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 Gedunin-Type Limonoid, 7-Deacetoxy-7-Oxogedunin, from Andiroba (Carapa guianensis Aublet) Reduced Intracellular Triglyceride Content and Enhanced Autophagy in HepG2 Cells.

The seed oil of Carapa guianensis Aublet (Andiroba) has been used in folk medicine for its insect-repelling, anti-inflammatory, and anti-malarial activities. This study aimed to examine the triglyceride (TG) reducing effects of C. guianensis-derived limonoids or other commercially available limonoids in human hepatoblastoma HepG2 cells and evaluate the expression of lipid metabolism or autophagy-related proteins by treatment with 7-deacetoxy-7-oxogedunin (DAOG; 1), a principal limonoid of C. guianensis. The gedunin-type limonoids, such as DAOG (% of control at 20 µM: 70.9 ± 0.9%), gedunin (2, 74.0 ± 1.1%), epoxyazadiradione (4, 73.4 ± 2.0%), 17ß-hydroxyazadiradione (5, 79.9 ± 0.6%), 7-deacetoxy-7α-hydroxygedunin (6, 61.0 ± 1.2%), andirolide H (7, 87.4 ± 2.2%), and 6α-hydroxygedunin (8, 84.5 ± 1.1%), were observed to reduce the TG content at lower concentrations than berberine chloride (BBR, a positive control, 84.1 ± 0.3% at 30 µM) in HepG2 cells pretreated with high glucose and oleic acid. Andirobin-, obacunol-, nimbin-, and salannin-type limonoids showed no effect on the intracellular TG content in HepG2 cells. The TG-reducing effect of DAOG was attenuated by the concomitant use of compound C (dorsomorphin), an AMPK inhibitor. Further investigation on the detailed mechanism of action of DAOG at non-cytotoxic concentrations revealed that the expressions of autophagy-related proteins, LC3 and p62, were upregulated by treatment with DAOG. These findings suggested that gedunin-type limonoids from Andiroba could ameliorate fatty liver, and that the action of DAOG in particular is mediated by autophagy.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Segmental Hypoganglionosis of the Colon: A Case Report.

A 64-year-old woman was admitted to hospital with persistent abdominal pain. She had been hospitalized with similar symptoms on five occasions during a period of 2 years. Computed tomography revealed dilatation and fecal impaction from the ileum to the transverse colon. A barium enema and simultaneous ileus tube radiography showed a narrow segment of descending-sigmoid colon. Colonoscopy showed no mucosal change. Her symptoms did not improve with conservative therapy, so descending and sigmoid colectomy was performed. Histologic examination showed disappearance of ganglion cells; axon of Meissner's plexuses was present, and the number of Auerbach's plexuses was decreased. The definitive diagnosis was segmental hypoganglionosis (SH) of the colon. The postoperative course was uneventful, and the functional result was positive at 1 year postoperatively. SH is extremely rare; however, surgical intervention is expected to be of benefit. Therefore, it is important to keep SH in mind when treating patients with chronic obstruction of the left side of the colon.

Oxaliplatin-induced increase in splenic volume: experiences from multicenter study in Japan.

BACKGROUND: Chemotherapy with oxaliplatin is known to induce sinusoidal obstruction syndrome (SOS). In a previous single-center study, we reported that oxaliplatin-induced increase in splenic volume (SV) is strongly indicative of SOS, and that this increase in SV persisted for > 1 year after completing chemotherapy. The aim of this study was to confirm the oxaliplatin-induced SV change in a multicenter study in patients with stage III colon cancer in Japan. METHODS: We enrolled 59 patients who underwent curative resection for stage III colon cancer in the FACOS study in a phase II multi-center clinical study. Participants received mFOLFOX6 or CAPOX as adjuvant chemotherapy. SV change was assessed three times by computed tomographic volumetry: before surgery, on completion of adjuvant chemotherapy, and 1 year after completing adjuvant chemotherapy. RESULTS: SV on completing and 1 year after chemotherapy was significantly higher than that before surgery (P < 0.001). Oxaliplatin-induced SOS persisted for > 1 year after the completion of adjuvant chemotherapy in half of the patients. There was no difference in 3-year disease-free survival with respect to the presence or absence of increased SV. An increase in SV was observed in 72% of patients treated with mFOLFOX6 and 94% of patients treated with CAPOX (P = 0.13). CONCLUSION: This study can be verified the findings observed in our previous single-center study, oxaliplatin-based adjuvant chemotherapy was associated with an increase in SV. Furthermore, this increase can persist for > 1 year. The continuous presence of SOS may have a negative impact on prognosis in patients that develop recurrent disease.

Bioactivity-based analysis and chemical characterization of hypoglycemic and antioxidant components from Artemisia argyi.

Diabetes is one of the metabolic disorders in the world. It is the prime reason of mortality and morbidity owing to hyperglycemia which is link with numerus obstacles. Artemisia argyi is commonly used as an ingredient in healthy foods as well as an herbal medicine in Asian countries. The present research aims to evaluate the hypoglycemic effects of A. argyi and reveal its the potentially active constituents. The chemical composition was identified by HPLC-DAD-Q-TOF-MS, and fractionation was performed by extraction. The fractions were assessed by the blood glucose level, oral glucose tolerance and small intestinal α-glucosidase inhibitory tests, and an analysis of the total phenolic content (TPC), antioxidant and α-glucosidase inhibitory activities. In our efforts to characterize the compounds responsible for hypoglycemic effect, bioactivity-guided fraction of the MeOH extract and chemical investigation of its active EtOAc fraction led to the successful identification of caffeoylquinic acids, which were elucidated by molecular docking, using the crystal structure of S. cerevisiae isomaltase (PD code: 3AXI). In summary, this bio-guided search revealed that caffeoylquinic acids from A. argyi as potential active constituents displayed with hypoglycemic activity, which provided a basis for further study of pharmacological activity.

A Japanese multicenter phase II study of adjuvant chemotherapy with mFOLFOX6/CAPOX for stage III colon cancer treatment after D2/D3 lymphadenectomy.

PURPOSE: A phase II trial was conducted to investigate the benefit of oxaliplatin-based adjuvant chemotherapy in Japanese stage III colon cancer patients. METHODS: Eligible patients were scheduled to receive 12 cycles of mFOLFOX6 or 8 cycles of CAPOX in adjuvant settings. The primary endpoint was the 3-year disease-free survival (DFS). Cox proportional hazards regression was performed to identify risk factors for a worse DFS. RESULTS: A total of 130 patients, including 73 patients receiving mFOLFOX6 and 57 patients receiving CAPOX, were enrolled from 16 institutions between April 2010 and April 2014. The 3-year DFS was 82.2%, exceeding the expected primary endpoint of 81.7%. The 3-year DFS tended to be higher in patients receiving mFOLOFOX6 than in those receiving CAPOX (mFOLFOX6, 86.3%; CAPOX, 76.9%; P = 0.06). The 3-year DFS rates did not differ markedly based on the risk stratification (T1/T2/T3 N1 vs. T4 or N2) indicated by the IDEA COLLABORATION study (P = 0.22). In the multivariate analysis, stage IIIC (P = 0.046) and early discontinuation (P < 0.01) were identified as independent significant risk factors for a worse DFS. CONCLUSION: Our findings represent the first positive results in a Japanese phase II trial of adjuvant chemotherapy with mFOLFOX6/CAPOX. Early discontinuation within 2 months was an independent risk factor for a shorter DFS.

Short-term outcomes of a self-expandable metallic stent as a bridge to surgery vs. a transanal decompression tube for malignant large-bowel obstruction: a meta-analysis.

PURPOSE: Preoperative intestinal decompression, using either a self-expandable metallic stent (SEMS) as a bridge to surgery (BTS) or a transanal decompression tube (TDT), provides an alternative to emergency surgery for malignant large-bowel obstruction (MLBO). We conducted this meta-analysis to compare the short-term outcomes of SEMS placement as a BTS vs. TDT placement for MLBO. METHODS: We conducted a comprehensive electronic search of literature published up to March, 2018, to identify studies comparing the short-term outcomes of BTS vs. TDT. Decompression device-related and surgery-related variables were evaluated and a meta-analysis was performed using random-effects models to calculate odd ratios with 95% confidence intervals. RESULTS: We analyzed 14 nonrandomized studies with a collective total of 581 patients: 307 (52.8%) who underwent SEMS placement as a BTS and 274 (47.2%) who underwent TDT placement. The meta-analyses showed that the BTS strategy conferred significantly better technical and clinical success, helped to maintain quality of life by allowing free food intake and temporal discharge, promoted laparoscopic one-stage surgery without stoma creation, and had equivalent morbidity and mortality to TDT placement. CONCLUSIONS: Although the long-term outcomes are as yet undetermined, the BTS strategy using SEMS placement could be a new standard of care for preoperative decompression to manage MLBO.

Sesquiterpenoids and triterpenoids from Secamone lanceolata blume with inhibitory effects on nitric oxide production.

Five previously undescribed sequiterpenoids, including three guaiane sesquiterpenoids secamonol A (2), secamonester (3), secamonether (4), and one elemanolide sequiterpenoid secamonol B (7), and one eudesmane sesquiterpenoid secamonol C (8) along with nine known compounds were isolated from Secamone lanceolata Blume. Their structures and absolute configurations were established by analyzing of NMR, CD, MS spectrum and single-crystal X-ray diffraction, as well as comparing with the literatures. Compounds 1 and 4-8 exhibited potential inhibition activities of NO production with IC50 values in the range of 27.9-57.5 µM with no obvious cytotoxicities even at the high concentration (100 µM). Whereas, compound 3 showed significant cytotoxicity with CC50 value of 5.6 µM against macrophages RAW264.7 Cells.

Collagen Synthesis-Promoting Effects of Andiroba Oil and its Limonoid Constituents in Normal Human Dermal Fibroblasts.

The seed oil of andiroba (Carapa guianensis, Meliaceae) was found to promote collagen synthesis in normal human dermal fibroblasts. To characterize the active constituents of this oil, the collagen synthesis-promoting activities of 10 principal limonoid constituents, gedunin (1), 6α-acetoxygedunin (2), 7-deacetoxy-7-oxogedunin (3), 7-deacetoxy-7α-hydroxygedunin (4), andirolide H (5), 6α-hydroxygedunin (6), methyl angolensate (7), 17ß-hydroxyazadiradione (8), and carapanosides C (9) and R (10), were examined. Among them, 1-4, 6, 7, and 9 were found to significantly promote collagen synthesis without cytotoxicity at the effective concentrations.

Three bisabolane-type sesquiterpenes from edible mushroom Pleurotus eryngii.

Three bisabolane-type sesquiterpenes (1-3) were isolated from the fruiting bodies of king trumpet mushrooms (Pleurotus eryngii), together with a known compound (4). All isolated compounds were evaluated for their inhibitory effects on nitric oxide (NO) production. Among these, 2 exhibited a moderate inhibitory effect on NO production with an IC50 of 90.9 µM.

Carapanosins D-F from the Seeds of Andiroba (Carapa guianensis, Meliaceae) and Their Effects on LPS-Activated NO Production.

A novel nor-phragmalin-type limonoid, named carapanosin D (1), and two novel mexicanolide-type limonoids, carapanosins E (2) and F (3), were isolated from the seed oil of andiroba (Carapa guianensis Aublet), a traditional medicine in Brazil and Latin American countries. Their structures were unambiguously determined on the basis of spectroscopic analyses using one-dimensional (1D) and two-dimensional (2D) NMR techniques and High resolution Fast Atom Bombardment Mass Spectrometry (HRFABMS). Compounds 1⁻3 were evaluated for their effects on the production of nitric oxide (NO) in Lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. The NO inhibitory assay suggested that compounds 2 and 3 have high potency as inhibitors of macrophage activation.

Feasibility of Neoadjuvant FOLFOX Therapy Without Radiotherapy for Baseline Resectable Rectal Cancer.

BACKGROUND/AIM: The combination of oxaliplatin, leucovorin and fluorouracil (FOLFOX) has been established as postoperative adjuvant chemotherapy for stage III colon cancer. However, the safety and efficacy of neoadjuvant FOLFOX in patients with rectal cancer are still controversial. This prospective pilot study aimed to evaluate the feasibility of neoadjuvant FOLFOX therapy without radiation for baseline resectable rectal cancer (RC). PATIENTS AND METHODS: The study included 30 patients with clinical stage II/III RC between February 2012 and December 2015. The patients were treated with six cycles of FOLFOX followed by elective surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were the scheduled treatment completion rate, adverse events, pathological response and the disease-free survival (DFS) rate. RESULTS: All the patients underwent elective R0 resection after neoadjuvant FOLFOX therapy. The completion rate of the 6-cycle regimen was 93.3% (28/30 patients). Grade 3-4 adverse events occurred in seven patients (23.3%). Pathological complete response was noted in two patients (6.7%). The 3-year DFS rate was 77.5% (95% confidence interval, 61.4%-93.7%). CONCLUSION: Neoadjuvant FOLFOX therapy without radiation is a feasible therapeutic strategy for baseline resectable RC.

Oxaliplatin-induced increase in splenic volume; irreversible change after adjuvant FOLFOX.

BACKGROUND AND OBJECTIVES: Oxaliplatin can cause hepatic sinusoidal obstruction syndrome (SOS). SOS can cause chemotherapy-related adverse effects or morbidity after liver resection. Conventionally, SOS is diagnosed using liver biopsy. Recently, it was reported that increased splenic volume (SV) can be used to detect SOS. In this study, we evaluated the changes in SV during adjuvant chemotherapy. METHODS: We enrolled 103 consecutive patients with stage III and high-risk stage II colorectal cancer treated with mFOLFOX6 (n = 37) or oral fluorouracil and leucovorin (n = 66) after curative surgery. SV was measured three times; pre-operatively, after chemotherapy, and 1 year after chemotherapy. RESULTS: SV was higher after mFOLFOX6 (median 135.89 mL) than pre-operatively (105.75 mL) (P < 0.001); SV at 1-year after finishing mFOLFOX6 (114.16 mL) returned to the same level as before surgery (P = 0.0015). SV increased in 28 patients (75.7%) treated with mFOLFOX6 (95%CI, 61.8-89.5), but had not recovered in 12 of these cases (42.9%) 1 year after finishing treatment (95%CI, 17.3-47.5). In contrast, oral fluorouracil and leucovorin did not change SV. CONCLUSIONS: SV increased after adjuvant mFOLFOX6, and had not recovered in almost half of cases 1-year after finishing chemotherapy. This increase may indicate continuous SOS, which can adversely affect treatment after recurrence.

Carapanosins A-C from Seeds of Andiroba (Carapa guianensis, Meliaceae) and Their Effects on LPS-Activated NO Production.

Two new phragmalin-type limonoids, Carapanosins A and B (1 and 2), and a new gedunin-type limonoid, Carapansin C (3), together with five known limonoids (4-8) were isolated from the oil of Carapa guianensis AUBLET (Meliaceae) seeds, a traditional medicine in Brazil and Latin American countries. Their structures were elucidated on the basis of spectroscopic analyses using 1D and 2D NMR techniques and HRFABMS. Compounds 1-8 were evaluated for their effects on the production of NO in LPS-activated mouse peritoneal macrophages. The NO inhibitory assay suggested that Compounds 3, 6, and 8 may be valuable as potential inhibitors of macrophage activation.

Efficacy and safety of neoadjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and levofolinate for T3 or T4 stage II/III rectal cancer: the FACT trial.

PURPOSE: A multicenter phase II clinical study was performed in patients with T3 or T4 stage II/III rectal cancer to evaluate the efficacy and safety of neoadjuvant chemotherapy with 5-fluorouracil, levofolinate, and oxaliplatin (mFOLFOX6). METHODS: Patients received four 2-week cycles of mFOLFOX6 therapy (oxaliplatin at 85 mg/m2 + leucovorin at 200 mg/m2 + fluorouracil as a 400 mg/m2 bolus followed by infusion of 2400 mg/m2 over 46 h, all on Day 1). They were evaluated by computed tomography after completion of the fourth cycle. If there was no disease progression, two additional cycles were administered and then surgery was performed. Adjuvant chemotherapy was generally administered for 6 months using appropriate regimens at the discretion of the physician. RESULTS: mFOLFOX6 therapy was given to 52 patients with locally advanced rectal cancer. The preoperative response rate was 48.8% and the operation rate was 80.8%. Serious adverse events of Grade 3-4 were neutropenia (n = 5), leukopenia (n = 1), thrombocytopenia (n = 1), febrile neutropenia (n = 1), nausea (n = 1), vomiting (n = 1), and peripheral neuropathy (n = 2). The R0 resection rate, pathologic complete response rate, and sphincter preservation rate were 91.0, 11.9, and 73.8%, respectively. Postoperative complications were tolerable. CONCLUSIONS: The present results suggested that neoadjuvant therapy with mFOLFOX6 is safe and effective, representing a reasonable treatment option for locally advanced rectal cancer.

The effect of Daikenchuto on postoperative intestinal motility in patients with right-side colon cancer.

PURPOSE: Daikenchuto (DKT) has a stimulant effect on intestinal motility and reportedly has a positive effect on postoperative intestinal motility in patients with sigmoid colon cancer. In this study, we investigated the effects of DKT in patients with right-side colon cancer. METHODS: This retrospective study included 88 patients with right-side colon cancer. We orally administered 7.5 g of DKT in the DKT group and did not administer any DKT to patients in the no-DKT group. All patients ingested radiopaque markers 2 h before surgery, which were used to assess intestinal motility. The postoperative intestinal motility was radiologically assessed by counting the numbers of residual markers in the large and small intestines. RESULTS: The DKT and no-DKT groups showed no marked differences in the total number of residual markers or number of residual markers in the small intestine. However, in the elderly subgroup, the total number of residual markers in the DKT group was significantly less than in the no-DKT group. CONCLUSION: Although DKT had some small effect on the postoperative intestinal motility for most patients, it may have positive effects in elderly patients.

Onset-to-device time of patients who arrive at off-hours: Importance of prehospital management and public awareness for patients with ST-segment elevation myocardial infarction.

AIM: The influence of the time of arrival at the hospital on the door-to-device (DTD) time has been investigated; however, the influence on the onset-to-device (OTD) time is unclear in ST-segment elevation myocardial infarction (STEMI) patients. The aim of this study was to investigate the relationship between the time of arrival at the hospital and the OTD time in STEMI patients. METHODS: We evaluated 377 STEMI patients who underwent primary percutaneous coronary intervention (pPCI) between January 2008 and December 2014. RESULTS: During the study period, 222 patients arrived at our hospital between 9 AM and 9 PM (on-hours group) and 155 patients arrived between 9 PM and 9 AM (off-hours group). The DTD time was longer in the off-hours group than in the on-hours group (50.4 vs 39.3 minutes; P<.001), while the OTD time was longer in the on-hours group than in the off-hours group (285.7 vs 184.5 minutes, P<.001). The 30-day mortality and peak creatinine kinase levels were similar between the groups. Transfer from a non-pPCI-capable facility to our hospital was more common in the on-hours group than in the off-hours group (49.1% vs 15.5%, P<.001). The OTD time was shorter in patients who directly visited our hospital than in those who were transferred (172.9 vs 338.5 minutes, P<.001). CONCLUSIONS: The OTD time might be markedly longer in STEMI patients who arrive at the hospital during on-hours than in those who arrive at the hospital during off-hours because of the underuse of emergency medical services at STEMI onset.

Two new ent-kaurane-type diterpene glycosides from zucchini (Cucurbita pepo L.) seeds.

Two new ent-kaurane diterpene glycosides; 12α-(ß-d-glucopyranosyloxy)-7ß-hydroxykaurenolide (1) and 7ß-(ß-d-glucopyranosyloxy)-12α-hydroxykaurenolide (2), a new steroid; (24S)-stigmasta-7,22E,25-trien-3-one (12), and known compounds (3-11, 13-14) were isolated from zucchini (Cucurbita pepo L.) seeds. The absolute structures of 1 and 2 were determined by acid hydrolysis and application of a modified Moscher's method. Furthermore, isolated compounds (1-14), and a derivative, 1a, were evaluated for their inhibitory effects on macrophage activation by an inhibitory assay of nitric oxide (NO) production.

Andirolides W-Y from the flower oil of andiroba (Carapa guianensis, Meliaceae).

Three new limonoids, andirolides W-Y (1-3), were isolated from the flower oil of Carapa guianasis AUBLET (Meliaceae). Their structures were elucidated on the basis of spectroscopic analyses using 1D and 2D NMR spectra and FABMS. Seven known limonoids: 7-deacetoxy-7-oxogedunin (4), 6α-acetoxygedunin (5), methylangolensate (6), 6α-hydroxygedunin (7), 6α-acetoxy-7α-deacetoxy-7α-hydroxygedunin (8), gedunin (9), and 7-deacetoxy-7-hydroxygedunin (10) from this flower oil were evaluated for the effects on the production of NO in LPS-activated mouse peritoneal macrophages.