B patients with a poor response to the previously used nucleos(t)ide analogs.

BACKGROUND: Few studies have demonstrated the potency of tenofovir alafenamide (TAF) in patients with poor response to other nucleos(t)ide analogs (NAs). METHODS: We conducted a retrospective study comprising consecutive 40 patients exhibiting a poor response to other NAs, who subsequently received TAF-containing regimens. The primary outcome was the prevalence of virological response (VR) at each time and maintained virological response (MVR) under TAF-containing regimens until week 96. RESULTS: In the entire cohort, the prevalence of MVR was 71.1% (27/38). Further, poor tenofovir disoproxil fumarate (TDF) response was significantly associated with a lower prevalence of MVR (p = 0.014). In TDF-naïve patients, the prevalence of MVR was 92.3% (12/13) and 62.5% (5/8) in patients with lamivudine resistance (LAM-r) and entecavir resistance (ETV-r), respectively. Further, viral load and HBeAg status at baseline were associated with a lower prevalence of MVR (p = 0.013). Among the seven patients with prior TDF exposure, 2 patients achieved MVR. Among them, one patient with development of viral breakthrough during TDF/LAM achieved MVR after switching to TAF/ETV. In contrast, one of the five patients with non-MVR had three substitutions (rtS106C, rtD134N/S, and rtL269I) of quadruple mutations in addition to ETV-r. Other patients with rtA181T + rtN236T also could not achieve MVR. CONCLUSION: TAF exhibited high antiviral potency in patients with LAM-r and ETV-r. However, TAF potency was associated with previous TDF response, viral load, and HBeAg status at baseline. Additionally, a quadruple mutation may impact tenofovir resistance; however, further studies are needed to verify this.

Effects of implant surgery on blood pressure and heart rate during sedation with propofol and midazolam.

PURPOSE: Intravenous (IV) sedation is commonly used in dentistry. However, no report has yet been published regarding age, hypertension, and antihypertensive drugs during implant surgery and their relationship with changes in blood pressure (BP) and heart rate in implant surgery under IV sedation with propofol and midazolam. MATERIALS AND METHODS: Medical records of 252 patients who underwent implant surgery were retrospectively analyzed. Patients were classified into four groups according to their age (in years) and hypertension status: A=≤64, no hypertension; B=≥65, no hypertension; C=≤64, hypertension; or D=≥65, hypertension. Hypertensive patients were further characterized by their antihypertensive medications: E=calcium channel blockers (CCBs), F=angiotensin II receptor blockers (ARBs), G=CCBs+ARBs, or H=no medication. IV sedation was administered in two stages. After midazolam injection to prevent angialgia, propofol was infused at the rate of 4 mg/kg/h, followed by a dose reduction. Systolic and diastolic BP and heart rate were recorded before, during, and after surgery. RESULTS: Systolic BP increased significantly after patients were draped in groups A, C, and D, with group D showing the most pronounced increase. Sedatives decreased BP in all groups. Diastolic BP in group F decreased significantly compared to group H after induction and before infiltration of local anesthetic. After infiltration, systolic BP decreased more significantly in group G than in group H. Intraoperative hypotension was observed in 25% of patients. The incidence of intraoperative hypertension in group D was markedly higher than in group A (23% vs 4%). CONCLUSION: IV sedation using midazolam and propofol reduces hypertensive risks during implant surgery. Nevertheless, care must be taken, especially in older hypertensive patients and in hypertensive patients on ARBs or ARBs+CCBs.

Effect of epivascular cardiac autonomic nerve stimulation on cardiac function.

BACKGROUND: The cardiac plexus contains sympathetic and parasympathetic cardiac nerves. Our goal was to assess the hemodynamic and functional effects of stimulating the cardiac autonomic nervous system (CANS) at the epivascular surfaces of the cardiac plexus. Although CANS therapy to modulate cardiovascular function has drawn widespread interest, research has focused only on stimulating parasympathetic or sympathetic nerves, not both at once. METHODS: Using general anesthesia and an open-chest surgical procedure, 12 dogs received epivascular stimulation of the cardiac plexus. A bipolar electrode was placed between the right pulmonary artery (PA) and the ascending aorta, with the stimulation frequency/pulse width held constant (20 Hz/4 ms) and the voltage varied (10-50 V). Left ventricular (LV) pressure-volume loops and hemodynamic data were recorded with and without stimulation. RESULTS: In all dogs, aortic and LV systolic pressures, maximum rate of change of LV pressure, and LV stroke work increased (p<0.0001), as did cardiac output (2.9±1.0-0.4±1.0 L/min; p=0.001), end-systolic elastance (1.2±0.4-1.5±0.5 mm Hg/mL; p=0.0001), preload recruitable stroke work (30.1±11.0-39.3±7.8 mm Hg; p=0.003), and LV ejection fraction (p=0.012). Systemic vascular resistance increased slightly (p=0.04), and pulmonary vascular resistance decreased (p=0.01). Mean heart rate and pulmonary arterial, central venous, and left atrial pressures remained unchanged (p>0.1). CONCLUSIONS: In contrast to inotropic drugs, epivascular CANS stimulation induced a significant and selective increase in LV contractility with no increase in heart rate.