Determining the Ratio of Wedge Height to Degree of Correction for Anterior Tibial Closing Wedge Osteotomies for Excessive Posterior Tibial Slope.

BACKGROUND: Anterior closing wedge osteotomy of the proximal tibia may be considered in revision anterior cruciate ligament (ACL) reconstruction surgery for patients with excessive posterior tibial slope (PTS). PURPOSE: (1) To determine the ratio of wedge thickness to degrees of correction for supratubercle (ST) versus transtubercle (TT) osteotomies for anterior closing wedge osteotomies and (2) to evaluate the accuracy of ST and TT osteotomies in achieving slope correction. STUDY DESIGN: Controlled laboratory study. METHODS: The computed tomography (CT) scans of 38 knees in 37 patients undergoing revision ACL reconstruction were used to simulate both ST and TT osteotomies. A 10° wedge was simulated in all CT models. The height of the wedge along the anterior tibia was recorded for each of the 2 techniques. The ratio of wedge height to achieved degree of correction was calculated. ST and TT osteotomies were performed on 3-dimensional (3D)-printed tibias of the 12 patients from the study group with the greatest PTS, after the desired degree of correction was determined. Pre- and postosteotomy slopes were measured for each tibia, and the actual change in slope was compared with the intended slope correction. RESULTS: According to CT measurements, the ratio of wedge height to degree of correction was 0.99 ± 0.07 mm/deg for the ST osteotomy and 0.83 ± 0.06 mm/deg for the TT osteotomy (P < .001). When these ratios were used to perform simulated osteotomies on the twelve 3D-printed tibias, the mean slope correction was within 1° to 2° of the intended slope correction, regardless of osteotomy location (ST or TT) or whether slope was measured on the medial or lateral plateau. The ST technique tended to undercorrect and the TT technique tended to overcorrect. CONCLUSION: When anterior tibial closing wedge osteotomies were removed to correct excessive PTS, removing a wedge with a ratio of 1 mm of wedge height for every 1° of intended correction for an ST technique and a ratio of 0.8 mm to 1° for a TT technique resulted in overall average slope correction within 1° to 2° of the target. CLINICAL RELEVANCE: The calculated ratios will allow clinicians to more accurately correct PTS when performing anterior closing wedge tibial osteotomy.

Anterior Cruciate Ligament Revision Reconstruction.

Revision anterior cruciate ligament (ACL) reconstruction is used in patients with recurrent instability after primary ACL reconstruction. Identifying the etiology of graft failure is critical to the success of revision reconstruction. The most common etiologies include technical errors, trauma, failure to recognize concomitant injuries, young age, incomplete rehabilitation, and hardware failure. Patients should undergo a complete history and physical examination with a specific focus on previous injury mechanism and surgical procedures. A revision ACL reconstruction is a technically demanding procedure, and the surgeon should be prepared to address bone tunnel osteolysis, concurrent meniscal, ligamentous, or cartilage lesions, and limb malalignment. Surgical techniques described in this article include both single-stage and two-stage reconstruction procedures. Rates of return to sport after a revision reconstruction are lower than after primary reconstruction. Future research should be focused on improving both single-stage and two-stage revision techniques, as well as concomitant procedures to address limb malalignment and associated injuries.

Orthopaedic Surgery Resident Financial Literacy: An Assessment of Knowledge in Debt, Investment, and Retirement Savings.

Most orthopedic residents carry significant debt and may enter their practice with little knowledge of business management, minimal retirement savings, and overall poor financial literacy. This study aimed to gauge financial literacy, debt, and retirement planning in United States orthopedic surgery residents. Willingness to participate in formalized financial education was also assessed. Eighty-five allopathic orthopedic surgery residents in the United States completed a 14-question anonymous online survey in 2016. The survey assessed demographic data, self-assessed financial knowledge, amount of credit card debt and loans, preparation for retirement, and willingness to participate in formal didactic education on these topics. Most respondents derive their financial knowledge from personal research (51%), whereas only 4 per cent have a formal curriculum. Despite most respondents reporting more than $200,000 in outstanding loans, only 31 per cent create and stick to a budget. Few programs offer retirement advice, and 48 per cent of respondents save $0 toward retirement. Eighty-five per cent of residents expressed interest in learning about personal investment, savings, and retirement planning. Orthopedic surgery residents carry significant debt and do not achieve their high-income potential until disproportionately later in life. Only 4 per cent of residents have formal training in investing, personal finance, or retirement despite a majority who desire such a curriculum. In fact, almost 75 per cent of those surveyed felt less prepared for retirement than their peers outside of medical training. This study suggests a role for formal financial education in the orthopedic curriculum to prepare residents for retirement, improve financial literacy, and enhance debt management.

Identification of distinct cytomorphologic features in the diagnosis of NIFTP at the time of preoperative FNA: Implications for patient management.

BACKGROUND: A major reclassification occurred with the redesignation of noninvasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its indolent nature. The aim of this study was to determine whether distinct cytomorphologic features could be identified on preoperative fine-needle aspiration (FNA) when NIFTP cases were compared with invasive follicular variant of papillary thyroid carcinoma (FVPTC) subtypes. METHODS: Thyroid resection cases with the diagnosis of FVPTC from 2012 to 2016 were reclassified as NIFTP, invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC), and invasive FVPTC subtypes. Corresponding FNA specimens were retrieved and retrospectively reviewed. A univariate analysis using Fisher's exact test was performed to determine any differences in the frequencies of various cytomorphologic features among NIFTP, IEFVPTC, and FVPTC cases. A multivariate analysis was performed to identify any independent salient features that would be helpful in differentiating NIFTP from its invasive counterparts. RESULTS: The study population consisted of 93 cases, including 51 cases of NIFTP, 21 cases of IEFVPTC, and 21 cases of infiltrative FVPTC. Demographics such as age, sex, and tumor size were comparable across the 3 groups. A predominantly microfollicular pattern, an absence of nuclear pseudo-inclusions, and less frequent nuclear elongations and grooves were significantly more likely to be associated with NIFTP versus its invasive counterparts. The absence of nuclear pseudo-inclusions and the presence of a microfollicular pattern were the only independent predictors of a NIFTP diagnosis. CONCLUSIONS: This study demonstrates that NIFTP cases have distinguishing cytomorphologic characteristics in comparison with invasive FVPTC cases. Therefore, a preoperative cytologic evaluation provides clues that can aid in the distinction between NIFTP and its invasive counterparts. Cancer Cytopathol 2017;125:865-75. © 2017 American Cancer Society.

Primary hyperparathyroidism with normal baseline intraoperative parathyroid hormone: A challenging population.

BACKGROUND: Patients with primary hyperparathyroidism and baseline intraoperative parathyroid hormone levels in the normal range are challenging. This study compares the predictive value of a commonly used intraoperative parathyroid hormone algorithm, a software model for cure prediction, and surgeon judgment in this population. METHODS: This was a retrospective review of consecutive patients who underwent parathyroidectomy for primary hyperparathyroidism at a single institution from March 2013 to October 2014. RESULTS: Of 541 operative patients, 114 (21.1%) had a mean normal baseline intraoperative parathyroid hormone of ≤69 pg/mL (median 59.0 ± 10.3; range 26-69). Of the 114 patients, 93 (81.6%) were women, median age was 61 years (range 18-88). Overall, 107/108 (99.1%) patients were cured; 47 (41.2%) patients had single adenomas, 16 (14%) had double adenomas, and 51 (44.7%) had multigland hyperplasia. Using the 50% decline algorithm, a correct prediction was made in 86 (75.4%) patients. Using the computer software, a correct prediction was made in 88 (77.2%) patients. Surgeon judgment, however, was 99.1% accurate. CONCLUSION: Patients with normal baseline intraoperative parathyroid hormone have a high incidence of multigland disease (58.8%), greater than reported previously. Current software modeling and the 50% decline algorithm are insufficient to predict cure in this population; intraoperative parathyroid hormone interpretation combined with operative findings and surgical judgment yield optimal outcomes.

Parathyroidectomy prior to kidney transplant decreases graft failure.

BACKGROUND: Uncorrected uremic hyperparathyroidism is associated with delayed graft function after kidney transplantation. The current guidelines of the Kidney Disease Improving Global Outcomes recommend maintaining parathyroid hormone ≤9x normal in patients pre-kidney transplantation. This study explores the effect of increased levels of serum parathyroid hormone and preoperative parathyroidectomy on outcomes after kidney transplantation. METHODS: A retrospective review was performed of adult patients who underwent kidney transplantation between January 1, 2005, and December 31, 2014, at a single institution. Biochemistries and outcomes were analyzed pre-kidney transplantation and at 30 days, 6 months, and 1 year post-kidney transplantation. RESULTS: A total of 913 patients underwent kidney transplantation from 2005-2014. Graft survival 1 year post-kidney transplantation was 97.8%. Overall, 462 (50.6%) patients had a pre-kidney transplantation diagnosis of uncorrected uremic hyperparathyroidism, which was associated with complications in the first year post-kidney transplantation (odds ratio 1.44; 95% confidence interval, 1.11-1.87); no statistical association with delayed graft function or graft failure was detected. Pre-kidney transplantation parathyroid hormone ≥6x normal was associated with post-kidney transplantation graft failure (P < .05). A total of 57 (6.2%) patients underwent pre-kidney transplantation parathyroidectomy, which was associated with lesser risk of graft failure (odds ratio: 0.547; 95% confidence interval, 0.327-0.913), but no statistically significant association with delayed graft function or complications were detected. CONCLUSION: Pre-kidney transplantation parathyroidectomy decreases post-kidney transplantation graft failure and may benefit patients whose serum parathyroid hormone levels decrease into the target range of current Kidney Disease Improving Global Outcomes guidelines.

Central venous parathyroid hormone monitoring using a novel, specific anatomic method accurately predicts cure during minimally invasive parathyroidectomy.

BACKGROUND: Measurement of intraoperative parathyroid hormone (PTH) levels is an important adjunct to confirm biochemical cure during parathyroidectomy. The purpose of this study was to evaluate a simplified anatomic technique for PTH sampling from the central veins through the minimally invasive neck incision, and to compare the predictive accuracy of central and peripheral PTH values. METHODS: A specific anatomic method for central PTH sampling was employed in 48 patients. Samples were drawn simultaneously from peripheral and central veins at baseline and 10 minutes postexcision of all hyperfunctioning parathyroid glands. RESULTS: The central venous PTH levels independently predicted biochemical cure according to the Miami criterion in all the patients. There was no significant difference in the postexcision central and peripheral values, which were 24.40 + 1.86 and 21.69 + 1.74, respectively (P = .877, ANOVA test). CONCLUSIONS: This study provides the original description of a simplified technique for measurement of intraoperative PTH levels in the central veins with direct comparison to peripheral venous levels, and confirmation of accuracy in predicting biochemical cure when relying on centrally obtained values alone.

Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma.

BACKGROUND: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis. METHODS: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples. RESULTS: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden. CONCLUSIONS: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis.

Dissection of Levels II Through V Is Required for Optimal Outcomes in Patients with Lateral Neck Lymph Node Metastasis from Papillary Thyroid Carcinoma.

BACKGROUND: Completeness of surgical resection is an important determinant of outcomes in patients with papillary thyroid carcinoma and regional lymph node metastasis. The extent of therapeutic lateral neck dissection remains controversial. This study aims to assess the impact of modified radical neck dissection of levels II to V in a large patient series. STUDY DESIGN: Retrospective analysis of consecutive patients with papillary thyroid carcinoma who underwent lateral neck dissection at a single institution from June 1, 2006 to December 31, 2014 was performed. RESULTS: A total of 241 lateral neck dissections were performed in 191 patients (118 [62%] women; median age 46 years [range 6 to 87 years]; median follow-up 14.3 months [range 0.1 to 107 months]). Overall, 202 initial neck dissections (195 modified radical neck dissections and 7 less extensive dissections) were performed. Among these initial dissections, 137 (68.8%), 132 (65.7%), 105 (52.0%), and 33 (16.9%) had positive lymph nodes in levels II, III, IV, and V, respectively. Ipsilateral lymph node persistence or recurrence occurred after 22 (10.9%) initial dissections, at level II in 10 (45.5%), level III in 8 (36.4%), level IV in 7 (31.8%), and level V in 3 (13.6%). Thirty-nine reoperative lateral neck dissection were performed, including 18 cases of persistence and recurrence after our initial dissections. In reoperative dissections, positive lymph nodes were confirmed in levels II, III, IV, and V in 18 (46.2%), 10 (25.6%), 13 (33.3%), and 5 (12.8%) dissections, respectively. Temporary nerve injury occurred in 6 (3.0%) initial and 4 (10.3%) reoperative dissections, respectively. There were no permanent nerve injuries. CONCLUSIONS: Omitting levels II and V during lateral neck dissection for papillary thyroid carcinoma potentially misses level II disease in two-thirds of patients and level V disease in one-fifth of patients. Formal modified radical neck dissection is necessary to avoid the morbidity of reoperative surgery.

Real-Time Super Selective Venous Sampling in Remedial Parathyroid Surgery.

BACKGROUND: Remedial cervical exploration for persistent or recurrent primary hyperparathyroidism can be technically difficult, but is expedited by accurate preoperative localization. We investigated the use of real-time super selective venous sampling (sSVS) in the setting of negative noninvasive imaging modalities. STUDY DESIGN: We performed a retrospective analysis of a prospective database incorporating real-time sSVS in a tertiary academic medical center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of primary hyperparathyroidism. Of these, 31 represented remedial patients who had undergone one (n=28) or more (n=3) earlier cervical explorations and had noninformative, noninvasive preoperative localization studies. RESULTS: We extended the use of the rapid parathyroid hormone assay in the interventional radiology suite, generating near real-time data facilitating onsite venous localization by a dedicated interventional radiologist. The predictive value of real-time sSVS localization was investigated. Overall, sSVS correctly predicted the localization of the affected gland in 89% of cases. Of 31 patients who underwent sSVS, a significant rapid parathyroid hormone gradient was identified in 28 (90%), localizing specific venous drainage of a culprit gland. All patients underwent subsequent surgery and were biochemically cured, with the exception of one who had metastatic parathyroid carcinoma. Three patients with negative sSVS were also explored and cured. CONCLUSIONS: Preoperative parathyroid localization is of paramount importance in remedial cervical explorations. Real-time sSVS is a sensitive localization technique for patients with persistent or recurrent primary hyperparathyroidism, when traditional noninvasive imaging studies fail. These results validate the utility and benefit of real-time sSVS in guiding remedial parathyroid surgery.

Modern experience with aggressive parathyroid tumors in a high-volume New England referral center.

BACKGROUND: Parathyroid carcinoma (PTCA) is an exceptionally rare malignancy, often with a clinical presentation similar to that of benign atypical parathyroid adenoma. Its low incidence portends unclear guidelines for management. Accordingly, thorough examination of clinical and pathologic variables was undertaken to distinguish between PTCA and atypical adenomas. STUDY DESIGN: This was a retrospective analysis of a prospective database at a tertiary academic referral center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of PHPT. Of these, 52 harbored aggressive parathyroid tumors: parathyroid carcinomas (n=18) and atypical adenomas (n=34). We analyzed the surgical and clinicopathologic tumor characteristics, and did a statistical analysis. We measured preoperative and intraoperative variables, and postoperative and pathologic outcomes. RESULTS: Parathyroid carcinoma patients present with significantly increased tumor size (3.5 cm vs 2.4 cm, respectively; p=0.002), mean serum calcium (13.0 vs 11.8 mg/dL, respectively; p=0.003) and intact parathyroid hormone (iPTH) levels (489 vs 266 pg/mL, respectively; p=0.04), and a higher incidence of hypercalcemic crisis, compared with patients with atypical adenomas (50% vs 19%, respectively; p=0.072). Parathyroid carcinoma more frequently lacks a distinct capsule (47.1% vs 12.9%, respectively; p=0.03) and adheres to adjacent structures (77.8% vs 20.6%, respectively; p=0.017). Of note, there was no significant difference in loss of parafibromin expression between groups. CONCLUSIONS: Clinical distinction between PTCA and atypical adenomas is of critical importance in determining the appropriate extent of resection and follow-up. Loss of parafibromin has not been shown to distinguish between PTCA and atypical adenoma; clearer definition of clinicopathologic criteria for PTCA is warranted and may lead to improved postoperative management.

Heart block and acute kidney injury due to hyperparathyroidism-induced hypercalcemic crisis.

We describe a patient who presented with multi-system organ failure due to extreme hypercalcemia (serum calcium 19.8 mg/dL), resulting from primary hyperparathyroidism. He was found to have a 4.8 cm solitary atypical parathyroid adenoma. His course was complicated by complete heart block, acute kidney injury, and significant neurocognitive disturbances. Relevant literature was reviewed and discussed. Hyperparathyroidism-induced hypercalcemic crisis (HIHC) is a rare presentation of primary hyperparathyroidism and only a small minority of these patients develop significant cardiac and renal complications. In cases of HIHC, a multidisciplinary effort can facilitate rapid treatment of life-threatening hypercalcemia and definitive treatment by surgical resection. As such, temporary transvenous cardiac pacing and renal replacement therapy can provide a life-saving bridge to definitive parathyroidectomy in cases of HIHC.

Lateralizing sensorimotor deficits in a case of pseudopheochromocytoma.

Pseudopheochromocytoma is a poorly understood, rare cause of severe paroxysmal hypertension that mimics the symptomatology of pheochromocytoma in the absence of biochemical evidence of this tumor. Symptoms such as headache, nausea, sweating, and palpitations during hypertensive episodes have been described. In this paper, we describe previously unreported findings of lateralizing sensorimotor deficits in a patient with pseudopheochromocytoma. These changes presented during a hypertensive episode and were concerning for stroke but were not accompanied by acute radiologic abnormalities. The deficits improved over 1.5 weeks as blood pressure stabilized with beta-blockade. We also review relevant literature on the clinical features, pathophysiology, and management of pseudopheochromocytoma.

A randomized, prospective trial of operative treatments for hyperparathyroidism in patients with multiple endocrine neoplasia type 1.

BACKGROUND: Hyperparathyroidism (HPT) in multiple endocrine neoplasia (MEN) type 1 is associated with multiglandular parathyroid disease. Previous retrospective studies comparing subtotal parathyroidectomy (SP) and total parathyroidectomy with autotransplantation (TP/AT) have not established clearly better outcomes with either procedure. METHODS: Patients were assigned randomly to either SP or TP/AT and data were collected prospectively. The rates of persistent HPT, recurrent HPT, and postoperative hypoparathyroidism were compared. RESULTS: The study cohort included 32 patients randomized to receive either SP or TP/AT (mean follow-up, 7.5 ± 5.7 years). The overall rate of recurrent HPT was 19% (6/32). Recurrent HPT occurred in 4 of 17 patients (24%) treated with SP and 2 of 15 patients (13%) treated with TP/AT (P = .66). Permanent hypoparathyroidism occurred in 3 of 32 patients (9%) overall. The rate of permanent hypoparathyroidism was 12% in the SP group (2/17) and 7% in the TP/AT group (1/15). A second operation was performed in 4 of 17 patients initially treated with SP (24%), compared with 1 of 15 patients undergoing TP/AT (7%; P = .34). CONCLUSION: This randomized trial of SP and TP/AT in patients with MEN 1 failed to show any difference in outcomes when comparing results of SP versus TP/AT. Both procedures are associated with acceptable results, but SP may have advantages in that is involves only 1 surgical incision and avoids an obligate period of transient postoperative hypoparathyroidism.

Minimally invasive, nonendoscopic thyroidectomy: a cosmetic alternative to robotic-assisted thyroidectomy.

BACKGROUND: The desire to improve cosmesis has driven the introduction of robotic-assisted and video-assisted thyroidectomy techniques. We report on minimally invasive thyroidectomy (MIT) through a 2-cm incision without the added need for video assistance and hypothesize similar clinical results to standard open thyroidectomy. METHODS: Between May 2012 and December 2013, 62 nonendoscopic MIT were evaluated for demographics, clinical outcomes, and patient satisfaction on a 1-10 scale. The results were compared with a case-matched control group who underwent conventional open thyroidectomy by the same surgeon. RESULTS: The 124 study patients demonstrated no differences between groups for demographics or clinical outcomes except a smaller thyroid lobe in the MIT group (9.2 vs 11.7 g; P = .05). There were longer operative times in the MIT group (135.4 vs 119.6 minutes; P = .07) that were not equivalent by equivalence testing (P = .534). In MIT patients, transient recurrent laryngeal nerve injury occurred per nerves at risk (1.1% vs 3.4%; P = .62) with no permanent injuries in either group. There was no difference in symptomatic hypocalcemia (9.7% vs 11.3%; P = .77) and postoperative hematoma (0% vs 3.2%; P = .50). On follow-up, the measured MIT scar was significantly shorter (2.22 vs 3.98 cm; P < .00001), which resulted in significantly improved cosmetic satisfaction ratings (9.56 vs 8.66; P = .03). CONCLUSION: In selected patients, MIT through a 2-cm incision without endoscopic assistance is a safe alternative to standard open thyroidectomy in the hands of an experienced endocrine surgeon. The operating time is slightly increased, but clinical results are equivalent and patient satisfaction is significantly improved.

Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment.

BACKGROUND: Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906. METHODS: Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors. RESULTS: We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection. CONCLUSIONS: PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.

Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft-versus-host disease.

Human and murine stromal progenitor cells (SPCs) can suppress alloresponse in vitro, suggesting that SPCs may have clinical application toward prevention or treatment of graft-versus-host disease (GVHD). However, th eresults of in vivo studies have been conflicting. This study utilized an established murine model of acute GVHD to assess the ability of bone marrow derived murine SPCs (mSPCs) to prevent or treat GVHD. GVHD was established by transplantation of B6 bone marrow and spleen cells into lethally irradiated (900 cGy) B6 x BALB/c F(1) recipients. mSPCs were administered using various dose and timing protocols designed to either prevent or treat GVHD. After transplantation, mice were monitored daily for weight and survival. Differences in symptom severity were compared using a clinical GVHD scoring system. All GVHD control mice died of lethal GVHD. All groups treated with mSPCs for the prevention of GVHD went on to develop clinical GVHD with no alteration of the disease course or severity compared to controls. Administration of mSPC after the development of GVHD failed to improve the disease course. We conclude that in this model, the ability of SPCs to suppress alloresponse in vitro does not correlate with in vivo prevention or treatment of acute GVHD.

In vivo Differentiation Potential of Mesenchymal Stem Cells: Prenatal and Postnatal Model Systems.

SUMMARY: Most of our knowledge of mesenchymal stem cell (MSC) biology is derived from in vitro systems that are often highly contrived to favor culture expansion or specific differentiation events. However, any conclusions drawn from in vitro studies regarding MSC differentiation capacity, immune properties, or therapeutic potential must be validated by in vivo studies to ultimately be meaningful. At the present time, there are relatively few in vivo studies demonstrating differentiation and functional integration of MSCs into host tissues after transplantation. There is a need for in vivo model systems to assay MSC biology and to move potential therapeutic strategies forward. Here, we review prenatal model systems as potentially advantageous for the in vivo characterization of MSCs, and we critically review the results of in vivo studies of MSC transplantation in prenatal and postnatal model systems with an emphasis on proven engraftment and differentiation.