Targeting CXCR4 with CTCE-9908 inhibits prostate tumor metastasis

Abstract Background CXCL12/CXCR4 transactivation of epidermal growth factor family receptors in lipid raft membrane microdomains on cell surface is thought to mediate tumor growth and subsequent development of metastatic disease. CTCE-9908 is a known inhibitor of CXCR4. Herein, we tested the efficacy of CTCE-9908 in inhibiting prostate cancer cell growth, invasion, and metastasis. Methods We used a panel of in vitro assays utilizing human prostate cancer cell lines and an in vivo orthotopic prostate cancer model to assess the anti-tumoral activity of CTCE-9908. Results We demonstrated that (a) CTCE-9908 treatment resulted in no significant change in the growth of PC-3 and C4-2B cells; (b) 50 μg/ml of CTCE-9908 inhibited the invasive properties of PC-3 cells; (c) 25 mg/kg of CTCE-9908 did not alter primary tumor growth but it did significantly reduce total tumor burden in the animal including the growth of prostate and soft tissue metastases to lymph node and distant organ tissues. Histological analysis showed that CTCE-9908 treatment resulted in tumor necrosis in primary prostate tumors and no significant change in proliferation of tumor cells as measured by Ki-67 staining; (d) CTCE-9908 inhibited the tumor angiogenesis as measured by CD34 positive vessels in tumors. Conclusions These data suggest that CXCR4 inhibition by CTCE-9908 decreases the invasion potential in vitro, which then translated to a reduction of tumor spread with associated reduction in angiogenesis. Hence, CTCE-9908 may prove to be an efficacious novel agent to prevent and treat the spread of metastatic prostate cancer

COLECTOMY OUTCOMES IN PATIENTS OVER 65 WITH ULCERATION COLITIS

Introduction: There are limited data regarding surgical outcomes for elderly patients with Ulcerative Colitis, and we sought to examine the post operative outcomes in this population. Methods: The ACS NSQIP was queried for all patients with a diagnosis of ulcerative colitis and compared elderly patients (those aged 65 and older) to younger patients under age 65. Univariate and multivariate logistic regression was done to evaluate differences in morbidity and mortality rates. Results: 2,699 patients were analyzed, of which 493 (18.3%) were defined as elderly. Elderly patients had more comorbidities compared to younger patients but were less likely to be on preoperative steroids (47.1% vs 74.2%, p\u3c0.0001). Elderly patients had a higher proportion of emergent cases (27.6% vs 8.2%, p\u3c0.0001) and an average 3 day longer hospital stay, (p\u3c0.0001). There were no significant differences in the rates of anastomotic leak, surgical site infections or 30-day readmission. Elderly patients had a higher rate of morbidity (47.3% vs 26.8%, p\u3c0.0001) and mortality (8.9% vs 1.2%, p\u3c0.0001). Multivariate analysis showed elderly patients had significantly increased odds for morbidity (OR 2.45, 95% CI: 2.00-2.99, p\u3c0.0001) and 30-day mortality (OR 7.91, 95% CI: 4.85-12.91, p\u3c0.001). Preoperative sepsis significantly increased the risk of morbidity (OR 3.457, 95% CI: 2.27-5.26, p \u3c0.0001) and mortality (OR 3.11, 95% CI: 1.48-6.57, p\u3c0.003). Conclusions: Elderly patients with Ulcerative Colitis that undergo a colectomy are at increased risk for both morbidity and mortality. Optimizing these patients may reduce the risk, but further prospective trials are warranted to further elucidate the ideal optimization strategies.https://scholarlycommons.henryford.com/sarcd2021/1009/thumbnail.jp

Is Esophagectomy for Benign Conditions Benign?

BACKGROUND: Outcomes data on esophagectomy performed for benign conditions is scarce. Using the National Surgical Quality Improvement Program database, we sought to analyze outcomes of esophagectomy performed for benign conditions. METHODS: The National Surgical Quality Improvement Program database was queried for all esophagectomies performed from 2005 to 2015. Outcomes for benign conditions were analyzed and compared with outcomes for malignant conditions. RESULTS: Esophagectomy was performed in 7,477 patients during the study period. Of those, 6,762 underwent esophagectomy for malignant conditions and 715 for benign conditions. For patients with benign conditions, reconstruction was performed using gastric conduit in 631 and colon/intestine in 84. The anastomosis was intrathoracic in 420 and cervical in 295. Benign esophagectomies were more likely to be emergent (10.1% vs 0.4%, p \u3c 0.001). In addition, these patients had a longer hospital length of stay (17.2 days vs 14.5 days, p \u3c 0.001) and higher occurrence of Clavien-Dindo grade IV complications (25% vs 20%, p = 0.003). Mortality was similar at 4%. In patients with benign conditions, reconstruction with colon/intestine had higher occurrence of Clavien-Dindo Grade IV complications (37% vs 23%, p = 0.006), surgical wound infections (33% vs 16%, p \u3c 0.001), and death (10% vs 4%, p = 0.017) compared with gastric reconstruction. Site of anastomosis did not affect outcomes. CONCLUSIONS: Benign esophagectomies are associated with significant morbidity. Although the site of the anastomosis does not alter outcomes, use of colon/intestine conduit should be pursued with caution

Long-Term Outcomes after Robotic-Assisted Ivor-Lewis Esophagectomy

Purpose: Robotic assistance has gained a measure of acceptance in thoracic procedures, including esophagectomy. However, there is a paucity of data regarding long-term outcomes for robotic esophagectomy. We have previously reported our initial series of robot assisted Ivor-Lewis (RAIL) esophagectomy. We report long-term outcomes to assess the efficacy of the procedure.Methods : We performed a retrospective review of 112 consecutive patients who underwent a RAIL at our institution. Patient demographics, diagnosis, pathology, operative characteristics, post-operative complications, and long-term outcomes were documented. Descriptive statistical analysis was performed for all the variables. Primary endpoints were mortality and disease-free survival. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Results: Of the 112 patients, 106 had a diagnosis of cancer, with adenocarcinoma the dominant histology (87.5%). Of the 106 cancer patients, 81(76.4%) received neo-adjuvant chemoradiation (stage 3A most common). The 30, 60, and 90-day mortality was 1 (0.9%), 3 (2.7%), and 4 (3.6%) respectively. There were 9 anastomotic leaks (8%) and 18 (16.1%) patients had a stricture requiring dilation. All patient OS at 1, 3, and 5 years was 81.4%, 60.5%, and 51.0%, respectively. For cancer patients, the 1, 3, and 5 years OS was 81.3%, 59.2%, and 49.4% respectively and the DFS was 75.3%, 42.3%, and 44.0%. Conclusion: We have shown that long term outcomes after RAIL esophagectomy are similar to other non-robotic esophagectomies. Given the potential advantages of robotic assistance, our results are crucial to demonstrate that RAIL does not result in inferior outcomes.https://scholarlycommons.henryford.com/merf2019clinres/1060/thumbnail.jp

Perianal Pigmented Variant of Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans (DFSP) is a low-to-intermediate grade cutaneous sarcoma with reported at 3 per 1,000,000 individuals. It is a locally aggressive tumor which originates in the dermis and invades deeper structures. Up to 90% of cases of DFSP are associated with a translocation between chromosomes 17 and 22. These tumors have a high risk of local recurrence but very rarely exhibit metastatic spread. Several histologic variants exist, including fibrosarcomatous DFSP, and in this case, pigmented DSFP. Pigmented dermatofibrosarcoma protuberans, otherwise also known as a Bednar tumor, is a rare variant of DFSP first described in 1956 which accounts for less than 5% of all DSFP cases. It is distinguished by the presence of melanin containing dendritic cells within the tumor. Histologically, tumor cells are arranged in compact spindle shaped bundles. These tumors may be derived from neuroectodermal cells although no consensus has been reached. DSFP occurs equally in men and women and most commonly occurs in young to middle aged adults. These cutaneous sarcomas typically present on the trunk, back and shoulders as a slow-growing mass or plaque that may be hyperpigmented. Less that 1% present on genitalia, and only two DSFP cases to date have been reported involving the perianal region.https://scholarlycommons.henryford.com/merf2019caserpt/1085/thumbnail.jp

PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling

Abstract Introduction The chemokine CXCL12, also known as SDF-1, and its receptor, CXCR4, are overexpressed in prostate cancers and in animal models of prostate-specific PTEN deletion, but their regulation is poorly understood. Loss of the tumor suppressor PTEN (phosphatase and tensin homolog) is frequently observed in cancer, resulting in the deregulation of cell survival, growth, and proliferation. We hypothesize that loss of PTEN and subsequent activation of Akt, frequent occurrences in prostate cancer, regulate the CXCL12/CXCR4 signaling axis in tumor growth and bone metastasis. Methods Murine prostate epithelial cells from PTEN+/+, PTEN +/− , and PTEN−/− (prostate specific knockdown) mice as well as human prostate cancer cell lines C4-2B, PC3, and DU145 were used in gene expression and invasion studies with Akt inhibition. Additionally, HA-tagged Akt1 was overexpressed in DU145, and tumor growth in subcutaneous and intra-tibia bone metastasis models were analyzed. Results Loss of PTEN resulted in increased expression of CXCR4 and CXCL12 and Akt inhibition reversed expression and cellular invasion. These results suggest that loss of PTEN may play a key role in the regulation of this chemokine activity in prostate cancer. Overexpression of Akt1 in DU145 resulted in increased CXCR4 expression, as well as increased proliferation and cell cycle progression. Subcutaneous injection of these cells also resulted in increased tumor growth as compared to neo controls. Akt1 overexpression reversed the osteosclerotic phenotype associated with DU145 cells to an osteolytic phenotype and enhanced intra-osseous tumor growth. Conclusions These results suggest the basis for activation of CXCL12 signaling through CXCR4 in prostate cancer driven by the loss of PTEN and subsequent activation of Akt. Akt1-associated CXCL12/CXCR4 signaling promotes tumor growth, suggesting that Akt inhibitors may potentially be employed as anticancer agents to target expansion of PC bone metastases

Patient and provider factors associated with the noninitiation of tamoxifen for young women at high-risk for the development of breast cancer

We sought to identify factors associated with disparities in tamoxifen utilization among young patients at high- risk for developing breast cancer. We identified 67 premenopausal, high- risk women age 35- 45, without surgical prophylaxis, who did not initiate tamoxifen. Factors associated with noninitiation were examined. About 37% of patients had no documented provider- based discussion regarding initiation. Type of high- risk diagnosis was the only factor associated with a provider- based discussion (P = .03). For patients offered tamoxifen, primary reasons for noninitiation were perceived minimal benefit (66.7%), fertility concerns (16.7%), and concerns about side effects (7.1%). Implementation of comprehensive educational strategies regarding the benefits of tamoxifen should be facilitated to improve initiation among young high- risk patients.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154627/1/tbj13528_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154627/2/tbj13528.pd

Patient and provider factors associated with the noninitiation of tamoxifen for young women at high-risk for the development of breast cancer

We sought to identify factors associated with disparities in tamoxifen utilization among young patients at high- risk for developing breast cancer. We identified 67 premenopausal, high- risk women age 35- 45, without surgical prophylaxis, who did not initiate tamoxifen. Factors associated with noninitiation were examined. About 37% of patients had no documented provider- based discussion regarding initiation. Type of high- risk diagnosis was the only factor associated with a provider- based discussion (P = .03). For patients offered tamoxifen, primary reasons for noninitiation were perceived minimal benefit (66.7%), fertility concerns (16.7%), and concerns about side effects (7.1%). Implementation of comprehensive educational strategies regarding the benefits of tamoxifen should be facilitated to improve initiation among young high- risk patients.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154627/1/tbj13528_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154627/2/tbj13528.pd

Current Status of the Radiologic Assessment of Diverticular Disease

Radiologic assessment plays a vital role in the management of diverticulitis. It not only helps in the diagnosis, but also helps to guide the management. As technology has progressed, different modalities have offered insight into the treatment of this disease process. Through various trials and studies, certain modalities stand above the rest in terms of sensitivity and specificity. Computed tomography (CT) imaging has also proved to help us guide the management through a grading system. Newer studies show us the advantages of other modalities such as ultrasound and magnetic resonance imaging (MRI). Though there is much research yet to be done with these modalities, they do show a lot of potential

Utility of an Oral Exam During the Third Year Surgery Clerkship

Purpose: The National Board of Medical Examiners (NBME) Surgery Shelf Exam is often criticized as not accurately reflecting surgical knowledge. As a result, medical schools implement an oral exam to better assess students’ surgical knowledge. There is no data on the correlation between performance on the shelf and oral exams. We sought to assess the utility of the oral exam as a correlate and predictor of shelf exam performance.Methods:We reviewed medical student surgery clerkship performance reports between 2012 through 2018. Students’ clinical evaluation, clinical site, clerkship dates, and exam scores were noted. Bivariate and multivariate analysis was performed to assess for the relationship between the two exams.Results:We reviewed 1,160 performance reports over four clinical sites. The average oral exam score was 20.0 [4.8]. Students with a higher clinical evaluation had a significantly higher oral exam score (21.1 [4.5] vs 19.5 [4.8], p\u3c0.001). There was a significant difference in oral exam scores among the four different clinical sites (p\u3c0.01). There was no difference in oral exam scores among the different clerkship dates (p = 0.23). Oral exam scores and shelf exam scores were positively correlated (r = 0.32, p \u3c 0.001). In multivariate analysis, oral exam performance was an independent predictor for shelf exam performance (b = 0.48, 95% CI: 0.39 – 0.57, p\u3c0.001).Conclusion:Oral exam performance correlates with and predicts shelf exam performance. Low performance on an oral exam may allow educators to intervene prior to students taking the shelf exam.https://scholarlycommons.henryford.com/merf2019edu/1006/thumbnail.jp