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Samuel A Wells,
Bruce G Robinson,
Robert F Gagel,
Henning Dralle,
James A Fagin,
Massimo Santoro,
Eric Baudin,
Rossella Elisei,
Barbara Jarzab,
James R Vasselli,
Jessica Read,
Peter Langmuir,
Anderson J Ryan,
Martin J Schlumberger
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ABSTRACT: There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC.
Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments.
Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%).
Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).
Journal of Clinical Oncology 01/2012; 30(2):134-41. · 18.37 Impact Factor
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ABSTRACT: PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.
Journal of Clinical Oncology 02/2010; 28(5):767-72. · 18.37 Impact Factor
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ABSTRACT: The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family alpha co-receptors (GFRalpha). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy.
Clinical Cancer Research 12/2009; 15(23):7119-23. · 7.74 Impact Factor
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Richard T Kloos,
Charis Eng,
Douglas B Evans,
Gary L Francis,
Robert F Gagel,
Hossein Gharib,
Jeffrey F Moley,
Furio Pacini,
Matthew D Ringel,
Martin Schlumberger, Samuel A Wells
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ABSTRACT: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and challenging malignancy. The American Thyroid association (ATA) chose to create specific MTC Clinical Guidelines that would bring together and update the diverse MTC literature and combine it with evidence-based medicine and the knowledge and experience of a panel of expert clinicians.
Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force, Agency for Healthcare Research and Quality.
Clinical topics addressed in this scholarly dialog included: initial diagnosis and therapy of preclinical disease (including RET oncogene testing and the timing of prophylactic thyroidectomy), initial diagnosis and therapy of clinically apparent disease (including preoperative testing and imaging, extent of surgery, and handling of devascularized parathyroid glands), initial evaluation and treatment of postoperative patients (including the role of completion thyroidectomy), management of persistent or recurrent MTC (including the role of tumor marker doubling times, and treatment of patients with distant metastases and hormonally active metastases), long-term follow-up and management (including the frequency of follow-up and imaging), and directions for future research.
One hundred twenty-two evidence-based recommendations were created to assist in the clinical care of MTC patients and to share what we believe is current, rational, and optimal medical practice.
Thyroid: official journal of the American Thyroid Association 07/2009; 19(6):565-612. · 2.60 Impact Factor
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ABSTRACT: The National Cancer Institute (NCI) sponsored the NCI Thyroid Fine-Needle Aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The 2-day meeting was accompanied by a permanent informational website and several on-line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document summarizes matters regarding training for the performance of thyroid FNA via palpation; training for the performance of thyroid FNA via ultrasound imaging, and credentialing/re-credentialing for the performance of a thyroid FNA. (http://thyroidfna.cancer.gov/pages/info/agenda/)
Diagnostic Cytopathology 07/2008; 36(6):400-6. · 1.16 Impact Factor
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Lester J Layfield,
Jacki Abrams,
Beatrix Cochand-Priollet,
Doug Evans,
Hossein Gharib,
Frank Greenspan,
Michael Henry,
Virginia LiVolsi,
Maria Merino,
Claire W Michael,
Helen Wang, Samuel A Wells
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ABSTRACT: The National Cancer Institute (NCI) sponsored the NCI Thyroid Fine Needle Aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The 2-day meeting was accompanied by a permanent informational Web site and several on-line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document addresses follow-up procedures and therapeutic options for suggested diagnostic categories. Follow-up options for "nondiagnostic" and "benign" thyroid aspirates are given. The value of ultrasound examination in the follow-up of "nondiagnostic" and "benign" thyroid aspirates is discussed. Ultrasound findings requiring reaspiration or surgical resection are described as are the timing and length of clinical and ultrasonographic surveillance for cytologically "benign" nodules. Options for surgical intervention are given for the diagnostic categories of "atypical/borderline," "follicular neoplasm," "suspicious for malignancy" and "malignant" (http://thyroidfna.cancer.gov/pages/info/agenda/).
Diagnostic Cytopathology 07/2008; 36(6):442-8. · 1.16 Impact Factor
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Journal of the American College of Surgeons 11/2007; 205(4 Suppl):S45-8. · 4.55 Impact Factor
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ABSTRACT: Properly performed clinical trials provide a foundation for evidence-based medical practice. The surgeon plays a central role in the management of patients with malignant solid tumors, including thyroid cancer, because operative extirpation of the malignancy is the essential first step in effective therapy. This article discusses the role of the surgeon in the clinical research of thyroid cancer and also reviews the important clinical trials that have influenced the treatment of patients with thyroid cancer. Recent discoveries defining the genetic mutations underlying the various types of thyroid cancers have led to the development of targeted therapies. These chemical compounds, which are now being evaluated in clinical trials, hold great promise for the treatment of patients with locally advanced and distant metastatic disease. The surgical investigator also plays an important role in procuring tumor tissue from patients in clinical trials. The molecular analysis of these tissues is of critical importance in selecting specific therapies and predicting patient response and prognosis.
World Journal of Surgery 05/2007; 31(5):987-95. · 2.36 Impact Factor
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ABSTRACT: BACKGROUND: Since the human genome has been sequenced many mysteries of cell biology have been unravelled, thereby clarifying the pathogenesis of several diseases, particularly cancer. In members of kindreds with certain hereditary diseases, it is now possible early in life to predict with great certainty whether or not a family member has inherited the mutated allele causing the disease. In hereditary malignancies this has been particularly important, because in affected family members there is the possibility of removing the organ destined to develop cancer before malignancy develops or while it is in situ. At first consideration, it would appear that "prophylactic surgery" would have a place in many hereditary malignancies; however, the procedure has applicability only if certain criteria are met: (1) the genetic mutation causing the hereditary malignancy must have a very high penetrance and be expressed regardless of environmental factors; (2) there must be a highly reliable test to identify patients who have inherited the mutated gene; (3) the organ must be removed with minimal morbidity and virtually no mortality; (4) there must be a suitable replacement for the function of the removed organ; and (5) there must be a reliable method of determining over time that the patient has been cured by "prophylactic surgery." CONCLUSIONS: In this monograph we review several hereditary malignancies and consider those where prophylactic surgery might be useful. As we learn, there are various barriers to performing the procedure in many common hereditary cancer syndromes. The archetype disease syndromes, which meet each of the five criteria mentioned above and where prophylactic surgery is most useful, are the type 2 multiple endocrine neoplasia (MEN) syndromes: MEN2A, MEN2B, and the related familial medullary thyroid carcinoma. An additional benefit of the Human Genome Project, has been the development of pharmacologic and biologic compounds that block the metabolic pathway(s) activated by specific genetic mutations. Many of these compounds have shown efficacy in patients with locally advanced or metastatic cancers, and there is the likelihood that they will prove beneficial in preventing the outgrowth of malignant cells in patients destined to develop a hereditary cancer.
World Journal of Surgery 04/2007; 31(3):450-64. · 2.36 Impact Factor
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ABSTRACT: Multiple endocrine neoplasia (MEN) type 1 and type 2 exhibit an autosomal dominant pattern of inheritance. In the past two decades the germline mutations that cause these inherited syndromes have been identified. The large majority of patients with MEN1 have mutations in the menin gene. Mutations in the REarranged during Transfection (RET) gene cause MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Specific codon mutations within RET correlate with disease phenotype and severity. Also, children from families with MEN2A, MEN2B, or FMTC, who are found to have inherited a mutated RET allele, can be managed by prophylactic thyroidectomy, thus preventing the development of medullary thyroid carcinoma (MTC), the dominant endocrinopathy in patients with these hereditary syndromes. New insights into the molecular pathway of RET signal transduction are leading to novel targeted therapies in patients with locally advanced or metastatic hereditary MTC.
Annual Review of Medicine 02/2007; 58:253-65. · 9.94 Impact Factor
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ABSTRACT: The goal in managing patients who have MTC is to detect and surgically remove disease at an early stage. Tumor marker-based biochemical screening and DNA-based genetic screening have created the opportunity for effective prophylactic surgery in patients at risk for hereditary MTC. Complete surgical resection is critical for cure because cervical reoperation for persistent or recurrent disease benefits only select patients. With the advent of therapies that target the RET-activated pathways, new hope may be emerging for patients who have locally advanced or metastatic disease.
Surgical Oncology Clinics of North America 08/2006; 15(3):639-60. · 1.12 Impact Factor
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World Journal of Surgery 08/2006; 30(7):1147-51. · 2.36 Impact Factor
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ABSTRACT: The functional results of cryopreserved heterotopic parathyroid autotransplantation (CHPA) are not well defined. The authors evaluated the outcomes of delayed CHPA for the treatment of surgically induced hypoparathyroidism.
Since November 1991, 448 parathyroid samples from 436 patients were cryopreserved at our institution. Of these, 29 patients underwent 34 CHPA procedures, with placement of 20 to 25 pieces of parathyroid tissue (approximately 50 to 75 mg) into the forearm. Outcomes were determined based on peripheral parathyroid hormone (PTH) levels and, where available, PTH gradients between grafted and nongrafted arms. Graft function results were defined as completely functional (patients with normal PTH and calcium levels off all calcium/vitamin D supplementation), partially functional (normal PTH levels and mild hypocalcemia on calcium supplementation), or nonfunctional (low PTH levels and dependent on calcium/vitamin D supplementation).
Of the 29 patients with CHPA, prospective data were available for 26 patients undergoing 30 CHPA procedures (9 patients with MEN 1, 4 with MEN 2A, 1 with MEN 2B, and 12 with sporadic hyperparathyroidism). The mean follow-up interval was 2 years. Twelve of 26 patients (46%) had completely functional grafts, 6 patients (23%) had partially functional grafts, and the remaining 8 patients (31%) had nonfunctional grafts. No patient with CHPA had graft-dependent recurrent hyperparathyroidism. Of the 14 patients (15 autografts) with MEN, 7 patients (50%) had fully functional grafts, and 2 patients (14%) had partially functional grafts. The mean cryopreservation period was 7.9 months (range, 1 week to 22 months) for functional autografts and 15.3 months (range, 2 weeks to 106 months) for nonfunctional autografts (P < .01).
Based on these data and those in previous studies, approximately 60% of delayed, cryopreserved parathyroid autografts are functional. In this study 40% autografts (46% of patients) achieved full competency off supplements. Some patients have evidence of graft function with normal PTH levels but are not normocalcemic. Results were similar for patients with MEN and nonhereditary hyperparathyroidism. The duration of cryopreservation was a significant indicator of graft failure, and no functional autograft was observed beyond 22 months of preservation. CHPA is a useful treatment modality for patients with postoperative hypocalcemia after thyroid or parathyroid surgery, who do not respond to immediate parathyroid autotransplantation.
Surgery 12/2005; 138(6):1033-40; discussion 1040-1. · 3.10 Impact Factor
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ABSTRACT: Medullary thyroid carcinoma is the most common cause of death in patients with multiple endocrine neoplasia (MEN) type 2A (MEN-2A) or type 2B or familial medullary thyroid carcinoma. We sought to determine whether total thyroidectomy in asymptomatic young members of kindreds with MEN-2A who had a mutated allele of the RET proto-oncogene could prevent or cure medullary thyroid carcinoma.
A total of 50 patients 19 years of age or younger who were consecutively identified through a genetic screening program as carriers of a RET mutation characteristic of MEN-2A underwent total thyroidectomy. Five to 10 years after the surgery, each patient was evaluated by physical examination and by determination of plasma calcitonin levels after stimulation with provocative agents.
In 44 of the 50 patients, basal and stimulated plasma calcitonin levels were at or below the limits of detection of the assay (proportion, 0.88; 95 percent confidence interval, 0.76 to 0.95). Two patients had basal and stimulated plasma calcitonin levels above the normal range. Stimulated plasma calcitonin levels had increased but remained within the normal range in four patients. The data suggest that there was a lower incidence of persistent or recurrent disease in children who underwent total thyroidectomy before eight years of age and in children in whom there were no metastases to cervical lymph nodes.
In this study, young patients identified by direct DNA analysis as carriers of a RET mutation characteristic of MEN-2A had no evidence of persistent or recurrent medullary thyroid carcinoma five or more years after total thyroidectomy. A longer period of evaluation will be necessary to confirm that they are cured.
New England Journal of Medicine 10/2005; 353(11):1105-13. · 53.30 Impact Factor
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ABSTRACT: Despite near complete penetrance and frequent early evaluation of medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia 2 (MEN 2) variants, a significant minority of patients are evaluated later in life.
With the aim of characterizing the expression of hereditary MTC in an older cohort, MEN 2 patients from our institutional database who were evaluated after age 50 years were identified, and clinical data were reviewed.
Thirty-nine patients (36 MEN 2A, 3 FMTC, and no MEN 2B) who were evaluated after age 50 years were identified; they represented 9% of all MEN 2 patients who were enrolled in our program. Most of the patients (79%) had abnormal screening examinations, and the AJCC staging was significantly higher in this cohort compared with younger patients. Overall, 43% of the patients had normal calcitonin levels after operation. There were 3 observed MTC-related deaths, all from distant metastases; the overall survival rate was 86% at 5 years and 74% at 10 years. The distribution of RET mutations in this cohort was similar to younger patients.
These results suggest the presence of modifiers of MTC expression. Despite the tendency of older patients with hereditary MTC to have advanced stage disease at evaluation, they have high rates of biochemical cure, and the overall survival is excellent.
Surgery 01/2005; 136(6):1116-21. · 3.10 Impact Factor
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ABSTRACT: Incidence and mortality rates for cancers vary by ethnic background and patient age. Accrual of diverse patient populations to cancer clinical trials is essential in order to ensure that findings related to new management strategies can be generalized. The goal of this study was to evaluate accrual patterns for patients participating in the American College of Surgeons Oncology Group (ACOSOG) cancer protocols. Ethnic diversity among clinical trial investigators may also influence accrual patterns, so the ethnic background of the ACOSOG membership was also evaluated.
Demographics for the patients registered on ACOSOG breast, thoracic, and colorectal clinical trials were evaluated and compared with data on the general population and the cancer population in the United States. Accrual patterns for patients from other reported cancer clinical trials were also presented, and the self-reported ethnic distribution of the ACOSOG membership was analyzed.
Distribution of African Americans, Hispanic Americans, and Asian Americans to the ACOSOG breast and colorectal clinical trials was relatively proportionate to the cancer population. African Americans were underrepresented in the thoracic clinical trials, and this disparity was partially offset by data on the proportion of African Americans with stage-eligible lung cancer. Accrual rates for patients age 65 years and older were better than those reported by most other clinical trialists.
Elderly patients are successfully recruited into surgical clinical trials, and this will provide important data for future analyses regarding cancer outcomes in this growing population of cancer patients. Aggressive outreach to minority-ethnicity cancer patients for accrual into clinical trials should continue.
Journal of the American College of Surgeons 11/2004; 199(4):644-51. · 4.55 Impact Factor
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ABSTRACT: Approximately 90% of patients with primary hyperparathyroidism (PHPT) are cured by parathyroidectomy at the initial neck exploration. Those not cured either remain hypercalcemic in the immediate postoperative period or develop hypercalcemia after a long period of normocalcemia. Almost all cases of hypercalcemia after neck exploration for PHPT are evident early in the postoperative period and are caused either by an overlooked parathyroid adenoma or an incomplete resection of hyperplastic parathyroid tissue. Less commonly, the surgeon has failed to recognize, and adequately treat, parathyroid carcinoma, or the diagnosis of PHPT was incorrect and there is another cause of the hypercalcemia. A successful neck exploration for PHPT is primarily dependent on the experience of the operating surgeon, the anatomic location of the parathyroid glands, either in "normal" or "ectopic" sites, and the presence of a single enlarged parathyroid gland as opposed to multiglandular disease or parathyroid carcinoma. In cases where an enlarged parathyroid gland is not identified at operation, noninvasive or invasive radiographic imaging procedures are useful in localizing the gland. Currently, the most reliable and practical procedure is technetium 99m sestamibi scanning. This technique identifies an enlarged parathyroid gland in 65-80% of cases. Single photon emission computed tomography (SPECT) in association with sestamibi scanning increases the sensitivity of the procedure to 85%. These imaging procedures are least reliable in patients with multiglandular disease. Ultrasound and computed tomographic scanning are less sensitive; however, they are commonly used as confirmatory tests in association with sestamibi scanning. When noninvasive imaging procedures fail to identify an enlarged parathyroid gland, invasive procedures, such as selective arteriography, are performed. Whereas invasive procedures are useful, they are associated with significant morbidity. Reoperations for persistent or recurrent hyperparathyroidism, compared with the initial operations, are associated with higher complication rates. In 90% of cases, the abnormal pathology can be reached through a cervical incision. The success rate of the reoperation depends primarily on the results of the localization procedure and whether the patient has a single enlarged parathyroid gland or multiglandular disease. Resection of a single enlarged gland is curative in virtually all patients. If, however, the patient has multiple gland disease, the operation is successful less often, especially in those with certain familial endocrinopathies.
Journal of Bone and Mineral Research 12/2002; 17 Suppl 2:N158-62. · 6.37 Impact Factor
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Samuel A Wells
Surgery 10/2002; 132(3):519-20. · 3.10 Impact Factor
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ABSTRACT: To determine the clinical features, natural history, and role of surgery for gastrointestinal manifestations of the multiple endocrine neoplasia type 2 (MEN 2) syndromes.
The MEN 2 syndromes are characterized by medullary thyroid carcinoma and other endocrinopathies. In addition, some patients with MEN 2A develop Hirschsprung's disease (HD), and all patients with MEN 2B have intestinal neuromas and megacolon that can cause significant gastrointestinal problems.
From 83 families with MEN 2A, eight patients with HD were identified (MEN 2A-HD). These and all patients with MEN 2B followed at the authors' institution (n = 53) were sent questionnaires to describe the onset and type of gastrointestinal symptoms and treatment they had before the diagnosis of MEN 2. Records of all patients responding were reviewed, including radiographic imaging, histology, surgical records, and genetic testing.
Thirty-six of the 61 patients (59%) responded (MEN 2A = 8, MEN 2B = 28) to the questionnaires. All patients with MEN 2A-HD were operated on for HD 2 to 63 years before being diagnosed with MEN 2. All patients responding were underweight as infants and had symptoms of abdominal pain, distention, and constipation. Eighty-eight percent had hematochezia, 63% had emesis, and 33% had intermittent diarrhea before surgery. All patients with MEN 2A-HD had rectal biopsies with a diverting colostomy as the initial surgical procedure. This was followed by a colostomy takedown and pull-through procedure at a later interval. Ninety-three percent of patients with MEN 2B had gastrointestinal symptoms 1 to 24 years before the diagnosis of MEN 2. Symptoms included flatulence (86%), abdominal distention or being underweight as a child (64%), abdominal pain (54%), constipation or diarrhea (43%), difficulty swallowing (39%), and vomiting (14%). Seventy-one percent of patients with MEN-2B with gastrointestinal symptoms had radiographic imaging, 32% were admitted to the hospital, and 29% underwent surgery.
Patients with MEN 2A-HD had a typical HD presentation and always required surgery. Patients with MEN 2B have significant gastrointestinal symptoms, but less than a third had surgical intervention. Understanding the clinical course and differences in these patients will improve clinical management.
Annals of Surgery 06/2002; 235(5):648-54; discussion 654-5. · 7.49 Impact Factor
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Samuel A Wells
Clinical Cardiology 02/2002; 25(1):43-5. · 2.15 Impact Factor
