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Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS., Methods: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS)., Results: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR)., Conclusions: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA., Competing Interests: Conflict of Interest: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Surgical wide resection is the mainstay of treatment of sarcomas, but the advent of multimodality therapy has improved outcomes and the rates of limb-sparing resection. Often, wounds are unable to be closed primarily and require plastic surgical reconstruction. Following adequate oncologic resection, reconstruction should focus on maintaining functional and esthetic outcomes with minimal postoperative complications. Reconstruction methods range from simple techniques such as skin grafting and local rotational flaps all the way to more complex procedures such as free flaps. The reconstructive surgeon is an integral member of the multidisciplinary team and should be actively involved in treatment planning., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Paratesticular sarcomas are defined as tumors that arise within the scrotum and include the subsites of epididymis, spermatic cord, and tunica vaginalis and represent the most common type of GU sarcoma. The mainstay of treatment is often surgical resection, combined with histology specific chemotherapy and radiotherapy. Due to the rare nature of the disease, there are limited data to guide management. We present our single-institution retrospective experience regarding the management and treatment of paratesticular sarcomas., Materials and Methods: We queried our oncology registry database for patients treated for testicular, spermatic cord, and scrotal soft tissue sarcomas between 1971 and 2017. Patients in this series had pathological confirmation of a sarcoma diagnosis by a sarcoma-specialized pathologist. Only patients with localized disease were included in this analysis with the exception of patients with a diagnosis of rhabdomyosarcoma where patients with both localized and metastatic disease were included on this study., Results: A total of 34 patients were included in this retrospective analysis. The median was 24 (range, 5-78), and the median tumor size was 6.25 cm. Twenty-six patients had localized disease (76.6%) at the time of diagnosis. A predominance of patients had tumors involving the spermatic cord (45.5%), and the most common histology was rhabdomyosarcoma (35.3%), leiomyosarcoma (26.5%), and well-differentiated liposarcoma (23.5%). The median follow-up was 71.0 months (range, 2.5-534.4 months). A total of 7 patients experienced an isolated local failure (20.6%), four patients developed distant metastatic disease (11.8%), and one patient (2.9%) with synovial sarcoma of the spermatic cord experienced a regional recurrence. The median progression-free survival (PFS) was 99.6 months, 95% CI (45.8-534.3 months), with a three-year PFS rate of 71%, 95% CI (53%-83%), and a 5-year PFS rate of 64% (range, 46%-78%). We did not find any statistically significant associations based on surgery type ( p =0.15), the use of chemotherapy, ( p =0.36), or final margin status ( p =0.21). Two patients who were treated with preoperative radiotherapy had significant wound healing complication with chronic sinus tracts, though these patients did not experience a local recurrence., Conclusions: We provide a characterization of the natural history and treatment patterns of paratesticular sarcomas. While effective at reducing a local recurrence, preoperative radiotherapy was associated with significant toxicity. As a result, we prefer the use of postoperative radiotherapy in patients as clinically indicated. We did not find any specific treatment patterns associated with an improvement in clinical outcomes., Competing Interests: The authors report no conflicts of interest with this work., (Copyright © 2021 Varun K. Chowdhry et al.)

Introduction: Appendiceal neoplasms are uncommon tumors. Optimal treatment for patients with perforation or high-grade pathology after initial resection is unknown. This study evaluated patients with increased risk for peritoneal dissemination after primary resection, but no evidence of peritoneal disease, who underwent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: This multi-institutional cohort study evaluated 56 patients with high-risk (HR) appendiceal neoplasms with a peritoneal carcinomatosis index of 0 who underwent HIPEC. The patients were divided into two groups: perforated low-grade appendiceal (LGA) carcinoma and HR neoplasms, which included perforated high-grade appendiceal carcinoma, positive margins after initial resection, minimal macroscopic peritoneal disease that was previously resected or completely responded to systemic chemotherapy prior to HIPEC, goblet cell carcinoma, and adenocarcinoma with signet ring cell features. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan-Meier analysis., Results: Thirty-eight percent of patients had perforated LGA and 68% had HR features. Five-year OS probability was 82.1% for the entire cohort, and 100% and 70.1% for patients with perforated LGA and HR features, respectively (p = 0.024). Five-year RFS probability was 79.3% for the entire cohort, and 90.0% and 72.4% for patients with perforated LGA and HR features, respectively (p = 0.025). Eight patients recurred after HIPEC and their OS was significantly worse (p < 0.001)., Conclusion: While adjuvant HIPEC is both safe and feasible, there appears to be little benefit over close surveillance when outcomes are compared with historical and prospective studies, especially for perforated LGA carcinoma.

Laparoscopic and thoracoscopic or robotic-assisted minimally invasive esophagectomy offers benefits in decreased postoperative complications and faster recovery. The choice of operation depends on patient and surgeon factors. McKeown or 3-field esophagectomy requires dissection in the abdomen, chest, and neck, with a cervical anastomosis. Ivor Lewis esophagectomy is performed with abdominal and right chest dissection and intrathoracic anastomosis. Transhiatal or transmediastinal esophagectomy is performed with abdominal and cervical dissections and a cervical anastomosis and is preferential in patients with significant pulmonary risk factors. Preparation and operative conduct for laparoscopic and robotic approaches for these operations, and the expected postoperative recovery are detailed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Pancreaticoduodenectomy is a complex surgical procedure associated with high morbidity and prolonged length of stay. Enhanced recovery after surgery principles have reduced complications rate and length of stay for multiple types of operations. We hypothesized that implementation of a standardized perioperative care pathway would facilitate safe discharge by five days after pancreaticoduodenectomy., Methods: We performed a retrospective cohort study of patients undergoing pancreaticoduodenectomy 18 months prior to and 18 months following implementation of a perioperative care pathway at a quaternary center performing high volume pancreatic surgery., Results: A total of 145 patients underwent pancreaticoduodenectomy (mean age 63 ± 10 years, 52% female), 81 before and 64 following pathway implementation, and the groups were similar in terms of preoperative comorbidities. The percentage of patients discharged within 5 days of surgery increased from 36% to 64% following pathway implementation (p = 0.001), with no observed differences in post-operative serious adverse events (p = 0.34), pancreatic fistula grade B or C (p = 0.28 and p = 0.27 respectively), or delayed gastric emptying (p = 0.46). Multivariate regression analysis showed length of stay ≤5 days three times more likely after pathway implementation. Rates of readmission within 30 days (20% pre- vs. 22% post-pathway (p = 0.75)) and 90 days (27% pre- vs. 36% post-pathway (p = 0.27)) were unchanged after pathway implementation, and were no different between patients discharged before or after day 5 at both 30 days (19% ≤5 days vs. 23% ≥ 6 days (p = 0.68)) and 90 days (32% ≤5 days vs. 30% ≥ 6 days (p = 0.81))., Conclusions: Standardizing perioperative care via enhanced recovery protocols for patients undergoing pancreaticoduodenectomy facilitates safe discharge by post-operative day five., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: Outcomes after recurrence of resected pancreatic neuroendocrine tumors (PNETs) are not well described. We aim to assess the rate and sites of recurrence, and its effect on clinical outcomes., Methods: Retrospective chart review of patients (n = 83) who underwent surgical resection of PNETs at 2 institutions. Patients were treated from September 2002 to July 2010., Results: There were 13 (16%) recurrences. The most common site of recurrence was the liver (9 patients, 9.6%). The most common treatment of recurrences was chemotherapy (5 patients, 36%). The 1-, 3-, and 5-year disease-free survival was 90.9%, 82.7%, and 72.5%, respectively. Median recurrence-free survival was 127 months. The median follow-up for all PNET patients was 25.8 months (range, 1-140 months). The 3-year survival was 97%. The median follow-up of patients after the diagnosis of a recurrence was 13.8 months. The overall survival for those with and without recurrence was 96.3% and 100%, respectively (P = .36). The age ( P = .002) and lymph node ratio ( P < .001) were predictors of recurrence on multivariate analysis., Conclusions: Age and lymph node ratio are significant predictors of recurrence after the resection of PNETs with hepatic metastases being the most common. Survival of patients with recurrence is not significantly different from patients without recurrence., (© 2018 Wiley Periodicals, Inc.)

Purpose: Current evidence regarding salvage resection for recurrent retroperitoneal (RP) sarcomas generally lacks detailed histology-specific analyses, but the aggressiveness of these tumors varies widely by histology. We investigated associations between timing and extent of salvage surgery and survival outcomes in patients with recurrent RP well-differentiated liposarcoma (WDLPS)., Methods: The University of Texas MD Anderson Cancer Center Surgical Oncology sarcoma database was reviewed to identify patients with RP WDLPS who underwent surgical resection for first recurrent disease (salvage surgery) in 1995-2015. Medical records were retrospectively reviewed to identify factors associated with overall survival and disease-free survival., Results: We identified 52 patients who underwent salvage surgery for RP WDLPS for first local recurrence; 28 (54%) underwent salvage surgery within 6 months after recurrence. Concomitant organ resections were performed in 32 (62%) patients, 4 (13%) of whom had pathologic invasion of resected organs. After R0/R1 resections (n = 45), 38 (84%) experienced a second local recurrence. Multivariable analyses revealed that organ invasion at the primary surgery [hazard ratio (HR) 13.08; p = 0.005] and disease-free interval < 1 year (HR 3.64; p = 0.044) were associated with shorter overall survival. Recurrence-to-salvage interval < 6 months was associated with shorter disease-free survival (HR 2.18; p = 0.025). Concomitant organ resection was associated with a longer hospital stay: ≥ 14 days (odds ratio 21.58; p = 0.007)., Conclusions: Early salvage surgery may not always be the best approach for recurrent RP WDLPS patients. Because organ invasion is rare among recurrent RP WDLPS patients and concomitant organ resection is associated with a longer hospital stay, preservation of uninvolved organs should be considered.

Background: We investigated whether concomitant organ removal as part of the primary resection of RP WDLPS confers an outcome advantage in patients treated at a major sarcoma center., Methods: The departmental sarcoma database was reviewed to identify patients with RP WDLPS who underwent initial surgical resection for primary disease at MD Anderson Cancer Center during the study period 1995-2011. We retrospectively reviewed medical records and examined associations between clinicopathologic variables and overall survival (OS) as well as disease-free survival (DFS)., Results: Among 83 patients included in this study, 76 patients (92%) underwent complete resection (R0/R1). Concomitant organ resections were performed in 38 patients (46%). Invasion of the resected organ/s was seen in six patients (7%). Estimated OS was 11.3 years (5-year OS, 86%), and DFS was 5.4 years (5-year DFS, 51%). By multivariate analysis, concomitant organ resection was not associated with improved OS (P = 0.428) or DFS (P = 0.946), and lack of organ resection was associated with a lower risk of postoperative complications (P = 0.01)., Conclusions: Concomitant organ resection was not associated with a survival benefit in RP WDLPS in this study. In patients with primary RP WDLPS, we recommend selective resection of contiguous organs only if there is clinical suspicion of invasion., (© 2017 Wiley Periodicals, Inc.)

Background: Elevated BNP is associated with adverse cardiac outcomes after noncardiac surgery. We assessed BNP values as markers of perioperative fluid status and their correlation with major/cardiopulmonary (CP) complications following CRS + HIPEC., Methods: Fluid balance, BNP levels, and morbidity data were collected for all patients undergoing CRS + HIPEC between 6/2014 and 2/2016., Results: One hundred and twenty-nine patients underwent CRS + HIPEC for appendiceal adenocarcinoma (n = 99), mesothelioma (n = 16), and colon cancer (n = 14). Less than 10% had CP comorbidities. The median PCI was 14 (range 4-39); 89% underwent CC0/1 resection (n = 115). Median blood loss (EBL) was 497 mL (50-2700). Major complications (Clavien III-V) occurred in 16 (12%), CP in 17 (13%), and major/CP in 24 (18%). Thirty-day mortality occurred in 2 (1.5%). Elevated BNP on POD1 correlated with increased risk of major/CP complications (OR 2.2, P = 0.052). This was most pronounced in the 25 patients receiving cisplatin: for each 100 unit increase in POD1 BNP the OR for major/CP complication was 7.4 versus 1.2 for the remaining patients, P = 0.083. Multivariate analysis identified increased EBL (OR 4.1 P = 0.011) and a trend toward increased BNP on POD1 (OR for each 100 unit increase 2.0, P = 0.10) as risk factors for major/CP complications., Conclusions: Postoperative BNP measurement after CRS + HIPEC may guide postoperative fluid resuscitation and facilitate identification of patients at risk for major and/or cardiopulmonary complications., (© 2017 Wiley Periodicals, Inc.)

Retroperitoneal liposarcomas (RPLPS) are rare tumors that represent at least 50% of all retroperitoneal sarcomas. Surgical resection remains the standard of care. Unfortunately, many RPLPS patients will develop a local recurrence and subsequently die in the absence of distant metastasis. This review outlines the factors that predict local recurrence and influence the management of first and subsequent multiply recurrent RPLPS., (© 2017 Wiley Periodicals, Inc.)

Background: Mucinous appendiceal neoplasms can contain radiopaque calcifications. Whether appendiceal radiographic calcifications indicate the presence of an appendiceal epithelial neoplasm is unknown. This study aimed to determine whether appendiceal calcifications detected by computed tomography (CT) correlate with the presence of appendiceal epithelial neoplasms., Methods: From prospective appendiceal and pathology databases, 332 cases of appendiceal neoplasm and 136 cases of control appendectomy were identified, respectively. Only cases with preoperative CT scans available for review were included in the study. Images were reviewed by two abdominal radiologists. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated, and the kappa statistic was used to determine agreement between the radiologists' interpretations., Results: Interobserver agreement between the radiologists was substantial, with a kappa of 0.74. Appendiceal mural calcifications were identified on CT scans in 106 appendiceal neoplasm cases (32%) and in 1 control case (1%) (P = 0.0001). In the appendiceal neoplasm subgroup, the presence of radiographic calcifications was associated with mucinous histology (35% vs 17%; P = 0.006; odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18-0.78) and with well-differentiated histologic grade (40% vs 24%; P = 0.002; OR, 0.47; 95% CI, 0.29-0.76). The findings showed a sensitivity of 31.9% (95% CI, 26.9-37.2%), a specificity of 99.3% (95% CI, 96-100%), a PPV of 99.1% (95% CI, 94.9-100%), and an NPV of 37.4% (95% CI, 32.4-42.6%)., Conclusion: This case-control study showed that appendiceal mural calcifications detected on CT are associated with underlying appendiceal epithelial neoplasms and that the identification of incidental mural appendiceal calcifications may have an impact on decisions regarding surgical intervention.

Background: The National Comprehensive Cancer Network (NCCN) has instituted treatment guidelines for stage 2A and stages 2B and 3 extremity and superficial trunk soft tissue sarcomas (ETSTS). This study examined adherence to the NCCN guidelines and factors associated with nonadherent treatment and survival outcomes., Methods: Patients with stage 2A and stages 2B and 3 ETSTS (n = 15,957) were categorized as undergoing adherent or nonadherent treatment based on the 2014 NCCN guidelines. Multivariate logistic regression models were used to determine factors associated with nonadherent treatment. Overall survival (OS) and disease-specific survival (DSS) were calculated, and Cox models were used to generate adjusted survival curves and hazard ratios (HRs)., Results: The findings showed that 87.2% of the patients with stage 2A disease and 58.3% of the patients with stage 2B or 3 disease received adherent treatment. Community treatment facilities and uninsured or unknown insurance status were associated with nonadherent treatment for both stage groups. Adherent treatment was associated with higher 5-year adjusted OS and DSS for stage 2A and stage 2B or 3 patients. In Cox models, nonadherent treatment was associated with worse survival for both stage 2A disease (HR, 2.31; 95% confidence interval [CI], 2.02-2.63) and stages 2B and 3 disease (HR, 1.63; 95% CI, 1.53-1.73). Increasing age and non-private insurance were associated with poorer outcomes. For stages 2B and 3 disease, treatment at a community center and African American race were associated with worse survival., Conclusions: Adherence to NCCN guidelines is excellent for stage 2A and poor for stages 2B and 3 ETSTS. Adherent treatment was associated with improved survival outcomes, highlighting the importance of adherence to NCCN guidelines.

Aim: To investigate the importance of a three-tiered histologic grade on outcomes for patients with mucinous appendiceal adenocarcinoma (MAA)., Methods: Two hundred and sixty-five patients with MAA undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were identified from a prospective database from 2004 through 2014. All pathology was reviewed by our gastrointestinal subspecialty pathologists and histological grade was classified as well-differentiated, moderately differentiated, and poorly differentiated. Survival analysis was performed using Cox proportional hazards regression., Results: There were 201 (75.8%) well-, 45 (16.9%) moderately- and 19 (7.2%) poorly-differentiated tumors. Histological grade significantly stratified the 5-year overall survival (OS), 94%, 71% and 30% respectively ( P < 0.001) as well as the 5-year disease-free survival (DFS) 66%, 21% and 0%, respectively ( P < 0.001). Independent predictors of DFS included tumor grade (HR = 1.78, 95%CI: 1.21-2.63, P = 0.008), lymph node involvement (HR = 0.33, 95%CI: 0.11-0.98, P < 0.02), previous surgical score (HR = 1.31, 95%CI: 1.1-1.65, P = 0.03) and peritoneal carcinomatosis index (PCI) (HR = 1.05, 95%CI: 1.02-1.08, P = 0.002). Independent predictors of OS include tumor grade (HR = 2.79, 95%CI: 1.26-6.21, P = 0.01), PCI (HR = 1.10, 95%CI: 1.03-1.16, P = 0.002), and complete cytoreduction (HR = 0.32, 95%CI: 0.11-0.92, P = 0.03). Tumor grade and PCI were the only independent predictors of both DFS and OS. Furthermore, histological grade and lymphovascular invasion stratified the risk of lymph node metastasis into a low (6%) and high (40%) risk groups., Conclusion: Our data demonstrates that moderately differentiated MAA have a clinical behavior and outcome that is distinct from well- and poorly-differentiated MAA. The three-tier grade classification provides improved prognostic stratification and should be incorporated into patient selection and treatment algorithms., Competing Interests: Conflict-of-interest statement: Dr. Taggart has received a small educational grant from Bristol-Meyers Squibb. The other authors have no disclosures.

Background: Optimal treatment strategies for retroperitoneal leiomyosarcoma (RPLMS), particularly recurrent disease, are unknown., Methods: We searched the tumor registry at The University of Texas MD Anderson Cancer Center (MDACC) to identify patients with RPLMS treated between 1994 and 2013., Results: We identified 172 patients with a diagnosis of a RPLMS. Among the 85 patients who underwent complete resection included in the survival analysis, the median overall survival (OS) was 8.3 years (95% confidence interval [CI], 5.7-12.3), 5-year local recurrence rate was 21%, and 5-year distant metastasis rate was 47%. Among 114 patients who experienced recurrence, patients who underwent salvage surgery for recurrent disease had longer OS after recurrence than patients who did not undergo salvage surgery (median survival after recurrence 5.6 vs 3.3 years, 3-year OS rates after recurrence 72.6% vs 58.1%, HR 0.402 [95%CI, 0.243-0.666]; P = 0.0004). Whether salvage surgery was performed for local or distant recurrence was not associated with OS. Patients who had a longer disease-free interval (≥12 months) had better progression-free survival after salvage surgery than those who had a shorter interval (HR, 0.437 [95%CI, 0.244-0.783]; P = 0.0055)., Conclusions: We recommend that salvage surgery be considered for selected patients with local or distant recurrence of RP LMS., (© 2017 Wiley Periodicals, Inc.)

Background: Moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death., Methods: Overall, 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database. Clinical, pathologic, and treatment factors were analyzed for outcomes., Results: Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42%) patients. These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease. Twenty-seven (41%) patients were excluded from cytoreductive surgery (CRS) because of findings on DL, while 116 (65%) patients underwent CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), with a median disease-free survival (DFS) of 23 months. Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS. The median OS following CRS and HIPEC was 48 months. Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with OS. Eight-five (73.3%) patients received neoadjuvant chemotherapy, and 40 (47.1%) patients achieved a radiographic response; 36 (42.3%) had stable disease, while 9 (10.6%) had progressive disease. Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011)., Conclusions: In selected patients, long-term survival can be obtained. Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI ≤ 20, and response/stable disease after neoadjuvant chemotherapy are important selection criteria for CRS and HIPEC.

Background: Mucinous appendiceal adenocarcinomas (AAs) are the most common histological subset of AAs. Nonmucinous AAs have been infrequently studied. We performed a single-center retrospective study to investigate this histological subtype., Methods: We reviewed 172 patient records with nonmucinous AAs treated at MD Anderson Cancer Center from Jan, 1990 to Jun, 2015 and recorded patient demographics, tumor characteristics, treatment, and outcomes. Response rate (RR) was assessed semi-quantitatively (response/no response) according to the treating physician's findings. Survival outcomes were calculated using the Kaplan-Meier product-limit method and compared using the log-rank test., Results: Median age at diagnosis was 52.9 years. Most patients presented with advanced-stage disease: stage I-II (35%), stage III (15%), and stage IV (50%). Moderate and poorly differentiated histology was seen in 56% and 44% tumors, respectively. Median overall survival (OS) of all patients was stage-dependent and was 88.5, 39.2, and 28.3 months for stages I-II, stage III, and stage IV disease, respectively (p < 0.0001). In patients with metastatic disease, only 10% had extraperitoneal disease without peritoneal involvement. Cytoreductive surgery (CRS) was attempted in 31/69 (45%) patients with disease confined to the peritoneum. Complete CRS was achieved in 18. Median OS for patients receiving complete CRS was 48.6 months. Systemic chemotherapy was administered to 109 (86%) patients with metastatic disease; a large majority of patients received either an oxaliplatin-based (55%) or irinotecan-based (27%) regimen. Chemotherapy resulted in a semi-quantitative RR of 54% and median time to progression (TTP) of 9.4 months (95% CI, 8.03-11.50). Patients who received combination chemotherapy (either oxaliplatin or irinotecan-based) showed significantly longer median OS (p = 0.003), compared to those receiving fluoropyrimidine monotherapy., Conclusions: This is one of the first studies to report specifically on nonmucinous AAs. Nonmucinous AAs presented with moderate or poorly differentiated histology with a predilection for peritoneal metastasis. Systemic chemotherapy is active in this AA subtype. Though CRS was infrequently used, complete CRS appears beneficial and warrants further investigation.

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is the preferred treatment for selected patients with mucinous appendiceal adenocarcinoma. Frequently, the hemidiaphragms are infiltrated with tumor, requiring partial diaphragm resection (DR) in order to obtain complete cytoreduction (CC-0). The clinical significance of diaphragmatic invasion and the optimum management to prevent transmission of disease from abdomen to chest is largely unknown., Methods: This was a retrospective review of 78 patients with mucinous appendiceal adenocarcinoma undergoing cytoreduction and partial DR at a single institution between 2010 and 2014., Results: Partial DR was necessary in 31 (39.7 %) patients in order to obtain CC-0. DR was not associated with increased morbidity or poor survival. Of the 31 patients who had a DR, 26 (83.9 %) were treated with thoracoabdominal chemoperfusion. The remaining five (16.1 %) patients had the diaphragm closed prior to HIPEC. Thoracoabdominal chemoperfusion was not associated with increased 30-day grade III/IV morbidity or respiratory complications. Overall, five (20 %) patients with a DR developed thoracic recurrence. There were two (8 %) thoracic recurrences in the 26 patients treated with thoracic chemoperfusion compared with three (60 %) in the five patients who had their diaphragm closed prior to HIPEC (p = 0.002). In univariate analysis histology, CC-0 and thoracoabdominal chemoperfusion were associated with thoracic disease-free survival; however, none of these were significant on multivariate analysis., Conclusion: DR is not associated with increased morbidity and should be performed, if needed, to obtain a CC-0. Following DR, patients remain at significant risk of developing thoracic recurrence. Thoracoabdominal chemoperfusion reduces this risk without increasing morbidity.

Background and Objectives: Maximal cytoreductive surgery (CS) with heated intraperitoneal chemotherapy perfusion (HIPEC) for peritoneal carcinomatosis can improve oncologic outcomes, but is associated with significant morbidity. Whether low-volume experience with CS/HIPEC results in acceptable outcomes is unknown., Methods: A retrospective review of all patients undergoing CS/HIPEC by a single surgeon. Experience was divided into first versus second 50 cases, and patient characteristics, operative details, and outcomes were compared., Results: Ninety patients underwent 100 CS/HIPEC procedures (mean age 57 years, 68% female). -Compared to the initial experience, the second 50 cases included more high grade tumors (68 vs. 52%) and greater disease burden (PCI 14.2 vs. 12.4). Operative times remained unchanged and mean blood loss decreased (978 vs. 684 ml). Hospital stay (mean 18.1 vs. 12.6 days), major complications (24 vs. 16%), and perioperative mortality (8 vs. 2%) declined. Overall median survival was 18 months and was longer with low grade tumors (26 vs. 16 months, P = 0.03)., Conclusions: Patients experienced reduced EBL, fewer major complications, and shorter hospital stay, despite having higher disease burden and higher grade tumors. This suggests that even low-volume experience with CS/HIPEC can lead to a trend in reduction of adverse perioperative events with acceptable oncologic outcomes., (© 2015 Wiley Periodicals, Inc.)

Total pelvic exenteration is a highly morbid procedure performed for locally advanced pelvic malignancies. We describe our experience with three patients who underwent robotic total pelvic exenteration with laparoscopic rectus flap and compare perioperative characteristics to our open experience. Demographic, tumor, operative, and perioperative factors were examined with descriptive statistics reported. Mean operative times were similar between the two groups. When compared to open total pelvic exenteration cases (n = 9), median estimated blood loss, ICU stay, and hospital stay were all decreased. These data show robotic pelvic exenteration with laparoscopic rectus flap is technically feasible. The surgery was well tolerated with low blood loss and comparable operative times to the open surgery. Further study is needed to confirm the oncologic efficacy and the suggested improvement in surgical morbidity.

Purpose: Retroperitoneal sarcomas (RPS) are rare malignancies, comprising just 10-15 % of all soft-tissue sarcomas. These are challenging tumors to treat, with surgical resection being the only modality capable of providing a cure. This study analyzed the management and survival of patients resected at a large academic institution., Methods: A retrospective study of all patients with primary localized RPS referred to the University of Washington between January 2000 and January 2013 was performed. Univariate and multivariate Cox regression models were used to analyze progression-free survival (PFS) and overall survival (OS) by patient, tumor, and treatment variables., Results: The study identified 132 patients. Median follow-up was 31.8 months. Median PFS was 33 months, and median OS was 111 months. Sixty patients (45.5 %) underwent a margin-negative resection (R0), 59 (44.7 %) had a microscopic margin-positive resection (R1), and 7 (5.3 %) had a macroscopic margin-positive resection (R2). Forty (30.3 %) patients received preoperative radiation, 28 (21.2 %) received neoadjuvant chemotherapy, and 7 (5.3 %) received both. Tumor grade and microscopic margin status emerged as statistically significant predictors for both PFS and OS. Tumor size was also found to correlate with PFS. No significant difference in OS or PFS was observed for histologic subtype, neoadjuvant chemotherapy, or neoadjuvant radiation., Conclusions: Complete surgical resection should remain the mainstay of management for RPS, with emphasis on achieving negative microscopic margins. Neither neoadjuvant chemotherapy nor radiation was shown to significantly improve survival, and their unclear role in the management of RPS requires evaluation in a prospective setting.

Background: Approximately 300 cases of leiomyosarcoma of the inferior vena cava (IVC) have been reported in the literature to date. In this study, we combined the experience from 2 institutions to provide additional clinical outcomes data., Methods: We performed a retrospective analysis from 1984 to 2009 that included 17 patients treated between the 2 institutions. Clinicopathologic data, surgical and adjuvant therapy, and survival outcomes were obtained., Results: The median age of patients in the study was 48 years. The tumor location was infrarenal in 8 patients, juxtarenal in 6, and suprahepatic in 2 patients; 7 patients had high-grade tumors. All patients underwent complete resection; the IVC was repaired primarily in 5 patients, ligated in 5, and reconstructed with a prosthetic tube graft in 7 patients. There was no perioperative mortality; 6 patients had complications. Median follow-up was 49 months; median survival had not been reached when this paper was written. The 5-year overall and disease -free survival were 56% and 37%, respectively. Of the 17 patients, 10 experienced disease recurrence and underwent numerous treatment modalities for these recurrences., Conclusion: Aggressive resection of primary leiomyosarcoma of the IVC can be performed safely and result in long-term survival, irrespective of IVC management. Despite high recurrence rates, no consensus yet exists regarding adjuvant treatment., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Rationale and Objectives: The aim of this study was to determine the sonographic visibility of implanted collagen-based breast biopsy marker clips in the clinic and operating room., Materials and Methods: Female patients aged > or =18 years who presented for preoperative surgical evaluation within 4 weeks of ultrasound-guided breast biopsy and collagen-based marker clip placement were eligible for this pilot study. The sonographic visibility of the marker clips was rated from 1 (not visible) to 5 (clearly visible) by surgeons at the preoperative appointment, by radiologists at wire localization, and by surgeons in the operating room. Visibility was considered inadequate for values of 1 or 2 and adequate for values of 3, 4, or 5. The data were compared using Wilcoxon's signed-rank test for paired differences across physician (radiologist vs surgeon), time (preoperative visit vs day of surgery), and target (lesion vs clip)., Results: Twenty-five patients with 26 lesions were enrolled, and 19 patients returned for all imaging procedures. The mean lesion size was 12 mm (range, 5-24 mm). Adequate marker clip visibility assessed by the surgeons decreased from 80% (20 of 25) at the preoperative appointment to 65% (11 of 17) in the operating room, but the difference was not significant (P=.27). Visibilities of the lesions and clips were similar at the preoperative appointment (P=.61), but the clips were significantly less visible on the day of operation (P=.03)., Conclusion: The sonographic visibility of collagen-based marker clips is variable and likely decreases over time but may be adequate to guide intraoperative surgical excision in many cases.

Head and neck melanoma often approaches critical structures. Therefore, excision is often limited, leading to positive margins, and increased local recurrence. Immediate reconstruction carries concern for rearrangement or concealment of cancerous tissues. Therefore, reconstruction is often delayed until confirming negative margins on permanent pathology. Our purpose is to identify variables associated with a positive margin and establish criteria for reconstruction timing. We reviewed 117 consecutive patients who underwent wide local excision of head and neck melanoma. Reconstruction was immediate for 107 and delayed for 10. Six percent of patients had a positive margin after wide local excision with no difference in incidence between immediate and delayed reconstruction (P = 0.11). Tumor characteristics associated with a positive margin were locally recurrent, ulcerated, and T4 tumors (P < 0.05); and delayed reconstruction should be considered in these circumstances. Immediate reconstruction is safe for the majority of head and neck melanoma and should be based on knowledge of tumor characteristics.

Background: Epithelioid sarcoma is a rare sarcoma with a high local recurrence rate that frequently metastasizes to lymph nodes. We reviewed our experience with adjuvant therapy in patients with this disease., Methods: Between 1990 and 2003, we treated 11 patients with epithelioid sarcoma. Patient, tumor, and treatment characteristics were analyzed, and effect of treatment on survival was evaluated by the Kaplan-Meier method., Results: Nine men and 2 women were treated. Tumors presented on the trunk, the upper extremities, and the lower extremities. Five patients developed nodal disease. All patients underwent surgery for the primary tumor, and 7 patients had nodal evaluation. Ten patients underwent adjuvant chemotherapy, and 9 underwent radiotherapy. Recurrence developed in 9 patients. Five-year disease-free and overall survival rates were 46% and 65%, respectively. Chemotherapy and radiation therapy did not impact disease-free survival., Conclusions: Although surgery remains the primary treatment modality, multi-institutional trials are needed to develop more effective adjuvant therapy for patients with epithelioid sarcoma.

Objective: To evaluate the effect of changing a 1-hour weekly all-resident didactic conference to an expanded 4-hour bimonthly level-specific didactic conference., Design: Prospective outcome measures included an anonymous 10-item perceptions survey administered at 4 time points (preintervention, 6 months postintervention, 1 year postintervention, and 2 years postintervention), mean attendance rates preintervention and postintervention, and mean ABSITE scores preintervention and postintervention., Setting: Large university-based surgical residency., Participants: Surgical residents (R1-R5, n = 75) were divided into junior (R1-R3, n = 56) and senior (R4-R5, n = 19) groups. Each group attended a session every other Wednesday., Results: Significant improvements were observed in overall resident satisfaction (55% vs 80%, p < 0.005) and level-specific appropriateness of content (81% vs 94%, p < 0.001). Furthermore, resident attendance rates were improved substantially (33% vs 55%, p < 0.001). ABSITE scores were not affected significantly by the change in curriculum structure., Conclusions: An expanded, bimonthly level-specific didactic curriculum is more effective than a shorter, weekly all-resident conference as evidenced by resident attitudes and attendance. Additional benefits of the alternating schedule include a reduced number of residents in each conference and the availability of residents for clinical educational activities (eg, operative cases or clinic). Expanded educational time has allowed the introduction of nontraditional topics that include leadership, communication, practice management, professionalism, and technical skills training.

Breast cancer chest wall recurrence is often treated with chemotherapy, radical surgery, and radiation. Extensive chest wall resection requires soft-tissue reconstruction with tissue that provides chest wall stability and durability for additional radiation. Local and regional muscle and musculocutaneous flaps are often used for reconstruction. Free flaps, such as the transverse rectus abdominis musculocutaneous flap, are used for large defects, although donor site morbidity can result. The free deep inferior epigastric perforator (DIEP) flap provides coverage for large defects and may have less donor site morbidity. We describe the use of the free DIEP flap to reconstruct large chest wall defects (mean, 501 cm2 defects) after the resection of recurrent breast cancer in two patients. One patient had 2% flap loss. No donor site morbidity occurred. The free DIEP flap is a durable and reliable flap that provided immediate and complete coverage of these large chest wall defects with no donor site morbidity and did not delay the administration of adjuvant therapy.

Objective: To describe the development of the EVATS rotation., Design: Descriptive document., Setting: University teaching hospital., Participants: Faculty and residents of the University of Washington., Methods: In July 2003 we identified the need for a new, independent, educational module within our residency training. Requirements for this rotation included dedicated time for technical skills training on simulators, independent competency learning modules, academic research project time, vacation time and coverage, and flexibility for unplanned leave (eg, interview travel, m/paternity leave)., Results: An EVATS rotation was created in July 2003 that is provided at each training level and lasts from 4 to 8 weeks depending on R-level. EVATS meets the following challenges: Emergency coverage (EVATS residents available for last-minute service coverage), vacation time/vacation coverage (2 weeks vacation + 1 week vacation coverage; this maintains vacations for all residents every 6 months), academic time (residents now must complete 1 academic project for graduation) and ACGME competency learning and assessment, and technical skills training (includes simulator work for open/lap skills). Initial implementation indices are high and include resident satisfaction, 80-hour work week compliance, academic productivity, and patient continuity of care., Conclusions: The 21st century brought new challenges for surgical training. Increased societal demands for skills training in a laboratory setting using simulators and the 6 ACGME competencies all require classroom-type training periods. Paradoxically, the 80-hour work week restricted the time available for these educational activities and made it more difficult for programs to accommodate resident vacations and emergencies. These challenges provided an opportunity to enhance the educational experience for our residency program. The product was the EVATS rotation. Early data after implementation are favorable.

Background: Pheochromocytomas are rare tumors of chromaffin cells for which the optimal management is surgical resection. Precise diagnosis and localization may be elusive. We evaluated whether positron emission tomography (PET) scanning with the combination of [18F]fluorodeoxyglucose (FDG) and the norepinephrine analogue [11C]metahydroxyephedrine (mHED) would allow more exact diagnosis and localization., Methods: Fourteen patients with suspected pheochromocytoma were evaluated by anatomical imaging (computed tomography or magnetic resonance imaging) and [131I]metaiodobenzylguanidine (MIBG) planar imaging. PET imaging was performed by using mHED with dynamic adrenal imaging, followed by a torso survey and FDG with a torso survey. Images were evaluated qualitatively by an experienced observer., Results: Eight patients had pathology-confirmed pheochromocytoma. Of the other six, two patients had normal adrenal tissue at adrenalectomy, and the other four had subsequent clinical courses inconsistent with a diagnosis of pheochromocytoma. In four of eight patients with pheochromocytoma, MIBG failed to detect one or more sites of pathology-confirmed disease. The mHED-PET detected all sites of confirmed disease, whereas FDG-PET detected all sites of adrenal and abdominal disease, but not bone metastases, in one patient. MIBG and FDG-PET results were all negative in the six patients without pheochromocytoma. One patient with adrenal medullary hyperplasia had a positive mHED-PET scan. PET scanning aided the decision not to operate in three of six patients. The resolution of PET functional imaging was superior to that of MIBG., Conclusions: PET scanning for pheochromocytoma offers improved quality and resolution over current diagnostic approaches. PET may significantly influence the clinical management of patients with a suspicion of these tumors and warrants further investigation.

Background: Anorectal melanoma (AM) is a rare tumor with a poor prognosis. Treatment with abdominoperineal resection (APR) over wide local excision (WLE) is still debated. This study aimed to compare median survival of WLE and APR in patients with AM., Methods: A systematic review of the literature was performed. Only series that allowed calculation of median survival were included., Results: Fourteen studies met inclusion criteria. Average median survival of stage I WLE patients (N=34) and stage I APR patients (N=31) was 44 and 22 months, respectively (P=.001). For stage II patients, 7 underwent WLE, and 10 underwent APR with an average median survival of 36 and 14 months, respectively (P=.19)., Conclusions: This study identified no stage-specific survival advantage to APR in favor of AM. Given that WLE is a more limited intervention associated with at least comparable survival, we propose that it be considered the initial treatment of choice for AM.

Purpose: The advent of sentinel lymph node mapping and biopsy in the staging of breast cancer has resulted in a significant decrease in the extent of axillary nodal surgery. As the extent of axillary surgery decreases, the radiation dose and distribution within the axilla becomes increasingly important for current therapy planning and future analysis of results. This analysis examined the radiation dose distribution delivered to the anatomically defined axillary level I and II lymph node volume and surgically placed axillary clips with conventional tangential breast fields and CT-based three-dimensional (3D) planning., Methods and Materials: Fifty consecutive patients with early-stage breast cancer undergoing breast conservation therapy were evaluated. All patients underwent 3D CT-based planning with conventional breast tangential fields designed to encompass the entire breast parenchyma. Using CT-based 3D planning, the dose distribution of the standard tangential breast irradiation fields was examined in relationship to the axillary level I and II lymph node volumes. Axillary level I and II lymph node anatomic volumes were defined by CT and surgical clips placed during complete level I-II lymph node dissection. Axillary level I-II lymph node volume doses were examined on the basis of the prescribed breast radiation dose and 3D dose distribution., Results: All defined breast volumes received > or =95% of the prescribed dose. By contrast, the 95% isodose line encompassed only an average of 55% (range, 23-87%) of the axillary level I-II lymph node anatomic volume. No patient had complete coverage of the axillary level I-II lymph node region by the 95% isodose line. The mean anatomic axillary level I-II volume was 146.3 cm(3) (range, 83.1-313.0 cm(3)). The mean anatomic axillary level I-II volume encompassed by the 95% isodose line was 84.9 cm(3) (range, 25.1-219.0 cm(3)). The mean 95% isodose coverage of the surgical clip volume was 80%, and the median value was 81% (range, 58-98%). The mean volume deficit between the axillary level I-II volume and the surgical clip volume was 41.7 cm(3) (median, 30.0 cc)., Conclusion: In this study, standard tangential breast radiation fields failed to deliver a therapeutic dose adequately to the axillary level I-II lymph node anatomic volume. No patient received complete coverage of the axillary level I-II lymph node volume. Surgically placed axillary clips also failed to delineate the level I-II axilla adequately. Definitive irradiation of the level I and II axillary lymph node region requires significant modification of standard tangential fields, best accomplished with 3D treatment planning, with specific targeting of anatomically defined axillary lymph node volumes as described, in addition to the breast parenchymal volumes.

In many parts of the United States, lymphatic mapping and sentinel lymph node biopsy has almost replaced axillary lymph node dissection (ALND) as the axillary staging procedure of choice for small, clinically node-negative breast cancers. However, the long-term outcome of patients undergoing a sentinel lymph node biopsy as the only axillary procedure in patients with tumor-free sentinel nodes remains to be determined. We present the first reported case of axillary recurrence in a patient with breast cancer following a tumor-negative sentinel lymph node biopsy. Whether sentinel lymph node biopsy can replace ALND in the management of patients with early breast cancer remains to be answered.

Myelolipomas are benign tumors composed of both mature adipose and myeloid tissues. They typically present as an incidental mass in one of the adrenal glands proper. However, they can occur in ectopic adrenal tissue or, rarely, without associated adrenal tissue in various locations and can grow to weights of several kilograms. These tumors have been linked to endocrinopathies, such as Cushing disease and congenital adrenal hyperplasia, which involve overproduction of adrenocorticotropic hormone. We report a case of three giant adrenal myelolipomas arising in a persistently virilized female with congenital adrenal hyperplasia, supporting a role for hormonal stimuli in myelolipoma formation.

Background: Improved preoperative assessment of focal liver disease and tumors could have a potentially significant impact on their treatment. Mangafodipir trisodium (Teslascan; Nycomed Amersham Imaging, Little Chalfont, UK) is a new hepatocellular contrast agent for use with state-of-the-art MR imaging that, in early reports, is accurate in detection and characterization of liver lesions., Methods: Records and diagnostic images of all patients undergoing enhanced Teslascan MRI (T-MRI) at our institution were reviewed. We assessed the relative sensitivities of contrast-enhanced CT scan (CECT) and T-MRI in detecting lesions, as well as the impact of T-MRI in the decision to operate or not on patients. In those patients taken to surgery, the correlation between T-MRI and intraoperative palpation and intraoperative ultrasound (IOUS) was determined., Results: Fifty-four patients were noted on CECT to have focal liver lesions and subsequently underwent imaging with T-MRI. The T-MRI correlated with CT findings in 22 patients (41%), upstaged the liver disease in 26, and demonstrated fewer lesions in 6. Only 43 patients were considered operative candidates and T-MRI influenced the operative decision in 32 patients (74%), dissuading operative intervention in 14. In the 25 patients without clear preoperative evidence of unresectability who were taken to the operating room, T-MRI correlated with findings of intraoperative palpation in 19 (76%). In the 20 patients who underwent IOUS, T-MRI correlated with IOUS in 14 patients (70%). IOUS detected an additional nine lesions, all of which were <1 cm. Seventeen patients underwent resection and/or ablation of their liver lesions. Compared with pathology, sensitivities of CECT, T-MRI, and intraoperative evaluation were 61%, 83%, and 93%, respectively. T-MRI failed to predict hepatic-specific unresectability in only one of eight patients, the other seven having extrahepatic disease., Conclusions: These findings suggest that T-MRI is more sensitive than CECT in the preoperative predicting of the resectability of hepatic lesions. Despite T-MRI accurately correlating with intraoperative surgical findings, IOUS should be performed on all patients prior to a final decision to resect or ablate a focal liver lesion.

Cystic mucinous tumors of the lung are recently described neoplasms whose histology is different from most lung adenocarcinomas, and represent a spectrum of malignant potential. Little is known of the behavior of the more malignant subtype. We present a cystic mucinous tumor of borderline malignancy that recurred locally following initial limited resection, and was treated with lobectomy.

Complicated colorectal carcinoma has several symptoms, the most common being bleeding and obstruction. Occasionally it will cause perforation, which carries a worse prognosis. We report a case of perforated adenocarcinoma of the cecum that presented as an abscess of the thigh. We also present a review of the literature on this subject.

Cyclosporine (CsA) is a potent immunosuppressant that has revolutionized the success of organ transplantation. Flurbiprofen (FB), a propionic acid derivative NSAID, has been demonstrated in vivo to reduce osteoclast numbers in normal rats. The aim of this experiment was to determine whether addition of FB to CsA-treated rats could prevent the bone changes associated with CsA therapy. Forty-eight 10-12-week-old male Sprague-Dawley rats were randomized to receive, daily for 28 days: (1) CsA vehicle p.o. plus FB vehicle sc; (2) CsA (15 mg/kg) p.o. plus FB vehicle sc, (3) CsA vehicle p.o. plus FB (1.5 mg/kg) sc; and (4) CsA (15 mg/kg) p.o. plus FB (1.5 mg/kg) sc. Rats were weighed and venous blood sampled at baseline, 14 days, and 28 days for determination of glucose, Ca+2, BUN, creatinine, PTH, osteocalcin, and 1,25(OH)2 vitamin D. Tibiae were removed following killing, after double labeling for histomorphometry. Body mass was significantly lower than control in all rats receiving CsA on days 14 and 28 while blood glucose was only elevated in the CsA alone group. Day 28 BUN and creatinine were significantly elevated in the CsA group and the combination of CsA and FB revealed an exacerbation of this trend. Vitamin D and osteocalcin were consistently increased in the CsA and CsA/FB groups. Bone histomorphometry showed evidence of trabecular osteopenia in CsA and CsA/FB groups. CsA alone resulted in elevated bone turnover. FB was unable to prevent the trabecular bone loss induced by CsA therapy. This experiment indicates no role for FB as a therapeutic option in CsA-induced bone disease at the given doses and duration of treatment by virtue of its lack of bone sparing ability and adverse renal effects when the two drugs are administered concurrently.

Immunosuppression with cyclosporin A (CsA) is effective in a number of immune-mediated diseases and in preventing rejection following organ transplantation. We have repeatedly demonstrated that CsA in the rat model produces accelerated bone remodelling with net bone loss, best characterized in trabecular bone. IGF-I holds promise as a treatment for various osteopenic conditions. Although currently a subject of much controversy, various studies have suggested that in vivo it is anabolic to cortical as well as trabecular bone. The purpose of this study was, in part, to further characterize the effects of CsA and IGF-I on trabecular and cortical bone, and to see whether systemic IGF-I is able to modulate CsA's deleterious skeletal effects. Sixty 10 week-old, male, Sprague-Dawley rats were randomized to receive the following daily for 3 weeks: (1) CsA vehicle (veh) per os (po) + recombinant human (rh) IGF-1 veh subcutaneously (sc); (2) CsA 15 mg/kg po + rhIGF-I-veh; (3) CsA-veh + rhIGF-I 200 microg/kg sc; (4) CsA-veh + rhIGF-I 600 microg/kg sc; (5) CsA 15 mg/kg + rhIGF-I 200 microg/kg, and (6) CsA 15 mg/kg + rhIGF-I 600 microg/kg. Rats were weighed and venous blood was sampled serially for determination of glucose, ionized calcium (Ca2+), PTH, vitamin D, and osteocalcin. Following sacrifice on day 20, histomorphometry was performed on double calcein-labeled tibial metaphysis and diaphysis. All rats receiving CsA had elevated levels of blood glucose and osteocalcin by day 9 and vitamin D at day 20. PTH was similar in all groups, and Ca2+ was only raised in the CsA and CsA + IGF-I 200 microg/kg groups. Rats receiving IGF-I 200 microg/kg and IGF-I 600 microg/kg gained more weight than either vehicle- or CsA-treated animals, attesting to IGF-1's anabolic properties. CsA caused severe trabecular bone loss, not prevented by IGF-I; it even further increased the eroded surface. CsA and IGF-I had little effect on cortical bone volume or marrow area. IGF-I increased endocortical matrix synthesis, as evidenced by the increases in the percent endocortical osteoid perimeter, an effect negated by the addition of CsA. This experiment demonstrates that trabecular bone is more susceptible than cortical bone to the deleterious effects of CsA and indicates little role for IGF-1 in the pathophysiology or treatment of CsA-induced bone disease at the given doses and duration of treatment.

The T lymphocyte suppressor, cyclosporin A, has been shown to cause high turnover osteoporosis. We postulated that cyclosporin A may exert its effects via the T cell rather than direct activity on bone. In this study we administered cyclosporin A (15 mg/kg.day by gavage) to 11 10-week-old Rowett athymic nude rats and to 12 age-matched immunocompetent Sprague-Dawley rats. Placebo was administered to control groups (n = 12 for both). After 28 days of treatment, the Sprague-Dawley rats displayed high turnover bone loss, but the nude rats were largely unaffected by the drug. Sprague-Dawley treated rats had less than half the percent trabecular area of their controls as measured at the secondary spongiosa of the proximal tibial metaphysis (P < 0.001; strain by treatment, P = 0.007). The same pattern was evident for trabecular number, separation, and thickness (strain by treatment, P = 0.034, P = 0.001, and P = 0.021, respectively). Only the Sprague-Dawley rats had an elevated percent eroded perimeter and an elevated bone area referent bone formation rate (strain by treatment, P = 0.002 and P = 0.0003, respectively). Mass, glucose, ionized calcium, PTH, osteocalcin, 1,25-dihydroxyvitamin D, and creatinine all responded similarly to cyclosporin A regardless of strain. T Lymphocytes thus appear to be a prerequisite for the development of cyclosporin A-induced osteopenia.

The immune and skeletal systems are known to interact. We have repeatedly shown that in contrast to in vitro data, the administration of T lymphocyte immunosuppressants, such as cyclosporin A, leads to an increase in bone resorption and a high turnover osteopenia. The purpose of this study was to characterize the bone metabolism of the T lymphocyte deficient Rowett athymic homozygous (rnu/rnu) nude rat. We wished to determine whether these rats share the bone abnormalities of cyclosporin A-treated rats. Eleven 10-week-old Sprague-Dawley rats and 12 similarly aged nude rats were studied over a 4-week period. Metaphyseal cancellous bone histomorphometry was similar in the two groups of rats and only differed with regard to percentage eroded perimeter (lower in nude rats, p = 0.0008) and longitudinal growth rate (49% lower in nude rats, p < 0.001). The nude rats had less body mass (p < 0.001) but nevertheless gained the same percentage of their body weight over the study period. The athymic rats had lower levels of serum, 1,25-dihydroxyvitamin D (p < 0.014) and serum osteocalcin(p < 0.009), and at the age of 14 weeks the nude rats had lower concentrations of serum creatinine (p = 0.001) and blood ionized calcium (p = 0.0002), yet serum PTH was similar throughout. RNA isolated from the contralateral tibias revealed that the nude group had lower steady-state levels of osteocalcin mRNA despite similar rates of bone formation. In its entirety, the data suggest that T cell deficiency per se is not necessarily associated with high turnover osteopenia.

Tamoxifen (TAM) is used primarily in the management of breast cancer, and it also has bone-sparing effects similar to estrogen. In breast cancer patients TAM may have a potential role in the prevention and management of osteoporosis. TAM therapy is associated with uterine hyperplasia, and medroxyprogesterone acetate (MPA) added to the regimen provides protection against this. Due to the potential combined use of MPA and TAM in the clinical setting, this study was conducted to assess whether MPA acted synergistically, dampened, or enhanced the TAM effect on bone. Seventy-five female rats (60 oophorectomized; Ox), were randomized into five groups and received either TAM (0.1 mg/kg.day) and/or MPA (0.3 mg/kg.day) therapy over 28 days as follows: 1) sham; 2) Ox; 3) Ox plus TAM; 4) Ox plus MPA; and 5) Ox plus TAM plus MPA. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium, PTH, 1,25-dihydroxyvitamin D, osteocalcin, and insulin-like growth factor 1. TAM-treated rats showed a reduction in body weight serum osteocalcin, PTH, and insulin-like growth factor 1. Histomorphometric analysis of the proximal tibia showed less cancellous bone volume in Ox rats, and the effect was attenuated by TAM. MPA alone had no significant effect on cancellous bone volume. All the bone formation parameters evaluated (bone formation rate, mineral apposition rate, percent calcein-labeled surface, and number of osteoblasts) were higher in Ox rats compared with sham-operated rats and were lower in TAM-treated rats compared with Ox rats. These parameters were not changed by MPA, alone or in combination with TAM. The number of osteoclasts was higher in Ox rats compared with sham-operated rats and was reduced by TAM. MPA therapy alone or in combination with TAM did not affect number of osteoclasts. These results suggest that MPA neither dampened nor enhanced the effect of TAM on bone.

Measurement of parathyroid hormone (PTH) in the rat is most often performed with competitive ligand radioimmunoassays (RIA) utilizing heterologous antibodies. We report here the validation of a newly developed homologous immunoradiometric assay (IRMA) for rat PTH. Two different goat antibodies to the amino-terminal sequence of rat PTH are utilized; one is immobilized onto plastic beads to capture the PTH molecules and the other is radiolabeled for detection. To test this new IRMA, 30 Sprague-Dawley rats were randomized into three treatment groups to receive by intraperitoneal injection: (1) saline 1 ml/kg (control); (2) calcium chloride 40 mg/kg (hypercalcemic); and (3) EDTA 300 mg/kg (hypocalcemic). Blood samples were taken at 0, 30, 60, 180, and 300 minutes after administration of the assigned treatment for measurement of ionized calcium (Ca2+) and serum PTH. Most of the variance in PTH levels was found to be due to changes in Ca2+ (r2 = 0.780, P < 0.0001). There was also a close temporal relationship between the two, with the highest levels of PTH occurring at the same measured time points as the lowest Ca2+, and vice versa. The measured detection limit of the IRMA was 3 pg/ml with intra- and interassay coefficients of variation of 1.74% and 3.07%, respectively. Serial dilutions with pooled rat serum, synthetic rat PTH-(1-34), and synthetic human PTH-(1-34) showed good parallelism with increased specificity for the pooled and synthetic PTH, despite a degree of crossreactivity with hPTH.(ABSTRACT TRUNCATED AT 250 WORDS)

The immunosuppressant agent cyclosporin A (CsA) induces a high turnover osteopenic state, while the effect on bone of the antimetabolite azathioprine, a drug often used in conjunction with CsA in transplant patients, is less clear. This study was therefore designed to investigate the outcome of azathioprine administration, with reference to CsA, on bone mineral metabolism using the rat model. Four groups of 10-week-old male Sprague-Dawley rats (12 per group) were randomly allocated to receive by daily gavage for a 28-day period: (1) no treatment (control group); (2) azathioprine 1.5 mg/kg bw; (3) CsA 15 mg/kg bw; and (4) a combination of azathioprine and CsA, as described above. Rats were weighed and blood assayed serially for osteocalcin, ionized calcium, 1,25-dihydroxyvitamin D (1,25(OH)2VitD), and parathyroid hormone (PTH). Tibiae were removed following sacrifice on day 28 after double calcein labeling for histomorphometric analysis. Immunosuppressant groups were compared with nontreated control. We confirmed our previous findings that CsA induces a state of high turnover bone loss which is accompanied by a diminished gain in body weight (p < 0.01) and elevated serum osteocalcin (p < 0.001) and 1,25(OH)2VitD levels (p < 0.001). Azathioprine treatment alone did not alter ionized calcium, 1,25(OH)2VitD, or PTH levels. However, there was biochemical evidence of impaired osteoblastic activity as seen by decreased osteocalcin values on days 14 and 28 (p < 0.001). Azathioprine caused no loss of bone volume nor any deviation from the norm in mineral apposition rate, bone formation rate, or longitudinal bone growth. All three treatment groups showed an increased recruitment of osteoclasts to the bone surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon-gamma (IFN gamma) in vitro inhibits both bone resorption and bone formation, resulting in a net decrease in bone turnover. In vivo administration of cyclosporin A (CsA) produces accelerated bone remodeling with resultant bone loss. The aim of this study was to investigate whether administration of IFN gamma to rats would favorably modify the high turnover osteopenia caused by CsA. Thirty-six male Sprague-Dawley rats were randomized into 4 equal groups to receive either CsA (15 mg/kg.day) or vehicle by gavage and IFN gamma (10(6) IU/kg.day) or vehicle by ip injection for 8 days. Group 1 received CsA vehicle plus IFN gamma vehicle; group 2 received CsA plus IFN gamma vehicle; group 3 received CsA vehicle plus IFN-gamma; group 4 received CsA plus IFN gamma. Blood was sampled on days 0, 4, and 8 for measurement of ionized calcium (Ca2+), PTH, 1,25-dihydroxyvitamin D, and bone gla protein. Tibiae were removed on day 8 after double tetracycline labeling for histomorphometric analysis. Ca2+ and PTH levels were similar in all groups during the study period. Rats receiving CsA (groups 2 and 4) had elevated levels of 1,25-dihydroxyvitamin D and bone gla protein, whereas rats receiving IFN gamma alone (group 3) had no change in levels of these parameters. Bone histomorphometry revealed that treatment with CsA and/or IFN gamma (groups 2-4) caused an increase in bone resorption surface and a decrease in some parameters of bone formation, resulting in a net loss of bone volume. Thus, IFN gamma failed to influence the osteopenia caused by CsA and on its own had adverse effects on bone in vivo. These results demonstrate that immune-mediating agents have opposing actions in vitro as compared to in vivo.

Administration of cyclosporine A to male and female rats accelerates bone remodeling and causes bone loss, among other side-effects. The newer immunosuppressant drugs, FK506 and CsG, have been synthesized to counteract the toxic effects of CsA, yet maintain clinical efficacy. We investigated the in vivo effects of long-term administration of these drugs on bone mineral metabolism in the rat. Five groups of Sprague-Dawley rats, 15 per group, were allocated to receive by daily gavage for a period of 28 days: (1) Cs-vehicle; (2) CsA 15 mg/kg b.w.; (3) CsG 15 mg/kg b.w.; (4) FK506 vehicle; (5) FK506 5 mg/kg b.w. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium (Ca2+), parathyroid hormone (PTH), 1,25-(OH)2-vitamin D, and bone gla protein (BGP). Tibiae were removed on day 28 after double calcein labeling for histomorphometric analysis. Immunosuppressant groups were compared with the respective vehicle groups. Neither CsA or CsG affected the levels of Ca2+ or PTH, whereas by day 28 FK506 caused a decrease in Ca2+ and a corresponding rise in PTH (P < 0.05). The 1,25-(OH)2-vitamin D and BGP levels in both the CsA and CsG groups were increased on days 14 and 28 (P < 0.05), while FK506 had no effect on these serum levels. Tibial bone histomorphometry revealed that all 3 immunosuppressants increased measures of bone formation and bone resorption, accompanied by a significant reduction in percent trabecular area, most marked with FK506. This report demonstrates that all three immunosuppressants have adverse effects on bone--most deleterious with FK506.