Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.

Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer.

Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC.

Does interaction occur between risk factors for revision total knee arthroplasty?

INTRODUCTION: Several risk factors for revision TKA have previously been identified, but interactions between risk factors may occur and affect risk of revision. To our knowledge, such interactions have not been previously studied. As patients often exhibit multiple risk factors for revision, knowledge of these interactions can help improve risk stratification and patient education prior to TKA. MATERIALS AND METHODS: The State Inpatient Databases (SID), part of the Healthcare Cost and Utilization Project (HCUP), were queried to identify patients who underwent TKA between January 1, 2006 and December 31, 2015. Risk factors for revision TKA were identified, and interactions between indication for TKA and other risk factors were analyzed. RESULTS: Of 958,944 patients who underwent TKA, 33,550 (3.5%) underwent revision. Age, sex, race, length of stay, Elixhauser readmission score, urban/rural designation, and indication for TKA were significantly associated with revision (p < 0.05). Age was the strongest predictor (p < 0.0001), with younger patients exhibiting higher revision risk. Risks associated with age were modified by an interaction with indication for TKA (p < 0.0001). There was no significant interaction between sex and indication for TKA (p = 0.535) or race and indication for TKA (p = 0.187). CONCLUSIONS: Age, sex, race, length of stay, Elixhauser readmission score, urban/rural designation, and indication for TKA are significantly associated with revision TKA. Interaction occurs between age and indication.

The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes.

BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).

Risk factors for degenerative, symptomatic rotator cuff tears: a case-control study.

BACKGROUND: Despite the considerable public health burden of rotator cuff tears, there is no consensus on risk factors associated with symptomatic rotator cuff tears. In this study, a large data source was used to identify factors associated with symptomatic rotator cuff tears. We defined cases of rotator cuff tears as those verified by imaging or operative reports and controls as symptomatic shoulders without rotator cuff tears as verified by imaging or operative reports. METHODS: We performed a case-control study of patients with and without symptomatic rotator cuff tears by use of the Vanderbilt University Medical Center de-identified electronic medical record system, the Synthetic Derivative, with records on >2.5 million patients from 1998 to 2017. Cases and controls were confirmed by individual chart review and review of imaging and/or operative notes. A final set of 11 variables were analyzed as potential risk factors for cuff tears: age, sex, body mass index (BMI), race, smoking history, hypertension, depression/anxiety, dyslipidemia, carpal tunnel syndrome, overhead activity, and affected side. Multivariable logistic regression was used to estimate the association between predictor variables and the risk of having a rotator cuff tear. RESULTS: A total of 2738 patients were selected from the Synthetic Derivative, which included 1731 patients with rotator cuff tears and 1007 patients without rotator cuff tears. Compared with individuals without tears, those with rotator cuff tears were more likely to be older (odds ratio [OR], 2.44; 95% confidence interval [CI], 2.12-2.89), to have a higher BMI (OR, 1.45; 95% CI, 1.24-1.69), to be of male sex (OR, 1.56; 95% CI, 1.32-1.85), and to have carpal tunnel syndrome (OR, 1.41; 95% CI, 1.03-1.93). Patients with rotator cuff tears were less likely to have left shoulder symptoms (OR, 0.68; 95% CI, 0.57-0.82) and to have depression/anxiety (OR, 0.77; 95% CI, 0.62-0.95) compared with the control group, which had symptomatic shoulder pain without rotator cuff tears. CONCLUSIONS: In a large imaging and operative report-verified case-control study, we identified advancing age, male sex, higher BMI, and diagnosis of carpal tunnel syndrome as risk factors significantly associated with an increased risk of rotator cuff tears. Left shoulder symptoms and depression/anxiety were less likely to be associated with rotator cuff tears compared with symptomatic shoulders without rotator cuff tears. Contrary to some prior reports in the literature, smoking was not associated with rotator cuff tears.

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade.

BACKGROUND: While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy. METHODS: Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data. RESULTS: RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB. CONCLUSIONS: Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone. TRIAL REGISTRATION: NCT01205815 (Sept 17, 2010).

Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.

OBJECTIVES: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. METHODS: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. RESULTS: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. CONCLUSION: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

Decision making in treatment after a first-time anterior glenohumeral dislocation: A Delphi approach by the Neer Circle of the American Shoulder and Elbow Surgeons.

BACKGROUND: The treatment of patients who sustain a first-time anterior glenohumeral dislocation (FTAGD) is controversial. The purpose of this study was to find consensus among experts using a validated iterative process in the treatment of patients after an FTAGD. METHODS: The Neer Circle is an organization of shoulder experts recognized for their service to the American Shoulder and Elbow Surgeons. Consensus among 72 identified experts from this group was sought with a series of surveys using the Delphi process. The first survey used open-ended questions designed to identify patient-related features that influence treatment decisions after an FTAGD. The second survey used a Likert scale to rank each feature's impact on treatment decisions. The third survey used highly impactful features to construct 162 clinical scenarios. For each scenario, experts recommended surgery or not and reported how strongly they made their recommendation. These data were analyzed to find clinical scenarios that had >90% consensus for recommending treatment. These data were also used in univariate and multivariate mixed-effects models to identify odds ratios (ORs) for different features and to assess how combining these features influenced the probability of surgery for specific populations. RESULTS: Of the 162 scenarios, 8 (5%) achieved >90% consensus for recommending surgery. All of these scenarios treated athletes with meaningful bone loss at the end of their season. In particular, for contact athletes aged > 14 years who were at the end of the season and had apprehension and meaningful bone loss, there was >90% consensus for recommending surgery after an FTAGD, with surgeons feeling very strongly about this recommendation. Of the scenarios, 22 (14%) reached >90% consensus for recommending nonoperative treatment. All of these scenarios lacked meaningful bone loss. In particular, surgeons felt very strongly about recommending nonoperative treatment after an FTAGD for non-athletes lacking apprehension without meaningful bone loss. The presence of meaningful bone loss (OR, 6.85; 95% confidence interval, 6.24-7.52) and apprehension (OR, 5.60; 95% confidence interval, 5.03-6.25) were the strongest predictors of surgery. When these 2 features were combined, profound effects increasing the probability of surgery for different populations (active-duty military, non-athletes, noncontact athletes, and contact athletes) were noted, particularly non-athletes. CONCLUSION: Consensus for recommending treatment of the FTAGD patient was not easily achieved. Certain combinations of patient-specific factors, such as the presence of meaningful bone loss and apprehension, increased the probability of surgery after an FTAGD in all populations. Over 90% of shoulder instability experts recommend surgery after an FTAGD for contact athletes aged > 14 years at the end of the season with both apprehension and meaningful bone loss. Over 90% of experts would not perform surgery after a first dislocation in patients who are not athletes and who lack apprehension without meaningful bone loss.

Which Is the Best Outcome Measure for Rotator Cuff Tears?

BACKGROUND: The American Shoulder and Elbow Surgeons Standardized Shoulder Form (ASES), the Shoulder Pain and Disability Index (SPADI), and the shortened Disability of the Arm, Shoulder, and Hand (quickDASH) are patient-reported upper extremity-specific outcome scales currently used to evaluate patients with rotator cuff tears. This heterogeneity does not allow for a uniform metric for research and patient care. QUESTIONS/PURPOSES: Our objective was to determine psychometric properties (reliability, convergent and discriminant validity, and responsiveness) of five commonly used outcome instruments (the ASES, the SPADI, the quickDASH, the SF-12, and the EuroQol-5D) in a longitudinal study of patients undergoing treatment for rotator cuff tears. METHODS: From February 2011 through June 2015, 120 patients completed a standardized history, the five outcome scales under study, a physical examination, and an MRI. Of these, 47 (39%) were lost to followup before 18 months, and another 24 (20%) were accounted for at 18 months but had missing data at one or more of the earlier prespecified followup intervals (3, 6, or 12 months). Reliability (the reproducibility of an outcome instrument between subjects; tested by Cronbach's alpha), convergent and discriminant validity (determining which outcome measures correlate most strongly with others; tested by Spearman's correlation coefficients), and responsiveness (the change in outcome scales over time based on percent improvement in shoulder functionality using the minimal clinically important difference [MCID] and the subjective shoulder value) were calculated. RESULTS: All outcomes measures had a Cronbach's alpha above 0.70 (range, 0.74-0.94) and therefore were considered reliable. Convergent validity was demonstrated as the upper extremity-specific measures (SPADI, ASES, and quickDASH) were more strongly correlated with each other (rho = 0.74-0.81; p < 0.001) than with any of the other measures. Discriminant validity was demonstrated because the Spearman's correlation coefficients were stronger for the relationships between upper extremity measures compared with the correlations between upper extremity measures and general health measures for 53 of the 54 correlations that were compared. Both internal and external responsiveness of the measures was supported. Patients who achieved the MCID and at least a 30% change on the subjective shoulder value had more positive change in scores over time compared with those who did not. Mixed model linear regressions revealed that all three upper extremity-specific measures had a group by time interaction for the MCID, indicating that patients who achieved the MCID had greater change over time compared with those who did not achieve the MCID. Results showed that the measure with the best discrimination between groups, or best internal responsiveness, was the ASES (beta = -8.26, 95% confidence interval [CI], -11.39 to -5.14; p < 0.001; η = 0.089) followed by the SPADI (beta = 6.88, 95% CI, 3.78-9.97; p < 0.001; η = 0.088) then the quickDASH (beta = 3.43, 95% CI, 0.86-6.01; p = 0.009, η = 0.027). Measures with the best external responsiveness followed the same pattern of results. CONCLUSIONS: All the upper extremity-specific scales had acceptable psychometric properties. Correlations were high and thus only one upper extremity-specific instrument is needed for outcome assessment. Given the overall psychometric assessment, we recommend SPADI be the shoulder-specific instrument used to assess outcomes in patients with rotator cuff tears. LEVEL OF EVIDENCE: Level III, diagnostic study.

Physical therapy versus natural history in outcomes of rotator cuff tears: the Rotator Cuff Outcomes Workgroup (ROW) cohort study.

BACKGROUND: We compared the outcomes of patients who performed physical therapy versus those who did not in a longitudinal cohort of patients undergoing nonoperative treatment of rotator cuff tears. We also assessed whether there was a dose effect in which the pain and functional outcomes in patients performing physical therapy plateaued. METHODS: From February 2011 to June 2015, a multicenter cohort of patients with rotator cuff tears undergoing nonoperative treatment completed a detailed health and demographic questionnaire and the Shoulder Pain and Disability Index (SPADI) at baseline and 3, 6, 12, and 18 months. Longitudinal mixed models were used to assess whether physical therapy in the first 3 months predicted SPADI scores and dose effect. RESULTS: Among the 55 patients in our cohort, the performance of physical therapy within the first 3 months predicted better SPADI scores versus nonperformance of physical therapy at 3 months (P = .02). Scores were similar between groups at 6, 12, and 18 months. A threshold of 16 physical therapy sessions was observed for pain and functional improvement during follow-up, after which significant improvement was not seen. CONCLUSIONS: Patients who performed physical therapy within the first 3 months had statistically significant improvements in pain and function as measured by the SPADI score at 3 months compared with patients who did not report performing physical therapy. Depending on the minimal clinically important difference used for the SPADI score, our results could be interpreted as meeting the minimal clinically important difference threshold or not. Improvement in outcomes was observed up to 16 sessions of physical therapy, after which outcomes plateaued.

Predictors of pain and functional outcomes after operative treatment for rotator cuff tears.

BACKGROUND: Optimal patient selection is key to success of operative treatment for cuff tears. We assessed predictors of pain and functional outcomes in a longitudinal cohort of patients undergoing operative treatment. METHODS: From March 2011 to January 2015, a cohort of patients with rotator cuff tears undergoing rotator cuff surgery was recruited. Patients completed a detailed health and demographic questionnaire, standardized shoulder questionnaires, including the Shoulder Pain and Disability Index (SPADI), and underwent a magnetic resonance imaging scan. Patients received follow-up questionnaires at 3, 6, 12, and 18 months. We assessed longitudinal predictors of SPADI using longitudinal mixed models. Interactions with follow-up duration after surgery were also assessed. RESULTS: In our analysis (n = 50), a lower Fear-Avoidance Beliefs Questionnaire physical activity score (P = .001) predicted a lower SPADI score (better shoulder pain and function). Those consuming alcohol 1 to 2 times per week or more had lower SPADI scores than those consuming alcohol 2 to 3 times per month or less (P = .017). Both of these variables had a significant interaction with duration of follow-up. Variables that were not significant predictors of SPADI included sociodemographic characteristics, magnetic resonance imaging characteristics, such as tear size and muscle quality, shoulder strength, and variations in surgical techniques/performance of adjuvant surgical procedures. CONCLUSIONS: Those with higher fear avoidance behavior and alcohol use of 1 to 2 times per week had worse shoulder pain and function at 18 months of follow-up. These data can be used to select optimal candidates for operative treatment of rotator cuff tears and assist with patient education and expectations before treatment.

The Yin/Yan of CCL2: a minor role in neutrophil anti-tumor activity in vitro but a major role on the outgrowth of metastatic breast cancer lesions in the lung in vivo.

BACKGROUND: The role of the chemokine CCL2 in breast cancer is controversial. While CCL2 recruits and activates pro-tumor macrophages, it is also reported to enhance neutrophil-mediated anti-tumor activity. Moreover, loss of CCL2 in early development enhances breast cancer progression. METHODS: To clarify these conflicting findings, we examined the ability of CCL2 to alter naïve and tumor entrained neutrophil production of ROS, release of granzyme-B, and killing of tumor cells in multiple mouse models of breast cancer. CCL2 was delivered intranasally in mice to elevate CCL2 levels in the lung and effects on seeding and growth of breast tumor cells were evaluated. The TCGA data base was queried for relationship between CCL2 expression and relapse free survival of breast cancer patients and compared to subsets of breast cancer patients. RESULTS: Even though each of the tumor cell lines studied produced approximately equal amounts of CCL2, exogenous delivery of CCL2 to co-cultures of breast tumor cells and neutrophils enhanced the ability of tumor-entrained neutrophils (TEN) to kill the less aggressive 67NR variant of 4T1 breast cancer cells. However, exogenous CCL2 did not enhance naïve or TEN neutrophil killing of more aggressive 4T1 or PyMT breast tumor cells. Moreover, this anti-tumor activity was not observed in vivo. Intranasal delivery of CCL2 to BALB/c mice markedly enhanced seeding and outgrowth of 67NR cells in the lung and increased the recruitment of CD4+ T cells and CD8+ central memory T cells into lungs of tumor bearing mice. There was no significant increase in the recruitment of CD19+ B cells, or F4/80+, Ly6G+ and CD11c + myeloid cells. CCL2 had an equal effect on CD206+ and MHCII+ populations of macrophages, thus balancing the pro- and anti-tumor macrophage cell population. Analysis of the relationship between CCL2 levels and relapse free survival in humans revealed that overall survival is not significantly different between high CCL2 expressing and low CCL2 expressing breast cancer patients grouped together. However, examination of the relationship between high CCL2 expressing basal-like, HER2+ and luminal B breast cancer patients revealed that higher CCL2 expressing tumors in these subgroups have a significantly higher probability of surviving longer than those expressing low CCL2. CONCLUSIONS: While our in vitro data support a potential anti-tumor role for CCL2 in TEN neutrophil- mediated tumor killing in poorly aggressive tumors, intranasal delivery of CCL2 increased CD4+ T cell recruitment to the pre-metastatic niche of the lung and this correlated with enhanced seeding and growth of tumor cells. These data indicate that effects of CCL2/CCR2 antagonists on the intratumoral leukocyte content should be monitored in ongoing clinical trials using these agents.

Reovirus-mediated induction of ADAR1 (p150) minimally alters RNA editing patterns in discrete brain regions.

Transcripts encoding ADAR1, a double-stranded, RNA-specific adenosine deaminase involved in the adenosine-to-inosine (A-to-I) editing of mammalian RNAs, can be alternatively spliced to produce an interferon-inducible protein isoform (p150) that is up-regulated in both cell culture and in vivo model systems in response to pathogen or interferon stimulation. In contrast to other tissues, p150 is expressed at extremely low levels in the brain and it is unclear what role, if any, this isoform may play in the innate immune response of the central nervous system (CNS) or whether the extent of editing for RNA substrates critical for CNS function is affected by its induction. To investigate the expression of ADAR1 isoforms in response to viral infection and subsequent alterations in A-to-I editing profiles for endogenous ADAR targets, we used a neurotropic strain of reovirus to infect neonatal mice and quantify A-to-I editing in discrete brain regions using a multiplexed, high-throughput sequencing strategy. While intracranial injection of reovirus resulted in a widespread increase in the expression of ADAR1 (p150) in multiple brain regions and peripheral organs, significant changes in site-specific A-to-I conversion were quite limited, suggesting that steady-state levels of p150 expression are not a primary determinant for modulating the extent of editing for numerous ADAR targets in vivo.

Traumatic spinal cord injury in the United States, 1993-2012.

IMPORTANCE: Acute traumatic spinal cord injury results in disability and use of health care resources, yet data on contemporary national trends of traumatic spinal cord injury incidence and etiology are limited. OBJECTIVE: To assess trends in acute traumatic spinal cord injury incidence, etiology, mortality, and associated surgical procedures in the United States from 1993 to 2012. DESIGN, SETTING, AND PARTICIPANTS: Analysis of survey data from the US Nationwide Inpatient Sample databases for 1993-2012, including a total of 63,109 patients with acute traumatic spinal cord injury. MAIN OUTCOMES AND MEASURES: Age- and sex-stratified incidence of acute traumatic spinal cord injury; trends in etiology and in-hospital mortality of acute traumatic spinal cord injury. RESULTS: In 1993, the estimated incidence of acute spinal cord injury was 53 cases (95% CI, 52-54 cases) per 1 million persons based on 2659 actual cases. In 2012, the estimated incidence was 54 cases (95% CI, 53-55 cases) per 1 million population based on 3393 cases (average annual percentage change, 0.2%; 95% CI, -0.5% to 0.9%). Incidence rates among the younger male population declined from 1993 to 2012: for age 16 to 24 years, from 144 cases/million (2405 cases) to 87 cases/million (1770 cases) (average annual percentage change, -2.5%; 95% CI, -3.3% to -1.8%); for age 25 to 44 years, from 96 cases/million (3959 cases) to 71 cases/million persons (2930 cases), (average annual percentage change, -1.2%; 95% CI, -2.1% to -0.3%). A high rate of increase was observed in men aged 65 to 74 years (from 84 cases/million in 1993 [695 cases] to 131 cases/million [1465 cases]; average annual percentage change, 2.7%; 95% CI, 2.0%-3.5%). The percentage of spinal cord injury associated with falls increased significantly from 28% (95% CI, 26%-30%) in 1997-2000 to 66% (95% CI, 64%-68%) in 2010-2012 in those aged 65 years or older (P < .001). Although overall in-hospital mortality increased from 6.6% (95% CI, 6.1%-7.0%) in 1993-1996 to 7.5% (95% CI, 7.0%-8.0%) in 2010-2012 (P < .001), mortality decreased significantly from 24.2% (95% CI, 19.7%-28.7%) in 1993-1996 to 20.1% (95% CI, 17.0%-23.2%) in 2010-2012 (P = .003) among persons aged 85 years or older. CONCLUSIONS AND RELEVANCE: Between 1993 and 2012, the incidence rate of acute traumatic spinal cord injury remained relatively stable but, reflecting an increasing population, the total number of cases increased. The largest increase in incidence was observed in older patients, largely associated with an increase in falls, and in-hospital mortality remained high, especially among elderly persons.

The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population.

The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, P < 0·0001). Patients with any variant CYP2C9 allele required 71% of the dose for wild-type (P = 0·001). The effect of variant VKORC1 alleles tended to vary with age, suggesting developmental ontogeny may influence warfarin sensitivity. Age, CYP2C9 genotype, VKORC1 genotype and age:VKORC1 interaction accounted for 53% of warfarin dose variability.

Tumor deposits in rectal adenocarcinoma after neoadjuvant chemoradiation are associated with poor prognosis.

Although tumor deposits have been associated with poor prognosis in colorectal carcinoma, the prevalence and clinical significance of tumor deposits in rectal adenocarcinoma following neoadjuvant chemoradiation are relatively unexplored. The aims of this study are to assess the clinical significance of tumor deposits in rectal adenocarcinoma patients, including those receiving neoadjuvant therapy. Pathology slides and medical records from 205 consecutive patients who underwent resection for rectal adenocarcinoma between 1990 and 2010 at a single tertiary care center were reviewed. Patients with tumor deposits had higher tumor grade (P=0.006) and worse tumor stage (P<0.001) at presentation than patients without tumor deposits. Among 110 patients who underwent neoadjuvant chemoradiation, tumor deposits were associated with higher rates of lymph node involvement (P=0.035) and distant metastases (P=0.006), and decreased survival (P=0.027). These patients had a trend toward lower treatment response scores (P=0.285) and higher local recurrence (P=0.092). Of 52 patients with tumor deposits, those who underwent neoadjuvant chemoradiation had significantly worse pretreatment stage by endoscopic ultrasound (P<0.001) but interestingly had significantly lower rates of lymphovascular invasion on resection (P<0.001) compared with those who had not received neoadjuvant chemoradiation. Despite treatment with neoadjuvant chemoradiation, tumor deposits were present in over one-fifth of rectal adenocarcinoma patients. Overall, the outcome of patients with tumor deposits in treated and untreated patients were similar, however the association of tumor deposits with deeply invasive tumors and less tumor regression when comparing with treated patients without tumor deposits raises the possibility that these tumors could have a more aggressive biology, possibly explaining the association of tumor deposits with higher rates of recurrence and lower survival after neoadjuvant chemoradiation. Overall, tumor deposits appear to be a poor prognostic marker among rectal adenocarcinoma patients following neoadjuvant chemoradiation and may identify a subset of patients who require aggressive adjuvant therapy to prevent recurrence.

Should mesenteric tumor deposits be included in staging of well-differentiated small intestine neuroendocrine tumors?

Well-differentiated small intestine neuroendocrine tumors can give rise to mesenteric tumor deposits, which are not included in the current American Joint Committee on Cancer staging system for small intestine neuroendocrine tumors, and their impact on patient prognosis is unknown. Seventy-two small intestine neuroendocrine tumors resections were identified in our files with slides, reports, and follow-up data available. Cases were assessed for T-category and for the presence of mesenteric tumor deposits, lymph node metastases, lymphovascular invasion, and liver metastases. Mesenteric tumor deposits were defined as discrete mesenteric tumor nodules ≥1 mm with an irregular growth profile. Similar lesions clearly resulting from extranodal extension or direct contiguous spread by the primary lesion were excluded. Forty-three of the 72 cases had mesenteric tumor deposits (60%). The deposits were significantly associated with lymphovascular invasion (P=0.001), pT3 or pT4 disease (P=0.001), nodal metastases (P=0.040), and liver metastases (P<0.001) at the time of surgery. In addition, four of six cases with tumor deposits and no nodal disease had liver disease. Tumor deposits were associated with an increased incidence of disease progression and death due to the disease (P=0.001). Finally, the presence of tumor deposits at the time of surgery was associated with an increase in hazard of progression or death due to disease (hazard ratio: 4.0; 95% confidence interval: 1.3, 12.5; P=0.016). Mesenteric tumor deposits are present in the majority of cases of small intestine neuroendocrine tumors and are indicators of poor prognosis for this disease. Therefore, they may have a place in staging of small intestine neuroendocrine tumors, perhaps as analogous to lymph node disease.

DCE-MRI analysis methods for predicting the response of breast cancer to neoadjuvant chemotherapy: pilot study findings.

PURPOSE: The purpose of this pilot study is to determine (1) if early changes in both semiquantitative and quantitative DCE-MRI parameters, observed after the first cycle of neoadjuvant chemotherapy in breast cancer patients, show significant difference between responders and nonresponders and (2) if these parameters can be used as a prognostic indicator of the eventual response. METHODS: Twenty-eight patients were examined using DCE-MRI pre-, post-one cycle, and just prior to surgery. The semiquantitative parameters included longest dimension, tumor volume, initial area under the curve, and signal enhancement ratio related parameters, while quantitative parameters included K(trans), v(e), k(ep), v(p), and τ(i) estimated using the standard Tofts-Kety, extended Tofts-Kety, and fast exchange regime models. RESULTS: Our preliminary results indicated that the signal enhancement ratio washout volume and k(ep) were significantly different between pathologic complete responders from nonresponders (P < 0.05) after a single cycle of chemotherapy. Receiver operator characteristic analysis showed that the AUC of the signal enhancement ratio washout volume was 0.75, and the AUCs of k(ep) estimated by three models were 0.78, 0.76, and 0.73, respectively. CONCLUSION: In summary, the signal enhancement ratio washout volume and k(ep) appear to predict breast cancer response after one cycle of neoadjuvant chemotherapy. This observation should be confirmed with additional prospective studies.

The utility of Bayesian predictive probabilities for interim monitoring of clinical trials.

BACKGROUND: Bayesian predictive probabilities can be used for interim monitoring of clinical trials to estimate the probability of observing a statistically significant treatment effect if the trial were to continue to its predefined maximum sample size. PURPOSE: We explore settings in which Bayesian predictive probabilities are advantageous for interim monitoring compared to Bayesian posterior probabilities, p-values, conditional power, or group sequential methods. RESULTS: For interim analyses that address prediction hypotheses, such as futility monitoring and efficacy monitoring with lagged outcomes, only predictive probabilities properly account for the amount of data remaining to be observed in a clinical trial and have the flexibility to incorporate additional information via auxiliary variables. LIMITATIONS: Computational burdens limit the feasibility of predictive probabilities in many clinical trial settings. The specification of prior distributions brings additional challenges for regulatory approval. CONCLUSIONS: The use of Bayesian predictive probabilities enables the choice of logical interim stopping rules that closely align with the clinical decision-making process.

Endogenous pAKT activity is associated with response to AKT inhibition alone and in combination with immune checkpoint inhibition in murine models of TNBC.

Triple-negative breast cancer (TNBC) is a heterogeneous and challenging-to-treat breast cancer subtype. The clinical introduction of immune checkpoint inhibitors (ICI) for TNBC has had mixed results, and very few patients achieved a durable response. The PI3K/AKT pathway is frequently mutated in breast cancer. Given the important roles of the PI3K pathway in immune and tumor cell signaling, there is an interest in using inhibitors of this pathway to increase the response to ICI. This study sought to determine if AKT inhibition could enhance the response to ICI in murine TNBC models. We further sought to understand underlying mechanisms of response or non-response to AKT inhibition in combination with ICI. Using four murine TNBC-like cell lines and corresponding orthotopic mouse tumor models, we found that hyperactivity of the PI3K pathway, as evidenced by levels of phospho-AKT rather than PI3K pathway mutational status, was associated with response to AKT inhibition alone and in combination with ICI. Additional mutations in other growth regulatory pathways could override the response of PI3K pathway mutant tumors to AKT inhibition. Furthermore, we observed that AKT inhibition enhanced the response to ICI in an already sensitive model. However, AKT inhibition failed to convert ICI-resistant tumors, to responsive tumors. These findings suggest that analysis of both the mutational status and phospho-AKT protein levels may be beneficial in predicting which TNBC tumors will respond to AKT inhibition in combination with ICI.