Matthew T. Menard

Induction chemoradiation compared with induction radiation for lung cancer involving the superior sulcus

BACKGROUND The usual approach of induction radiation therapy (RT) followed by resection of superior sulcus tumors results in many incomplete resections, a high local recurrence rate, and suboptimal survival. Induction chemoradiotherapy (CT/RT) has been shown to reduce local and distant recurrences and improve survival in stage III lung cancer. We investigated the role of induction CT/RT in superior sulcus patients. METHODS This was a single-institution, retrospective study. RESULTS From 1985 to 2000, 35 consecutive patients underwent induction treatment followed by resection of a superior sulcus tumor. All patients had mediastinoscopy first to exclude N2 disease, and all were N0 at final pathologic examination. Twenty patients had induction RT (mean, 39 Gy), and 15 had induction CT/RT (mean, 51 Gy) with concurrent cisplatin-based chemotherapy. There was no treatment mortality. Complete resection was performed in 16 of 20 (80%) of the RT patients and in 14 of 15 (93%) of the CT/RT patients (p = 0.15). The pathologic response from the induction treatment was complete or near complete in 7 of 20 (35%) of the RT patients and in 13 of 15 (87%) of the CT/RT patients (p = 0.001). The median follow-up was 167 months in the RT patients and 51 months in the CT/RT patients. Two-year and 4-year survival was 49% and 49% (95% confidence interval, 26% to 71%) in the RT patients and 93% and 84% (95% confidence interval, 63% to 100%) in the CT/RT patients, respectively (p = 0.01). The local recurrence rate was 6 of 20 (30%) in the RT patients and 0 in the CT/RT patients (p = 0.02). CONCLUSIONS Induction CT/RT for superior sulcus tumors appears to offer improved survival compared with induction RT alone.

Skin-specific alloantigens in miniature swine

BACKGROUND The acceptance of skin allografts has historically been among the most challenging problems in the field of transplantation, attributed, at least in part, to the existence of antigens expressed by skin but not by other tissues. Many studies have suggested the existence of skin-specific antigens in rodents, but data in large-animal models are more limited. METHODS We have recently developed protocols for attaining stable mixed hematopoietic chimerism in miniature swine, using MHC-matched donors and recipients. We have now assessed tolerance to donor-derived skin and cardiac allografts in these chimeric animals. RESULTS Skin-graft rejection was seen in four of six animals receiving skin grafts taken from the respective hematopoietic donors. In the other two animals, donor-derived skin grafts survived indefinitely. No cardiac-allograft rejection was observed in mixed-chimeric animals that received heart transplants from their hematopoietic donors, even in animals that had already rejected skin allografts from the same donors. In all animals assessed, in vitro hyporesponsiveness to donor hematopoietic cells persisted. CONCLUSION These findings support the concept that skin expresses immunogenic alloantigens that either are not expressed or are not immunogenic in cardiac or hematopoietic tissue.

The BEST-CLI Trial: A Multidisciplinary Effort to Assess Which Therapy is Best for Patients With Critical Limb Ischemia

Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease and is associated with a significant risk of limb loss. It is currently treated with limb revascularization by a variety of specialists. Although both open vascular bypass and endovascular therapy are offered to patients with infrainguinal peripheral arterial disease and CLI, significant disagreement exists as to which therapy works best in candidates for both types of intervention. Persistent clinical equipoise in combination with a paucity of comparative effectiveness data to guide treatment of CLI has led to a multidisciplinary effort to organize the Best Endovascular versus Best Surgical Therapy in patients with CLI (BEST-CLI) trial. The BEST-CLI trial is a pragmatic, multicenter, open label, randomized trial that compares best endovascular therapy with best open surgical treatment in patients eligible for both treatments. This trial is highly innovative in both its design and its collaborative nature. BEST-CLI aims to provide urgently needed clinical guidance for CLI management by using (1) a pragmatic design comparing the effectiveness of established techniques while allowing for the introduction of newer therapies as they become available; (2) a novel primary end point that includes limb amputation rates, repeat intervention, and mortality; (3) a multidisciplinary structure that fosters cooperation among interventional cardiologists, interventional radiologists, vascular surgeons, and vascular medicine specialists; and (4) novel techniques to evaluate the cost-effectiveness and quality-of-life outcomes of the 2 treatment strategies being tested.

Mixed hematopoietic chimerism induces long-term tolerance to cardiac allografts in miniature swine

BACKGROUND Tolerance to cardiac allografts has not been achieved in large animals using methods that are readily applicable to human recipients. We investigated the effects of mixed hematopoietic chimerism on cardiac allograft survival and chronic rejection in miniature swine METHODS Recipients were T-cell depleted using a porcine CD3 immunotoxin, and each received either of two nonmyeloablative preparative regimens previously demonstrated to permit the establishment of stable mixed hematopoietic chimerism across MHC-matched, minor antigen-mismatched histocompatibility barriers. Five to 12 months after the chimerism was induced, hearts from the original cell donors were heterotopically transplanted into the stable mixed chimeras. RESULTS Cardiac allografts transplanted into untreated recipients across similar minor antigen barriers were rejected within 44 days (within 21, 28, 35, 39, 44 days among individual study subjects). In contrast, hearts transplanted into the mixed chimeras were all accepted long term ( > 153, > 225, > 286, > 362 days) without immunosuppressive drugs and developed minimal vasculopathy. CONCLUSIONS Mixed hematopoietic chimerism, established in miniature swine using clinically relevant, non-myeloablative conditioning regimens, permits long-term cardiac allograft survival without chronic immunosuppressive therapy, significant vasculopathy, or graft-versus-host disease.

Nutcracker Syndrome: When Should It Be Treated and How?:

Nutcracker syndrome refers to compression of the left renal vein by the superior mesenteric artery and aorta. Patients typically present with left flank pain and associated symptoms of pelvic congestion. Hematuria is frequently present, and vulvar or lower extremity varices are seen in a subset of patients. Clinical suspicion of the syndrome is confirmed by duplex scanning, computerized tomography, or magnetic resonance imaging. Documentation of a hemodynamically significant pressure gradient across the point of compression during venographic assessment in patients with appropriate symptom severity is important prior to undertaking treatment. A variety of surgical procedures have been described to achieve venous decompression, the most popular being that of transposition of the left renal vein to the more distal inferior vena cava. Long-term data on the success of surgical treatment is scarce. More recently, endovascular stenting of the left renal vein has been used.

Ethmoid sinus carcinomas: Results and prognosis after neoadjuvant chemotherapy and combined surgery—A 10-Year experience

From June 1982 to June 1992, 144 ethmoido-sphenoido-orbital tumors have been referred to the neurosurgical department of Ste Anne Hospital. One hundred five of them were malignant lesions, among which 83 were included into our therapeutic protocol (1) neo-adjuvant chemotherapy (CDDP + 5-FU), (2) combined surgical procedure (subfrontal and transfacial), (3) postoperative radiotherapy. Fifty nine percent of the patients had no response to chemotherapy; 19% had a partial response (reduction of the tumoral volume > 50% and < 100%), 22% had a complete response. One patient had an immediate and transient postoperative rhinorrhea responsible for meningitis (acinetobacter) that was cured after a 3-day treatment. Four patients had postoperative meningitis without any cerebrospinal fluid leakage; they were also cured. Five patients had a local suppuration that was treated by subcutaneous drainage (n = 1) or the removal of the cranial basis graft (n = 4). Oncologic results are presented for only adenocarcinomas (n = 63) because they represent the only population of this series large enough to assure significant statistical figures. The global actuarial survival rate was 53% at 3 years and 42.5% at 5 years. The 5-year actuarial survival rate was 80% for T1 tumors, 60% for T2, 40% for T3, and 25% for T4. Patients with an intracranial extension had a 3-year survival rate of 19%; none survived after 4-year follow-up. Neo-adjuvant chemotherapy seemed to influence the survival: 100% survival rate at 5 and 10 years for the complete responders. We discuss the opportunity of intraorbital exenteration, the indications, and the limits of combined surgery. We emphasize the importance of neo-adjuvant chemotherapy and of combined surgical procedures, even when the patients are complete responders to chemotherapy: complete responders who had only a transfacial approach have a 5-year actuarial survival rate of 80% (instead of 100% when a combined procedure was performed). Those who were not operated primarily recurred within 3 years and then had to be operated. We propose to follow such a combined surgery for all large ethmoidal cancers (T3 and T4) and for small tumors (T1 and T2) developed superiorly and posteriorly. Anterior T1 and T2 tumors should be operated through a single transfacial route.

The effect of thymectomy on tolerance induction and cardiac allograft vasculopathy in a miniature swine heart/kidney transplantation model.

BACKGROUND We have previously demonstrated that MHC class I disparate hearts transplanted into miniature swine treated with a short course of cyclosporine developed florid cardiac allograft vasculopathy (CAV) and were rejected within 55 days. However, when a donor-specific kidney is cotransplanted with the heart allograft, recipients become tolerant to donor antigen and accept both allografts long-term without the development of CAV. In the present study, we have investigated the role of the host thymus in the induction of tolerance and prevention of CAV in heart/kidney recipients. METHODS Total thymectomies were performed in six animals (postoperative day [POD]-21), which on day 0 received either an isolated MHC class I disparate heart allograft (n=3) or combined class I disparate heart and kidney allografts (n=3), followed in both cases by a 12-day course of cyclosporine (POD 0-11). Graft survival and the development of CAV in these thymectomized recipients were compared to the same parameters in non-thymectomized, cyclosporine-treated recipients bearing either class I disparate heart allografts (n=5) or heart and kidney allografts (n=4). RESULTS In the group of animals bearing isolated class I disparate heart allografts, the thymectomized recipients rejected their allografts earlier (POD 8, 22, 27) than the non-thymectomized recipients (POD 33,35,45,47,55). The donor hearts in both the thymectomized and non-thymectomized animals developed florid CAV. In the group of animals bearing combined class I disparate heart and kidney allografts, the nonthymectomized recipients accepted both donor organs long term with no evidence of CAV. In contrast, none of the thymectomized heart/kidney recipients survived >100 days, and they all developed the intimal proliferation of CAV. CONCLUSION Thymic-dependent mechanisms are necessary for the induction of acquired tolerance and prevention of CAV in porcine heart/kidney recipients.

A multi-center, dose-escalation study of human type I pancreatic elastase (PRT-201) administered after arteriovenous fistula creation

Purpose To explore the safety and efficacy of PRT-201. Methods Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.0033 to 9 mg) applied after arteriovenous fistula (AVF) creation. Participants were followed for one year. The primary outcome measure was safety. Efficacy measures were the proportion with intra-operative increases in AVF outflow vein diameter or blood flow ≥25% (primary), changes in outflow vein diameter and blood flow, AVF maturation and lumen stenosis by ultrasound criteria and AVF patency. Results The adverse events in the PRT-201 group (n=45) were similar to those in the placebo group (n=21). There were no differences in the proportion with ≥25% increase in vein diameter or blood flow, successful maturation or lumen stenosis. There was no statistically significant difference in primary patency between the dose groups (placebo n=21, Low Dose n=16, Medium Dose n=17 and High Dose n=12). In a subgroup analysis that excluded three participants with early surgical failures, the hazard ratio (HR) for primary patency loss of Low Dose compared with placebo was 0.38 (95% CI 0.10-1.41, P=0.15). In a Cox model, Low Dose (HR 0.27, 95% CI 0.04-0.79, P=0.09), white race (HR 0.17, 95% CI 0.03-0.79, P=0.02), and age <65 years (HR 0.25, CI 0.05-1.15, P=0.08) were associated (P<0.10) with a decreased risk of primary patency loss. Conclusions PRT-201 was not different from placebo for safety or efficacy measures. There was a suggestion for improved AVF primary patency with Low Dose PRT-201 that is now being studied in a larger clinical trial.

Critical Limb Ischemia : An Expert Statement

Critical limb ischemia (CLI), the most advanced form of peripheral artery disease, is associated with significant morbidity, mortality, and health care resource utilization. It is also associated with physical, as well as psychosocial, consequences such as amputation and depression. Importantly, after a major amputation, patients are at heightened risk of amputation on the contralateral leg. However, despite the technological advances to manage CLI with minimally invasive technologies, this condition often remains untreated, with significant disparities in revascularization and amputation rates according to race, socioeconomic status, and geographic region. Care remains disparate across medical specialties in this rapidly evolving field. Many challenges persist, including appropriate reimbursement for treating complex patients with difficult anatomy. This paper provides a comprehensive summary that includes diagnostic assessment and analysis, endovascular versus open surgical treatment, regenerative and adjunctive therapies, and other important aspects of CLI.

Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST‐CLI) Trial

Background Critical limb ischemia (CLI) is increasing in prevalence, and remains a significant source of mortality and limb loss. The decision to recommend surgical or endovascular revascularization for patients who are candidates for both varies significantly among providers and is driven more by individual preference than scientific evidence. Methods and Results The Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST‐CLI) Trial is a prospective, randomized, multidisciplinary, controlled, superiority trial designed to compare treatment efficacy, functional outcomes, quality of life, and cost in patients undergoing best endovascular or best open surgical revascularization. Approximately 140 clinical sites in the United States and Canada will enroll 2100 patients with CLI who are candidates for both treatment options. A pragmatic trial design requires consensus on patient eligibility by at least 2 investigators, but leaves the choice of specific procedural strategy within the assigned revascularization approach to the individual treating investigator. Patients with suitable single‐segment of saphenous vein available for potential bypass will be randomized within Cohort 1 (n=1620), while patients without will be randomized within Cohort 2 (n=480). The primary efficacy end point of the trial is Major Adverse Limb Event–Free Survival. Key secondary end points include Re‐intervention and Amputation‐Free‐Survival and Amputation Free‐Survival. Conclusions The BEST‐CLI trial is the first randomized controlled trial comparing endovascular therapy to open surgical bypass in patients with CLI to be carried out in North America. This landmark comparative effectiveness trial aims to provide Level I data to clarify the appropriate role for both treatment strategies and help define an evidence‐based standard of care for this challenging patient population. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02060630.