Phase I study of napabucasin in combination with FOLFIRI + bevacizumab in Japanese patients with metastatic colorectal cancer.

BACKGROUND: Napabucasin is an oral NAD(P)H:quinone oxidoreductase 1 bioactivatable agent that generates reactive oxygen species, is hypothesised to affect multiple oncogenic cellular pathways, including STAT-3, and is expected to result in cancer cell death. This phase I study investigated the safety, tolerability, and pharmacokinetics of napabucasin co-administered with fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) chemotherapy plus bevacizumab in Japanese patients with metastatic colorectal cancer (CRC). METHODS: Patients with histologically confirmed unresectable stage IV CRC received oral napabucasin 240 mg twice daily (BID). Intravenous FOLFIRI and bevacizumab therapy was initiated on day 3 at approved doses. Unacceptable toxicity was evaluated over the first 30 days of treatment, after which treatment continued in 14-day cycles until toxicity or disease progression. Endpoints included safety, pharmacokinetics, and tumour response based on RECIST v1.1. RESULTS: Four patients received treatment; three were evaluable during the unacceptable toxicity period. All four patients experienced diarrhoea and decreased appetite (considered napabucasin-related in four and two patients, respectively), and three patients experienced neutrophil count decreased. No unacceptable toxicity was reported during the 30-day evaluation period. No grade 4 events, deaths, or serious adverse events were reported. The addition of FOLFIRI and bevacizumab to napabucasin did not significantly change the pharmacokinetic profile of napabucasin; however, results were variable among patients. The best overall response was stable disease in two patients (50.0%). CONCLUSIONS: Napabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC.

[The Examination of Spring Back Force in Frozen Elephant Trunk;Matsui-Kitamura Stent versus J Graft Open Stent Graft].

OBJECTIVES: We examined the spring back force (SBF) in the frozen elephant trunk technique between patients receiving a Matsui-Kitamura stent (M group) or a J Graft Open Stent Graft (J group). METHODS: There were 11 cases in the M group and 10 cases in the J group. For all cases, we performed computed tomography( CT) scan and measured distal arch angle( DAA) and stent graft angle (SGA). RESULTS: There was no difference between groups with regards to patient characteristics. The insertion graft length[155±19 mm (M group) versus 138±17 mm (J group)]was significantly longer in the M group( p<0.05). In the J group, the SGA at 1 and 2 years postoperatively( 105°±18.5° and 114°±19.1°, respectively) were significantly increased compared to that at 1 month postoperatively (99.9°± 18.7°). In addition, the SGA in the J group was significantly larger than that in the M group during the postoperative period. CONCLUSIONS: The SBF in the J group was thought to be significantly larger than that in the M group. SBF was thought to be associated with the stent frame characteristic.

[Constrictive Pericarditis with Intractable Ascites after Aortic Valve Replacement;Report of a Case].

We report a 68-year-old man, who developed refractory ascites of unknown cause after aortic valve replacement. He was diagnosed with constrictive pericarditis because of "dip-and-plateau" waveform findings via cardiac catheterization and operated with cardiopulmonary bypass. Following waffle procedure, we incised pericardium for decompression, so that pericardial mobility and diastolic dysfunction was improved. Postoperative computed tomography (CT) image also showed decrease of ascites fluid. We concluded that pericardiotomy is an established surgical procedure and is excellent indication to constrictive pericarditis.

[Efficacy of Total Debranching Thoracic Endovascular Aortic Repair for the Re-operation of Aortic Arch Aneurysm].

Thoracic endovascular aortic repair (TEVAR) combined with all-neck-branch reconstruction (total debranching TEVAR)[td TEVAR] is applied to aortic arch aneurysms as a minimally invasive procedure to improve treatment results. We report the initial and long-term results of td TEVAR for the reoperation of aortic arch aneurysm. By September 2016, td TEVAR for reoperation had been applied in 5 cases. The reasons for the reoperation were dilation of the arch aneurysm after ascending aorta replacement in 4 cases and localized dissection of the proximal landing zone after zone 2 TEVAR in 1 case. We reconstructed the neck branches under cardiopulmonary bypass (CPB). At that time, we kept in mind to perform anastomosis with an artificial graft at just above the sinus of Valsalva by using a single aortic clamp. Both the 30-day operative mortality and CPB-related complication rates were 0%. One patient had paraparesis, and one had left upper limb ischemia. Our strategy of td TEVAR provided durable results in the patients who underwent reoperation for aortic arch aneurysms.

[Marked Aneurysmal Expansion Caused by Type II Endoleaks Eight Years after Thoracic Endovascular Aortic Repair;Report of a Case].

We report a case of marked aneurysmal expansion by type II endoleaks 8 years after thoracic endovascular aortic repair. The preoperative chest computed tomography (CT) demonstrated the descending thoracic aorta of 95 mm with type II endoleak. We performed suture closure of 3 endoleaks and partial aneurysmorrhaphy via left thoracotomy under partial cardiopulmonary bypass. The postoperative CT showed no endoleak with shrinkage of the aneurysm. The patient was discharged on the 21th postoperative day uneventfully.

[Strategy of Thoracic Endovascular Aortic Repair for Uncomplicated Type B Aortic Dissection in Subacute and Chronic Phase;Interval From Onset and Maximum Diameter].

We classified 59 patients who underwent thoracic endovascular aortic repair for uncomplicated type B aortic dissection from April 2008 to April 2016 into 3 groups based on time from onset and maximum aortic diameter:SA (2weeks to 1 year since onset;n=29), C (>1 year since onset;n=17), and D(maximum aneurysm size≥60 mm;n=13). We used the Kaplan-Meier method tso analyze survival, major adverse cardiovascular event and the need for additional treatment. There was no significant difference in outcomes between the SA and C groups (p=0.998) or C and D groups (p=0.279), but the results in group D tended to be consistently inferior. The freedom from aneurysm rupture rate was inferior in this group, with a significant difference between groups C and D (p=0.044). The time from onset to the procedure and maximum aortic diameter were not significantly associated with the longterm outcomes;however, more aortic ruptures occurred in the group with maximum aortic diameter≥60 mm. Simultaneous treatment for re-entry closure or conventional surgical procedures should be considered for such cases.

A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND AND OBJECTIVE: For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC. METHODS: Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy. RESULTS: In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan-Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%. CONCLUSIONS: These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02358395, registered on 9 February 2015.

What Did Endovascular Aortic Repair Bring for the Treatment Strategy of Abdominal Aortic Aneurysm?

Objective: We examined the effects of the introduction of endovascular aortic repair (EVAR) on treatment for abdominal aortic aneurysms (AAAs). Subjects: We compared patients in the following three periods: period I (January 2002-December 2006, 105 patients), period II (January 2007-December 2011, 242 patients, duration of 5 years after the introduction of EVAR), and period III (January 2012-December 2016, 237 patients, duration of 5 years after period II). We used the American Society of Anesthesiologists (ASA) classification for risk assessment. Results: In the Open repair (OR) group, the incidences of ASA class 2 increased and classes 3 and 4 decreased significantly in periods II and III compared with period I. In all periods, there were no in-hospital deaths. Suprarenal aortic cross-clamping was required in 18 patients (19.1%) in period III and 5 patients (6.3) in period I, and the difference was significant (P<0.05). In the EVAR group, no differences in age, sex, or ASA classification class were observed between periods II and III. In period II, one patient died due to aneurysm rupture during surgery. Significant differences were observed when comparing both groups in periods II and III: patients in the EVAR group were older (P<0.01) and the OR group had a higher proportion of ASA class 2 patients and the EVAR group had a higher proportion of ASA class 3 or 4 patients (P<0.01). Among all AAA surgeries, rupture occurred in 25 patients (23.8%) in period I, 18 patients (7.4) in period II, and 16 patients (6.8) in period III. The number of ruptures was significantly lower in periods II and III than in period I (P<0.01). Conclusions: The findings of this study suggest that EVAR should be indicated for high-risk patients and had the good outcome of AAA treatment. (This is a translation of Jpn J Vasc Surg 2018; 27: 27-32.).