Artificial Intelligence and Machine Learning in Lower Extremity Arthroplasty: A Review.

BACKGROUND: Driven by the rapid development of big data and processing power, artificial intelligence and machine learning (ML) applications are poised to expand orthopedic surgery frontiers. Lower extremity arthroplasty is uniquely positioned to most dramatically benefit from ML applications given its central role in alternative payment models and the value equation. METHODS: In this report, we discuss the origins and model specifics behind machine learning, consider its progression into healthcare, and present some of its most recent advances and applications in arthroplasty. RESULTS: A narrative review of artificial intelligence and ML developments is summarized with specific applications to lower extremity arthroplasty, with specific lessons learned from osteoarthritis gait models, joint-specific imaging analysis, and value-based payment models. CONCLUSION: The advancement and employment of ML provides an opportunity to provide data-driven, high performance medicine that can rapidly improve the science, economics, and delivery of lower extremity arthroplasty.

SLC5A8 nuclear translocation and loss of expression are associated with poor outcome in pancreatic ductal adenocarcinoma.

OBJECTIVES: This study aimed to assess the role of SLC5A8 expression in the survival of pancreatic cancer. METHODS: We determined SLC5A8 expression in pancreatic ductal adenocarcinoma and adjacent non-neoplastic pancreas (NNP) obtained from 110 patients who underwent pancreatectomy. Formalin-fixed paraffin-embedded core sections in a tissue microarray were immunostained using polyclonal anti-SLC5A8 antibody, and a semiquantitative measure of SLC5A8 expression was determined. RESULTS: SLC5A8 expression was low in 56% (62/110) of pancreatic cancers as compared to NNP that had low expression in only 9% (10/107) of specimens (P < 0.0001). All cells expressing SLC5A8 did so in the cytoplasm, whether they are neoplastic or not. Nuclear expression of SLC5A8 occurred in 38% (42/110) of cancers, but it was uncommon in NNP (7%, 8/107) (P < 0.0001). Kaplan-Meier estimates showed that survival in patients whose cancers had low SLC5A8 expression, and/or nuclear expression, was significantly worse than in patients whose cancers had none of these abnormalities (P = 0.02). For the 88 patients whose cancers had abnormal SLC5A8 expression, median survival was 1.4 years, as compared to 3.9 years in patients whose cancers both expressed high levels of SLC5A8 and lacked nuclear expression. CONCLUSIONS: SLC5A8 nuclear translocation and loss of expression are associated with poor outcome in pancreatic ductal adenocarcinoma.

Palladin is a marker of liver metastasis in primary pancreatic endocrine carcinomas.

BACKGROUND: Palladin is a metastasis-associated gene regulating cell motility. The expression of palladin protein in pancreatic neuroendocrine tumors (PET) and carcinomas (PECA) is not known. MATERIALS AND METHODS: A tissue microarray (TMA) of well-differentiated (WD) PETs/PECAs (AJCC 2010) and non-neoplastic, histologically normal pancreatic tissue/islets (HNPIs) was immunostained with palladin antibody and quantified using the Allred score. The results were correlated with the presence or absence of liver metastases. RESULTS: The retrospective study included 19 males and 19 females of age 27-79 years (mean 54). Tumor size was 0.9-11.5 cm (mean 3.8). Palladin expression was cytoplasmic and/or membranous. The tumors with high palladin expression were associated with liver metastasis (p<0.0001). All 14 primary PECA with hepatic metastases (MP-PECAs) exhibited palladin expression whereas 14 out of 24 (58%) clinically-localized primary PET (CLP-PETs) expressed palladin (p<0.01) with median Allred scores of 5 (range 3-7) and 2 (range 0-6) respectively (p<0.0001). The mean Allred score for the HNPIs in the MP-PECAs (N=6) was higher (4.2) as compared to that in the CLP-PETs (2.5,N=11) (p=0.23). CONCLUSION: Palladin may identify primary pancreatic endocrine neoplasms with a propensity to metastasize to the liver.

Neoadjuvant GTX chemotherapy and IMRT-based chemoradiation for borderline resectable pancreatic cancer.

BACKGROUND AND OBJECTIVES: To improve the likelihood of achieving a margin-free resection, neoadjuvant induction chemotherapy with GTX (gemcitabine, docetaxel, and capecitabine) followed by 5-FU-IMRT was administered to patients with borderline resectable pancreatic cancer. The utility of computed tomography (CT), endoscopic ultrasound (EUS), positron emission tomography (PET), and CA 19-9 during diagnostic workup and assessment of response was also examined. METHODS: Seventeen patients with borderline resectable pancreatic cancer received a median of three cycles of neoadjuvant GTX induction chemotherapy followed by 5-FU-IMRT with dose painting. CA 19-9, CT mass size, and PET SUV were examined before and after neoadjuvant treatment. RESULTS: Diagnostic EUS and CT scans displayed similar mean mass sizes and extent of vascular involvement. Eight of the 17 patients achieved an R0 resection. Median CA 19-9 levels, CT mass size, and PET SUV all significantly decreased after neoadjuvant therapy. The median progression-free survival and overall survival were 10.48 and 15.64 months, respectively. Six patients are still alive. CONCLUSIONS: Neoadjuvant GTX induction chemotherapy followed by 5-FU-IMRT shows promise in improving the likelihood of resectability with negative margins in borderline resectable pancreatic cancer. CT and EUS play complimentary roles during diagnostic workup. CT scans, CA 19-9, and PET scans are useful in judging response to neoadjuvant therapy.

RUNX1T1: a novel predictor of liver metastasis in primary pancreatic endocrine neoplasms.

OBJECTIVES: Using gene expression profiling on frozen primary pancreatic endocrine tumors (PETs), we discovered RUNX1T1 as a leading candidate progression gene. This study was designed (1) to validate the differential expression of RUNX1T1 protein on independent test sets of metastatic and nonmetastatic PETs and (2) to determine if RUNX1T1 underexpression in primary tumors was predictive of liver metastases. METHODS: Immunohistochemical expression of RUNX1T1 protein was quantified using Allred scores on archival metastatic (n = 13) and nonmetastatic (n = 24) primary adult PET tissues using custom-designed tissue microarrays. Wilcoxon rank sum/Fisher exact tests and receiver operating characteristic curves were used in the data analysis. RESULTS: Median RUNX1T1 scores were 2 (2-7) and 6 (3-8) in metastatic versus nonmetastatic primaries (P < 0.0001). Eleven of 13 metastatic and 1 of 24 nonmetastatic primaries exhibited RUNX1T1-scores of 4 or less (P < 0.0001). Low RUNX1T1 expression was highly associated with hepatic metastases (P < 0.0001), whereas conventional histological criteria (Ki-67 index, mitotic rate, necrosis) were weakly associated with metastases (P = 0.08-0.15). Considering RUNX1T1 expression (Allred) score of 4 or less to be predictive, the sensitivity to predict hepatic metastases was 85%, with a specificity of 96%. CONCLUSIONS: RUNX1T1 protein is underexpressed in well-differentiated metastatic primary PETs relative to nonmetastatic primaries and emerges as a promising novel biomarker for prediction of liver metastases.

MicroRNAs in pancreatic ductal adenocarcinoma.

Ductal adenocarcinoma of the pancreas is a lethal cancer for which the only chance of long-term survival belongs to the patient with localized disease in whom a potentially curative resection can be done. Therefore, biomarkers for early detection and new therapeutic strategies are urgently needed. miRNAs are a recently discovered class of small endogenous non-coding RNAs of about 22 nucleotides that have gained attention for their role in downregulation of mRNA expression at the post-transcriptional level. miRNAs regulate proteins involved in critical cellular processes such as differentiation, proliferation, and apoptosis. Evidence suggests that deregulated miRNA expression is involved in carcinogenesis at many sites, including the pancreas. Aberrant expression of miRNAs may upregulate the expression of oncogenes or downregulate the expression of tumor suppressor genes, as well as play a role in other mechanisms of carcinogenesis. The purpose of this review is to summarize our knowledge of deregulated miRNA expression in pancreatic cancer and discuss the implication for potential translation of this knowledge into clinical practice.

Down-regulation of Bax-interacting factor 1 in human pancreatic ductal adenocarcinoma.

OBJECTIVE: Bax-interacting factor 1 (Bif-1) protein plays a critical role in apoptosis, mitochondrial morphogenesis, and autophagy, and its loss promotes tumorigenesis. The role of Bif-1 in pancreatic cancer has not been studied. METHODS: We determined Bif-1 expression in 82 human pancreatic ductal adenocarcinomas (PDCs) and in 82 nonmalignant pancreatic specimens (NMPs), using immunohistochemistry and tissue microarray. Bif-1 immunostain was semiquantitatively scored on a scale of 0 to 9. RESULTS: Bif-1 scores in NMP were either 6 or 9, with lower scores in only 19 (23.2%) of 82 NMPs. Low Bif-1 expression (score <6) was found in 37 (45.1%) of 82 PDCs, a proportion significantly greater than that found in NMP (P = 0.005). The expression of Bif-1 was twice as likely to be low in PDC as in NMP (relative risk = 1.95, 95% confidence interval, 1.23-3.09). Kaplan-Meier survival estimates showed no difference in survival between patients with low and high Bif-1 expression (P = 0.21, log-rank test). CONCLUSIONS: The expression of Bif-1 is downregulated in a subset of PDC. This novel finding is in agreement with the tumor suppressor function of Bif-1. The lack of association between Bif-1 expression and patient survival may be best explained by the complexity of carcinogenesis.

First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas.

BACKGROUND: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS). METHODS: Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days. RESULTS: Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events. CONCLUSIONS: The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.

Correlation between Mcl-1 and pAKT protein expression in colorectal cancer.

Mcl-1 inhibits apoptosis in well-differentiated cells by sequestering BAD, BID, and BAX and other apoptotic molecules. pAKT blocks apoptotsis by facilitating the interaction of BAD with BCL-XL. Expression of pAKT and Mcl-1 have been described in colon cancer, however, the relationship between pAKT and Mcl-1 has not. Mcl-1 and pAKT immunohistochemistry was performed using colorectal cancer tissue microarray (TMA). The Holm step-down method was used to adjust for multiple testing. Mcl-1 and pAKT scores, stage, and grade were compared using Spearman's correlation coefficient. Metastasis and no metastasis groups were compared using the Wilcoxon rank sum test. Mcl-1 and pAKT scores were compared for normal colorectal mucosa (NR), adenoma (AD), and colorectal cancer (CRC) cohorts. The mean (SD) pAKT expression in NR (14) was 2.0 (1.4), in AD (8) was 3.0 (1.7), and in CRC (101) was 5.6 (2.4). These differences were statistically significant. For Mcl-1 the mean (SD) expression was 4.1 (1.7) in NR, 3.2 (1.2) in AD, and 3.3 (2.6) in CRC. Mcl-1 and pAKT scores were directly correlated during various stages of colon car-cinogenesis (p = 0.04). Mcl-1 showed direct correlation with tumor grade (p = 0.001) and tumor stage (p = 0.02) and with presence of metastasis (p = 0.008). We report the correlation of Mcl-1 protein expression with higher grade and stage in colorectal cancer. Mcl-1 correlated also with pAKT expression. We also report the up regulation of pAKT during the transition from NR to CRC.

Histologic characteristics enhance predictive value of American Joint Committee on Cancer staging in resectable pancreas cancer.

BACKGROUND: American Joint Committee on Cancer (AJCC) anatomic stage group is considered relatively nondiscriminatory for predicting differences in survival after pancreatectomy for ductal adenocarcinoma, a perception confirmed in the authors' patients and by other reports. The authors' aim was to investigate the potential for improving the predictive value of AJCC staging by incorporating individually predictive histologic features into AJCC tumor-node-metastasis classification of anatomic extent, and determine the simplest combination of tumor characteristics predicting survival. METHODS: The authors determined survival of 137 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage Groups IA-IIB) at Moffitt Cancer Center during the last 2 decades using data obtained from medical record review, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic characteristics were confirmed by expert review. RESULTS: Median survival was 21.2 months after pancreatectomy with a 3-year disease-specific survival of 36%. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard modeling found worse survival with local extrapancreatic extension, poorly differentiated histology, and lymphatic invasion within tumor (P<.05). Survival was not worse with nodal metastases, microscopically positive resection margins, and perineural or venous invasion, nor was survival better with cancer arising from an intraductal papillary mucinous neoplasm. Kaplan-Meier estimates for different variable combinations showed prognosis was best for well- or moderately differentiated tumors without lymphatic invasion and confined to the pancreas (9.9 years median survival), worst for poorly differentiated tumors with lymphatic invasion and local extension beyond the pancreas (8.5 months median survival), and intermediate for well- or moderately differentiated tumors with either lymphatic invasion or local extension beyond the pancreas (21.2 months median survival). CONCLUSIONS: A simple combination of tumor differentiation, lymphatic invasion within the tumor, and local extrapancreatic extension predicts survival after pancreatectomy for ductal adenocarcinoma.

Outcomes following resection of pancreatic adenocarcinoma: 20-year experience at a single institution.

BACKGROUND: Pancreatectomy for ductal adenocarcinoma has been performed with increasing frequency since the late 1980s as postoperative mortality decreased and long-term survival became more common. However, the belief persists among some clinicians that pancreatectomy offers little survival benefit. This report reviews our institutional experience with pancreatectomy for pancreatic adenocarcinoma and provides a critical overview of the controversies regarding the benefits of surgical intervention for patients who are candidates for curative resection. METHODS: We determined the survival of 142 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage IA-IIB) at Moffitt Cancer Center during the last two decades by using data obtained from review of the medical record, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic diagnosis was confirmed by expert review of stained sections cut from fixed surgical specimens. RESULTS: In the 137 patients who survived at least 30 days after surgery, the median survival was 21.2 months after resection, with Kaplan-Meier 3- and 5-year disease-specific survival rates of 36% and 32%, respectively. One patient has survived without evidence of recurrent disease for more than 15 years after pancreatectomy. Survival for patients greater than 75 year of age did not differ from that of younger patients. The postoperative mortality rate was 1.5% during the most recent years of highest operative volume (2003 to 2006) and 3.5% for the entire patient cohort. CONCLUSIONS: Review of our 20-year experience with resection of pancreatic adenocarcinoma indicates that pancreatectomy with curative intent offers a real chance of long-term survival to patients with this highly lethal disease for which there is no other curative modality.

Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer.

OBJECTIVES: Few genetic mutations have been identified in pancreatic adenocarcinoma, whereas epigenetic changes that lead to gene silencing are known in several genes. Because SLC5A8 is regarded as a potential tumor suppressor gene that is down-regulated by epigenetic changes in several other cancers, we sought to characterize promoter methylation status and its relationship to SLC5A8 expression in pancreatic cancer. METHODS: Promoter methylation and expression of SLC5A8 were evaluated in pancreatic cancer cell lines, tumor, and adjacent nontumor tissues from pancreatic cancer patients using methylation-specific polymerase chain reaction analysis, quantitative real-time and semiquantitative reverse transcriptase-polymerase chain reaction, and bisulfate-modified sequencing. RESULTS: Complete or partial loss of SLC5A8 expression was observed in all tumor tissues. Bisulfite sequencing analysis on pancreatic cancer cell lines that did not express SLC5A8 detected dense methylation of the promoter region. SLC5A8 expression was reactivated by treatment with aza-deoxycytidine or trichostatin A. Methylation-specific polymerase chain reaction detected methylation in 7 of 10 pancreatic tumor tissues, whereas in only 3 of 28 adjacent nontumor tissues (P < 0.001). CONCLUSIONS: Our findings indicate loss of SLC5A8 expression as a result of aberrant promoter methylation in pancreatic adenocarcinoma. We suggest that SLC5A8 may function as a tumor suppressor gene whose silencing by epigenetic changes may contribute to carcinogenesis and progression of pancreatic cancer.

Green tea polyphenols in the prevention of colon cancer.

Several plant-based nutrients and non-nutrients that can inhibit mutagenesis and proliferation have been identified. Some of the most promising nutrients identified as chemopreventive agents in colon cancer prevention include isoflavones, curcumin, calcium, vitamin D and more recently Green tea polyphenols (GTP). In addition to inhibiting mutagenesis and proliferation, these compounds are relatively non-toxic, are of low cost and can be taken orally or as a part of the daily diet. Epidemiological and laboratory studies have identified epigallocatechin gallate (EGCG) in green tea polyphenols (GTP), as the most potent chemopreventive agent that can induce apoptosis, suppress the formation and growth of human cancers including colorectal cancers (CRC). It is only logical then, that future clinical studies should focus on examining the efficacy of phytochemicals such as EGCG in cancer chemoprevention as an alternative to pharmacological agents, especially in populations where administration of COX-2 inhibitors, Aspirin and NSAIDS is contraindicated. The goal of this review is to provide the rationale, and discuss the use of EGCG in GTP as a chemopreventive agent for prevention of colon carcinogenesis and present evidence for the efficacy and safety of these agents based on epidemiological, animal, in vitro studies and Phase I clinical trials.

Dedifferentiation precedes invasion in the progression from Barrett's metaplasia to esophageal adenocarcinoma.

PURPOSE: Adenocarcinoma arises in Barrett's esophagus by progression from metaplasia to cancer through grades of dysplasia. Our aim in this exploratory study was to characterize the broad changes in gene expression that underlie this histologic progression to cancer and assess the potential for using these gene expression changes as a marker predictive of malignant progression in Barrett's epithelium. EXPERIMENTAL DESIGN: Microarray analysis was used to obtain individual gene expression profiles from endoscopic biopsies of nine esophageal adenocarcinomas and the Barrett's epithelia from which three of the cancers had arisen. Pooled samples from the Barrett's epithelia of six patients without cancer or dysplasia served as a reference. RESULTS: Barrett's epithelia from which cancer had arisen differed from the reference Barrett's epithelia primarily by underexpression of genes, many of which function in governing cell differentiation. These changes in gene expression were found even in those specimens of Barrett's epithelia from which cancer had arisen that lacked dysplasia. Each cancer differed from the Barrett's epithelium from which it had arisen primarily by an overexpression of genes, many of which were associated with tissue remodeling and invasiveness. Cancers without identifiable Barrett's epithelium differed from cancers that had arisen from a Barrett's epithelium by having an even greater number of these overexpressed genes. CONCLUSIONS: Histologic progression from Barrett's epithelium to cancer is associated with a gradient of increasing changes in gene expression characterized by an early loss of gene function governing differentiation that begins before histologic change; gain in function of genes related to remodeling and invasiveness follows later. This correlation of histologic progression with increasing changes in gene expression suggests that gene expression changes in biopsies taken from Barrett's epithelium potentially could serve as a marker for neoplastic progression that could be used to predict risk for developing cancer.

Current and evolving strategies for colorectal cancer screening.

BACKGROUND: Colorectal cancer is a major cause of cancer mortality and morbidity. Screening can potentially prevent most colorectal cancers by detection and removal of precursor adenomas. METHODS: The literature and clinical practice guidelines are reviewed, with an emphasis on advances of the last 10 years and evolving screening methods. RESULTS: Colonoscopy has come to be used for screening in persons at average risk for colorectal cancer because of the comparative ineffectiveness of other methods, although these methods continue to be recommended. Virtual colonoscopy and fecal DNA testing are emerging technologies with promise to be more effective than fecal occult blood testing or sigmoidoscopy in selecting those persons who should undergo colonoscopy. Next to age, family history is the most common risk factor for colorectal cancer and one that warrants more aggressive screening and, in some instances, genetic counseling and testing. Hereditary nonpolyposis colorectal cancer accounts for as many as 1 in 20 colorectal cancers, but to take advantage of recent advances in genetic testing for this disorder, a high level of clinical suspicion must be maintained. CONCLUSIONS: If we are to reduce mortality and morbidity from colorectal cancer, practicing clinicians need to be aware of current and evolving strategies for colorectal screening, and assertively recommend the appropriate strategy to their patients.

Dynamics of Rhynchosporium secalis pathotypes in relation to barley cultivar resistance.

Rhynchosporium secalis isolates E97-2 and H97-2, represented the major pathotypes in populations on barley in Alberta, Canada, but differed widely in their virulence. Following greenhouse co-inoculation with the two pathotypes, E97-2, originally isolated from resistant cv. 'CDC Earl', predominated over H97-2, isolated from the susceptible cv. 'Harrington', from the first to the last of four infection cycles on both 'CDC Earl' and 'Harrington'. These results indicated that the host can rapidly influence pathotype composition and that pathotype E97-2 may have a competitive advantage over H97-2 on these cultivars. DNA polymorphisms were found between isolates from single or mixed inoculations on cvs 'CDC Earl' and 'Harrington' for four successive cycles. Co-inoculation with the two isolates resulted in a shift to a molecular phenotype more similar to E97-2 than H97-2. The competitive advantage of E97-2 over H97-2, combined with the selective pressure exerted by the host, would explain the increased susceptibility of cv. 'CDC Earl' and other cultivars with similar sources of scald resistance, in fields across Alberta. However, H97-2 will likely remain one of the major pathotypes in Alberta due to the relatively large acreage of cv. 'Harrington' in this province.