Long-term results following off-pump coronary-artery bypass grafting in left ventricular dysfunction.

Severe left ventricular (LV) dysfunction is an independent risk factor for early and long-term mortality after coronary-artery bypass grafting (CABG). Off-pump CABG (OPCAB) significantly reduces the early incidence of major complications in high-risk patients. Moreover, bilateral internal thoracic artery (BITA) grafting after CABG is associated with improved long-term outcomes. We aimed to evaluate the impact of multivessel OPCAB with BITA grafting for complete revascularization on postoperative and long-term outcomes in patients with low LV ejection fraction (EF). We included 121 patients with EF ≤ 30.0% who underwent isolated multivessel OPCAB (average LVEF, 24.8%) between April 2007 and December 2019. Sixty-six patients received BITA grafts, while 55 had single internal thoracic artery (SITA) grafts. We conducted multivariate analyses to examine the correlation between perioperative data and late mortality rate. The early mortality rate was 1.65%. After excluding in-hospital mortality cases, we performed long-term follow-up of 119 patients. Early postoperative echocardiography showed significant LVEF improvement in 89 (75.2%) patients. However, LVEF remained ≤ 30.0% in 30 (24.8%) patients. We recorded 15 and 30 cases of cardiac death and cardiac events, respectively, during the long-term follow-up period. Postoperative LVEF ≤ 30.0% (P < 0.01) and no use of BITA grafting (P = 0.03) were significant predictors of cardiac death and events; moreover, hemodialysis was a significant predictor of all-cause mortality rather than cardiac death. Multivessel OPCAB in patients with severe LV dysfunction was associated with acceptable in-hospital mortality and early postoperative improvement in LV function. Additionally, OPCAB with BITA grafting may provide long-term benefits with respect to cardiac death and events. However, the long-term benefits were significantly limited in patients without early postoperative improvement in LV function and patients with chronic hemodialysis.Clinical registration number: 5590 (14/5/2020 Tokyo Women's Medical University).

Propensity score-matched comparison of total arterial off- and on-pump coronary artery bypass with complete revascularization.

Little is known regarding the long-term (> 10 years) outcomes and risk factors of total arterial coronary artery bypass grafting (CABG). This study evaluated the long-term outcomes and risk factors for all-cause mortality and major adverse cardiac and cerebrovascular events (MACCEs) following total arterial on-pump CABG (ONCAB) or off-pump CABG (OPCAB) with complete revascularization. This retrospective cohort analysis enrolled patients with stable angina who underwent total arterial CABG with complete revascularization in our institute between July 2000 and June 2019. The endpoints were all-cause mortality and MACCE incidence, including a comparison between OPCAB and ONCAB. Long-term (10-year) outcomes were analyzed using propensity score-matched pairs, and risk factors were evaluated using univariate and multivariate analyses. Overall, 401 patients who underwent primary total arterial CABG were classified into the OPCAB (n = 269) and ONCAB (n = 132) groups. Using propensity score matching (PSM), 88 patients who underwent OPCAB were matched with 88 patients who underwent ONCAB. The mean follow-up period was 7.9 ± 6.3 years. No significant difference in all-cause mortality (hazard ratio, 1.04; 95% confidence interval, 0.53-2.04; p = 0.9138) and MACCE incidence (hazard ratio, 1.06; 95% confidence interval, 0.68-1.65; p = 0.7901) was observed between the two groups. Renal failure requiring dialysis was a significant risk factor for mortality (p < 0.0001) and MACCEs (p = 0.0003). Long-term outcomes of total arterial OPCAB and ONCAB with complete revascularization showed similar findings using PSM. Renal failure requiring dialysis was a significant risk factor for mortality and morbidity.Journal standard instruction requires an unstructured abstract; hence the headings provided in abstract were deleted. Kindly check and confirm.Thank you for your kindness.Clinical registration number 5598, Tokyo Women's Medical University Hospital.

Thirty-year outcomes of low-intensity anticoagulation for mechanical aortic valve.

The long-term safety, efficacy, and outcomes of low-intensity anticoagulation for mechanical heart valves remain unclear. This study aimed to evaluate the long-term outcomes of low-intensity anticoagulation therapy after aortic valve replacement (AVR) with a mechanical prosthesis. This retrospective cohort study consulted medical records and conducted a questionnaire to investigate 519 patients who underwent single AVR with the St. Jude Medical bileaflet valve and were in sinus rhythm. All patients were followed up with an international normalized ratio (INR) target of 1.6-2.5, and their INR values were checked throughout the follow-up period. The survival rate, incidence of major adverse cardiac and cerebrovascular events (MACCE), and risk factors for cardiac death and MACCE were investigated. The total follow-up was 9793 patient-years, and the follow-up periods were 19.9 (standard deviation [SD]: 7.9) years. The mean INR was 2.03 (SD: 0.54). Survival rates from cardiac death were 93.6% in 20 years and 85.2% in 30 years. Advanced age ≥ 70 years was the only significant risk factor for cardiac death and MACCE, and the INR < 2.0 was not significant risk factor for MACCE including thromboembolism or bleeding events. Low-intensity anticoagulation with an INR of 1.6-2.5 for patients with sinus rhythm after AVR with a bileaflet mechanical valve is safe and effective, even over 30 years.

Trans-cuff leakage in bio-Bentall operation.

We have reported a case of trans-cuff leakage that occurred in a composite graft of bio-Bentall operation. The leakage resolved several months after surgery, similar to the trans-cuff leakage seen in simple aortic valve replacement. We have proposed hypotheses on the mechanism of trans-cuff leakage during a bio-Bentall operation and suggested ways to prevent it from occurring.

Coronary artery bypass using bilateral internal thoracic artery grafts in polyarteritis nodosa.

Polyarteritis nodosa (PAN) affects small- and medium-sized arteries but rarely occurs in coronary artery aneurysms and stenosis. For patients with PAN, coronary artery bypass grafting (CABG) can be challenging, especially with respect to graft selection. We performed CABG using a bilateral internal thoracic artery (ITA) graft for a 21-year-old patient with PAN, with successful postoperative outcomes. Arterial grafts have the risk of stenosis in PAN, but the patient's condition was controlled by steroids and immunosuppressants, and angiography showed no stenosis. We decided to use the ITA graft as a bypass conduit and found that long-term follow-up and continuous treatment are necessary.

[Hybrid Treatment for Left Internal Thoracic Artery-Pulmonary Artery Fistula with Aneurysm Complicated with Mitral Regurgitation:Report of a Case].

A 78-year-old man with mitral regurgitation incidentally diagnosed with aneurysm of the left internal thoracic artery(LITA) and several internal thoracic artery-pulmonary artery( ITA-PA) fistulas originating from the aneurysm. To prevent rupture of the aneurysm, ITA ligation was performed during surgery for the mitral valve. Because of the complex anatomy surrounding the aneurysm, the main duct of the ITA was ligated at the peripheral and center of the aneurysm, then arterial fistulae were resected as many as possible. Postoperative computed tomography (CT), however, showed patent LITA and contrast material in the aneurysm. Second stage coil embolization procedure was performed with successful results. Intravascular treatment is effective for ITA aneurysms or ITA-PA fistulae because we can clearly visualize and confirm blood flow during operation.

[Re-operation for Saccular Aneurysm after Ascending Aortic Replacement with Homograft;Report of a Case].

A 62-years-old female had undergone ascending aortic replacement with homograft for graft infection and mediastinitis after initial replacement of ascending aorta due to acute type A dissection. Ten years after homograft replacement, follow up computed tomography showed acute growing saccular aneurysm of the homograft without infectious symptoms. We urgently performed Bentall procedure and hemiarch replacement successfully. Pathological diagnosis was true aneurysm of the homograft. She was discharged from hospital without any complication and has been quite uneventful 7 years after surgery. True aneurysm of the homograft is very rare and our case is the 1st report of successful reoperation.

Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification.

Chondrocyte hypertrophy during endochondral ossification is a well-controlled process in which proliferating chondrocytes stop proliferating and differentiate into hypertrophic chondrocytes, which then undergo apoptosis. Chondrocyte hypertrophy induces angiogenesis and mineralization. This step is crucial for the longitudinal growth and development of long bones, but what triggers the process is unknown. Reactive oxygen species (ROS) have been implicated in cellular damage; however, the physiological role of ROS in chondrogenesis is not well characterized. We demonstrate that increasing ROS levels induce chondrocyte hypertrophy. Elevated ROS levels are detected in hypertrophic chondrocytes. In vivo and in vitro treatment with N-acetyl cysteine, which enhances endogenous antioxidant levels and protects cells from oxidative stress, inhibits chondrocyte hypertrophy. In ataxia telangiectasia mutated (Atm)-deficient (Atm(-/-)) mice, ROS levels were elevated in chondrocytes of growth plates, accompanied by a proliferation defect and stimulation of chondrocyte hypertrophy. Decreased proliferation and excessive hypertrophy in Atm(-/-) mice were also rescued by antioxidant treatment. These findings indicate that ROS levels regulate inhibition of proliferation and modulate initiation of the hypertrophic changes in chondrocytes.

A modification of the palmaris longus-to-extensor pollicis longus transfer for radial nerve palsy.

PURPOSE: The standard palmaris longus (PL)-to-rerouted extensor pollicis longus (EPL) transfer was modified by taking the PL with an extension of the palmar aponeurosis (PA) and performing the transfer at the level of the thumb metacarpal. Our purpose was to evaluate whether this modified transfer could restore both the extension and the radial abduction of the thumb without rerouting the EPL. METHODS: We restored thumb function of 5 patients with unrecovered radial nerve palsy (4 men and 1 women; mean age at surgery, 47 years; mean duration between onset of palsy and surgery, 13 months; and mean follow-up period after surgery, 17 months). The PA was dissected in continuity with the PL (PA/PL) tendon, as is done in Camitz thumb opponensplasty. Another skin incision was made on the dorsal side of the thumb metacarpal, and the EPL tendon was exposed. The PA/PL tendon was drawn into this skin incision, passing under the abductor pollicis longus and extensor pollicis brevis tendons. The PA/PL tendon was woven into the undivided EPL tendon and immobilized for 3 weeks. RESULTS: The mean values of active hyperextension and flexion of the interphalangeal joint, radial abduction, palmar abduction of the thumb, grip strength, and tip pinch strength of the involved/contralateral sides were 3°/7°, 41°/49°, 59°/65°, 65°/70°, 37 kg/47 kg, and 4.0 kg/5.2 kg, respectively. DISCUSSION: We used the PA to lengthen the PL tendon, to transfer it to the EPL at a level distal to the Lister tubercle. Because our procedure is based on the concept of standard transfer, it should yield similar long-term results. Our procedure should be a good alternative, especially in cases of closed radial nerve injury, because it preserves the paralyzed EPL for possible future recovery.

Successful Removal of a Posterior Cardiac Lipoma by Transection of the Ascending Aorta and Main Pulmonary Artery.

Primary cardiac tumors are unusual, whereas lipomas are particularly rare. We successfully removed a very large posterior cardiac lipoma by transecting the ascending aorta and main pulmonary artery. Transecting both the ascending aorta and the main pulmonary artery facilitated surgical exposure and complete removal of the posterior cardiac lipoma.

DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells.

Osteoclasts are bone-resorbing cells that play a pivotal role in bone remodeling. Osteoclasts form large multinuclear giant cells by fusion of mononuclear osteoclasts. How cell fusion is mediated, however, is unclear. We identify the dendritic cell-specific transmembrane protein (DC-STAMP), a putative seven-transmembrane protein, by a DNA subtraction screen between multinuclear osteoclasts and mononuclear macrophages. DC-STAMP is highly expressed in osteoclasts but not in macrophages. DC-STAMP-deficient mice were generated, and osteoclast cell fusion was completely abrogated in homozygotes despite normal expression of osteoclast markers and cytoskeletal structure. As osteoclast multinucleation was restored by retroviral introduction of DC-STAMP, loss of cell fusion was directly attributable to a lack of DC-STAMP. Defects in osteoclast multinucleation reduce bone-resorbing activity, leading to osteopetrosis. Similar to osteoclasts, foreign body giant cell formation by macrophage cell fusion was also completely abrogated in DC-STAMP-deficient mice. We have thus identified an essential regulator of osteoclast and macrophage cell fusion, DC-STAMP, and an essential role of osteoclast multinucleation in bone homeostasis.

Association between the elbow flexion test and extraneural pressure inside the cubital tunnel.

PURPOSE: The elbow flexion test is a standard, provocative diagnostic test for cubital tunnel syndrome (CubTS). The purpose of this study was to investigate the association between the elbow flexion test and the degree of extraneural pressure in the cubital tunnel of CubTS patients. METHODS: Extraneural pressure on the ulnar nerve in the cubital tunnel was evaluated using 0.7-mm thickness catheter during surgery of 25 CubTS cases and compared with the results of preoperative elbow flexion testing. Statistic analysis was performed using Student's t-test with a confidence level of 95% (p < .05). RESULTS: Forty-eight percent of the patients were positive for the elbow flexion test. Mean extraneural pressure was significantly higher in maximum elbow flexion than in maximum elbow extension (p < .001). No significant association was seen between the result of 45 seconds of the elbow flexion test and the extraneural pressure in the cubital tunnel induced by maximum elbow flexion (p = .45). CONCLUSIONS: Our results suggested that the mechanism of provocation of symptoms of CubTS by the elbow flexion could not be explained simply by dynamic pressure in the cubital tunnel, and other pathophysiological factors could also be contributing. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III.

Comparison of shoulder internal rotation test with the elbow flexion test in the diagnosis of cubital tunnel syndrome.

PURPOSE: To compare the shoulder internal rotation test-a new, provocative test-with the elbow flexion test in the diagnosis of cubital tunnel syndrome (CubTS). METHODS: Twenty-five patients with CubTS were examined before and after surgery with 10 seconds each of the elbow flexion and shoulder internal rotation tests. Fifty-four asymptomatic individuals and 14 neuropathy patients with a diagnosis other than CubTS were also examined as control cases. For the shoulder internal rotation test, the patient's upper extremity was kept at 90° abduction, maximum internal rotation, and 10° flexion at the shoulder, with 90° elbow flexion and neutral position of the forearm and wrist, with finger extension. Test results were considered positive if any slight symptom attributable to CubTS occurred within 10 seconds. Extraneural pressure inside the cubital tunnel was intraoperatively measured with the positions of both the elbow flexion and shoulder internal rotation tests, in 15 of the CubTS cases. Statistical analyses were performed using Student's t-test with a confidence level of 95%. RESULTS: The preoperative sensitivity in CubTS cases was 80% in the 10-second shoulder internal rotation test and 36% in the 10-second elbow flexion test, and these differences were significant. None of the control cases had positive results in either test. All the CubTS cases improved with surgery; after surgery, neither test provoked symptoms in any surgical patient. The extraneural pressure increased in both provocative positions with no significant difference. CONCLUSIONS: Positive results for the 10-second shoulder internal rotation test were more sensitive than that for the elbow flexion test of the same duration and seemed specific to CubTS.

Surgical management for dual left anterior descending artery with anomalous origin of left coronary artery from pulmonary artery: a case report.

A dual left anterior descending artery with an anomalous origin of the left coronary artery from the pulmonary artery is an extremely rare coronary artery anomaly, with only one case known previously reported. However, that study presented coronary anatomical findings with images and little is known regarding patient outcome following surgical management for this unique condition. We present here the first case report of an affected patient, who underwent off-pump coronary artery bypass grafting and ligation of the coronary anomaly, as well as postoperative course details.

Induction of DC-STAMP by alternative activation and downstream signaling mechanisms.

UNLABELLED: DC-STAMP is essential for fusion of osteoclasts and foreign body giant cells; however, it is not known whether dc-stamp expression in these two cell types is differentially regulated. Here, we show that dc-stamp expression and cell-cell fusion are regulated in a cell type-specific manner. INTRODUCTION: The transcription factors c-Fos and NFATc1 cooperate to regulate osteoclast differentiation, whereas PU.1 and NF-kappaB are activated in macrophages and osteoclasts or in both cell types. Thus, we asked what role c-Fos, NFATc1, PU.1, and NF-kappaB played in regulating dendritic cell-specific transmembrane protein (dc-stamp) expression and fusion of osteoclasts and macrophage giant cells. MATERIALS AND METHODS: Transcriptional activation by c-Fos and NFATc1 was examined by dc-stamp promoter analysis. Multinuclear cell formation was analyzed in cells from c-Fos-deficient mice or in wildtype cells treated with the NFAT inhibitor FK506. The role of DC-STAMP in cell fusion was examined in vitro in a macrophage giant cell formation assay using DC-STAMP-deficient cells. Recruitment of c-Fos, NFATc1, PU.1, and NF-kappaB to the dc-stamp promoter in osteoclasts and macrophage giant cells was analyzed by chromatin-immunoprecipitation analysis. RESULTS: Both activator protein-1 (AP-1) and NFAT binding sites in the dc-stamp promoter were needed for dc-stamp expression after RANKL stimulation of osteoclasts. dc-stamp expression was induced in osteoclasts and macrophage giant cells, and cells from DC-STAMP-deficient mice failed to form either multinuclear osteoclasts or macrophage giant cells. In contrast, c-Fos is indispensable for dc-stamp expression and cell-cell fusion under conditions favoring in vitro and in vivo induction of osteoclasts but not macrophage giant cells. Consistently, an NFAT inhibitor suppressed multinuclear osteoclast formation but not macrophage giant cell formation. In addition, PU.1 and NF-kappaB binding sites were detected in the dc-stamp promoter, and both PU.1 and NF-kappaB were recruited to the dc-stamp promoter after granulocyte-macrophage colony stimulating factor (GM-CSF) + interleukin (IL)-4 stimulation. CONCLUSIONS: dc-stamp expression is regulated differently in osteoclasts and macrophage giant cells. c-Fos and NFATc1, both of which are essential for osteoclast differentiation, are needed for dc-stamp expression and cell-cell fusion in osteoclasts, but both factors are dispensable for giant cell formation by macrophages. Because PU.1 and NF-kappaB are recruited to the dc-stamp promoter after stimulation with GM-CSF + IL-4, dc-stamp transcription is regulated in a cell type-specific manner.

Elective neck irradiation on ipsilateral side in patients with early tongue cancer for high-risk group with late cervical lymph node metastasis.

A prospective study was performed to assess the efficacy of elective neck irradiation (ENI) on the ipsilateral side in patients with early tongue cancer among a high-risk group with late cervical lymph node metastasis. Patients in the high-risk group had T2-tumors, excluding superficials or T1-tumors > or =19 mm in maximal diameter with invasion or ulcer. Between February 1989 and October 1997, 70 patients with tongue cancer of Stages I and II were enrolled in the present study (ENI group: 31, non-ENI group: 39). In a combination therapy of external beam irradiation and brachytherapy, the standard dose of interstitial brachytherapy for primary tumors was approximately 60 Gy. Irradiation was initiated with a 9-MeV electron beam at a dose of 50 Gy on the ipsilateral side of the neck only when the day of brachytherapy approached. Three patients (9.7%) in the ENI group had neck lymph node metastasis as did 5 (12.8%) in the non-ENI group (p= 0.684). In patients with ulceration, the incidence of subsequent lymph node metastasis was significantly higher (p=0.029). Neck lymph node metastasis occurred in 2 (16.7%) of 12 patients with ulcers in the ENI group and in 2 (66.7%) of 3 with ulcers in the non-ENI group. Although we could not demonstrate the significant efficacy of ENI in the high-risk group in this study, ENI decreased the neck lymph node metastasis. In addition, our results suggested that ENI particularly inhibits cervical lymph node metastasis in tongue tumor patients with ulcers.

Myectomy as an alternative solution for systolic anterior motion in a patient who underwent mitral valve repair.

Systolic anterior motion (SAM) of the mitral apparatus is a relatively frequent complication of mitral valve repair. When significant SAM persists despite intraoperative medical therapies, a second repair is generally required. We describe a rare case of SAM due to a hypertrophic septum in a patient who underwent mitral valve repair, with no preoperative obstruction of the left ventricular outflow tract. The present case of SAM was successfully treated only with transaortic septal myectomy. Therefore, myectomy might be considered as an alternative solution for SAM that is suspected to be caused by a hypertrophic septum after mitral valve repair.

Comparison of early haemodynamics of 19-mm aortic valve bioprostheses in patients with a small aortic annulus.

OBJECTIVES: A potential problem in aortic valve replacement (AVR) for patients with a small aortic annulus is prosthesis-patient mismatch (PPM). Although larger size prostheses have been well studied, the haemodynamics of 19-mm bioprostheses has been reported in only a small number of patients. The Trifecta valve is a novel bioprosthesis and its unique design is conceived to increase effective orifice area (EOA) and prevent PPM. This study aims at comparing the early haemodynamics of the new Trifecta valve with that of other conventional 19-mm valves. METHODS: We retrospectively evaluated 128 consecutive patients who underwent AVR with 19-mm bioprosthesis (39 Trifecta valve, 67 Magna Ease valve and 22 Mosaic Ultra valve) at Saitama International Medical Center between April 2012 and December 2014. Haemodynamics was evaluated by transthoracic echocardiography at 1 month after discharge and at 1-year follow-up. RESULTS: The average body surface area of all patients was 1.37 m(2). There was no difference in postoperative clinical outcomes between the three groups. Among the three groups, the mean pressure gradient (MPG) was the smallest (10.6 ± 4.3 mmHg, P < 0.001) and the EOA was the largest (1.63 ± 0.36 cm(2), P < 0.001) in the Trifecta group at 1 month after discharge. In the Trifecta group, PPM was not observed (P < 0.001), the MPG was the smallest (12.8 ± 3.6 mmHg, P < 0.001) and the EOA was the largest (1.50 ± 0.30 cm(2), P < 0.001) at the 1-year follow-up. CONCLUSIONS: The new 19-mm Trifecta valve showed favourable early haemodynamics compared with the conventional valves and may be useful for preventing PPM in patients with a small aortic annulus.

Impacts of intraoperative flow on graft patency of sequential and individual saphenous vein grafts.

OBJECTIVE: We sought to delineate the predictor of saphenous vein graft (SVG) failure and to evaluate the impact of sequential grafting of SVG on graft flow as the significant predictor of patency. METHODS: Angiograms and clinical records of 439 patients who underwent coronary artery bypass grafting with aortocoronary SVG were reviewed. Of these, 708 distal anastomoses were created by 480 SVGs. Of 349 patients who underwent isolated coronary artery bypass grafting, operation was performed with an off-pump technique in 347 patients (99%). For 90 patients, a combined procedure on cardiopulmonary bypass was performed. A postoperative angiography was performed in 230 SVGs for clinical reasons. Insufficient flow (IF) was defined as a graft flow of 20 mL/min or less, measured by transit-time Doppler flowmetry during operation. RESULTS: In 480 SVGs, 44 (9.2%) presented IF, and 24 SVGs presented partial or total occlusion. Six of the nine failed individual SVG had IF, whereas none of the failed sequential SVG was associated with IF. Univariate and multivariate logistic regression analyses demonstrated that IF (P = 0.002; odds ratio, 6.63) and sequential grafting (P = 0.004; odds ratio, 2.51) were significantly correlated with a failure of the SVG. The patency rate of sequential SVG to the most distal target was 78/93 (83.9%), which was significantly lower than 9/139 (93.5%) of the individual SVG (P = 0.02) and 7/113 (93.8%) of the sequential SVG to proximal targets (P = 0.02). CONCLUSIONS: When both targets seem to have sufficient demand, avoidance of sequential grafting would be reasonable. Moreover, the important target should be grafted by individual grafting or sequential proximal anastomosis.

Continuous infusion low-dose CDDP/5-FU plus radiation in inoperable or recurrent non-small-cell lung cancer: preliminary experience.

The combination therapy of continuous infusion low-dose cisplatin plus 5-fluorouracil (5-FU) with radiation for non-small-cell lung cancer (NSCLC) was performed to assess its effectiveness and any adverse reactions. During the period from April 1994 to December 1998, 18 patients with inoperable or recurrent NSCLC at Aichi Cancer Center Hospital had been treated by chemoradiation with continuous infusion of low-dose cisplatin/5-FU. The median total radiation dose was 66 Gy (range: 60-74.4 Gy). The daily doses of cisplatin and 5-FU ranged from 3 to 6 mg/m2, and from 170 to 250 mg/m2, respectively. In 18 total patients, a complete response was achieved in 4 patients (22%), and a partial response was observed in 12 patients (67%). Grade III toxicity was limited to leukopenia (14.3%). The 1-year and 2-year survival rate in 14 previously untreated patients were 77.4% and 53.1%, respectively. This combination therapy is a well-tolerated regimen. In the future, a study protocol should be designed with a dose-escalation component to further define the optimal doses and schedule for this regimen.