Series on the Lancet Oncology Commission on Global Cancer Surgery: Introduction-Intent and Content.

BACKGROUND: Surgery plays a key role in the multi-disciplinary cancer care pathway. Nearly 80% of patients with solid tumors will require surgical intervention during the course of their disease. Unfortunately, the vast majority of these patients do not have access to safe, timely, high-quality, and affordable cancer surgical care. The first Lancet Oncology Commission on Global Cancer Surgery shone a light on this grave situation and outlined some strategies to address them. The second Lancet Oncology Commission on Global Cancer Surgery (TLO- II) was conceived to continue the work of its predecessor by developing a roadmap of practical solutions to propel improvements in cancer surgical care globally. METHODS: The Commission was developed by involving approximately 50 cancer care leaders and experts from different parts of the world to ensure diversity of input and global applicability. RESULTS: The Commission identified nine solutional domains that are considered essential to deliver safe, timely, high-quality, and affordable cancer surgical care. These nine domains were further refined to develop solutions specific to each of the six World Health Organization regions. Based on the above solutions, we developed eight action items that are intended to propel improvements in cancer surgical care on the global stage. CONCLUSIONS: The second Lancet Oncology Commission on Global Cancer Surgery builds on the first Commission by developing a pragmatic roadmap of practical solutions that we hope will ensure access to safe, timely, high-quality, and affordable cancer surgical care for everyone regardless of their socioeconomic status or geographic location.

DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS.

Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

Hospital Service Volume as an Indicator of Treatment Patterns for Colorectal Cancer.

INTRODUCTION: A hospital's approach (volume of cancer treatment services provided) to treating metastatic colorectal cancer influences a patient's treatment as strongly as patient disease status. The implications of hospital-level treatment approaches across disease stages remain understudied. We sought to determine if hospital service volume (SV) for metastatic colorectal cancer could be predictive of nonstandard treatment patterns in stages I-III colon cancer. MATERIALS AND METHODS: Using the National Cancer Database, we examined rates of nonstandard treatment patterns among patients with colon cancer between 2010 and 2017. After adjusting for clinicopathological characteristics using multivariable logistic regression, we evaluated the relationship between hospital-level SV for metastatic colorectal cancer and nonstandard treatment approaches for patients with stages I-III colon cancer. RESULTS: There were significant associations between hospital-level SV for metastatic colorectal cancer and the odds of chemotherapy overtreatment among patients with stage I-III colon cancer, as well as undertreatment among patients with stages II-III disease after adjusting for hospital-, patient-, and tumor-level covariates. Patients at the highest-level SV hospitals for metastatic disease had 1.29 higher odds (95% CI = 1.18-1.41; P < 0.0001) of receiving overtreatment compared to patients from lowest SV hospitals. The odds ratio of undertreatment in highest SV compared to lowest SV was 0.64 (95% CI 0.56-0.72; P< 0.0001). CONCLUSIONS: Hospital-level SV of patients with metastatic colon cancer is a significant indicator of nonstandard treatment patterns among patients with stage I-III colon cancer. Hospitals with the highest volume of cancer treatments have higher odds of providing overtreatment, while low SVs are associated with higher odds of undertreatment.

Comparison of Prognostic Performance of 8th and 7th Edition of AJCC Staging System for Patients With Gallbladder Cancer Undergoing Curative Intent Surgery.

BACKGROUND: We compared the predictive performance of the 7th and 8th editions of the AJCC staging systems in stratifying disease-related survival outcomes in patients with GBC undergoing curative intent surgery. METHODS: Patients that underwent curative intent surgery for GBC at our institution (2014 and 2021) were included in the study. Various clinico-pathological data were extracted to perform Kaplan-Meier survival analysis. RESULTS: A total of 240 patients were included in the study. Both, TNM-7, and TNM-8 staging systems can stratify patients into stages with statistically significant differences in disease-free and overall survival. Survival rates drop with stage progression. Using TNM-8, 8/240 (3.33%) patients were upstaged from Stage IIIB (TNM-7) to IVB (TNM-8) and 12/240 (5%) were down-staged from Stage IVB(TNM-7) to IIIB(TNM-8). Survival curves of the re-classified patients matched those of the corresponding TNM-8 stage. Additionally, there was statistically significant difference in their survival (p < 0.001) compared to their corresponding TNM-7 stage. There was no statistically significant difference in survival rates between stages IIA, IIB (TNM-8), and stage II (TNM-7). However, stage IIA had a slightly better survival than stage IIB. CONCLUSION: Though both TNM-7 and TNM-8 are useful for stratifying patients with GBC, TNM-8 has a better prognostic performance than TNM-7.

A Prospective Multimodal Education Intervention for Providers Does Not Increase Hepatic Encephalopathy Treatment Rates.

BACKGROUND: Over 50% of hospitalizations from hepatic encephalopathy (HE) are preventable, but patients often do not receive medical treatment. AIMS: To use a multimodal education intervention (MMEI) to increase HE treatment rates and to evaluate (1) trends in HE treatment, (2) predictors of receiving treatment, and (3) the impact of treatment on hospitalization outcomes. METHODS: Prospective single-center cohort study of patients hospitalized with HE from April 1, 2020-September 30, 2022. The first 15 months were a control ("pre-MMEI"), the subsequent 15 months (MMEI) included three phases: (1) prior authorization resources, (2) electronic order set, and (3) in-person provider education. Treatment included receiving any drug (lactulose or rifaximin), or combination therapy. Treatment rates pre- vs. post-MMEI were compared using logistic regression. RESULTS: 471 patients were included. There were lower odds of receiving any drug post-MMEI (p = 0.03). There was no difference in receiving combination therapy pre- or post-MMEI (p = 0.32). Predictors of receiving any drug included alcohol-related or cryptogenic cirrhosis (p's < 0.001), and the presence of ascites (p = 0.005) and/or portal hypertension (p = 0.003). The only significant predictor of not receiving any drug treatment was having autoimmune cirrhosis (p < 0.001). Patients seen by internal medicine (p = 0.01) or who were intoxicated (p = 0.02) were less likely to receive rifaximin. Any treatment was associated with higher 30-day liver disease-specific readmission (p < 0.001). CONCLUSION: This MMEI did not increase HE treatment rates, suggesting that alternative strategies are needed to identify and address barriers to treatment.

Global Cancer Surgery: pragmatic solutions to improve cancer surgery outcomes worldwide.

The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.

A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.

OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Factors associated with pathologic complete response following neoadjuvant chemoradiation and esophagectomy for carcinoma of esophagus and gastroesophageal junction.

BACKGROUND AND OBJECTIVES: The aim of this study was to analyze factors associated with pathologic complete response (pCR) following neoadjuvant chemoradiation (NCRT) and esophagectomy for carcinoma of the esophagus (EC) and gastroesophageal junction (GEJ). METHODS: Patients with EC and GEJ tumors who received NCRT and underwent esophagectomy between January 2010 to March 2021 were included. Univariate and multivariate analyses were performed to evaluate the factors associated with pCR by comparing the patients who achieved pCR (pCR group) with those who did not achieve pCR (non-pCR group). RESULTS: A total of 321 patients were included in the study, with squamous cell carcinoma (SCC) accounting for the majority of cases (76%). One hundred and sixty (49.8%) patients had pCR. SCC histology and pretreatment radiographic node-negative status (cN0) were associated with pCR. Patients in the pCR group had significantly better overall and disease-free survival compared with patients in the non-pCR group. CONCLUSIONS: SCC histology and pretreatment radiographic node-negative status were associated with pCR. For patients with tumors of EC and GEJ who received NCRT and underwent esophagectomy, pCR was associated with improved prognosis compared with those not achieving pCR.

Mortality Increased Among Hospitalized Patients with Cirrhosis Before and Following Different Waves of the COVID-19 Pandemic.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic disrupted patient care and worsened the morbidity and mortality of some chronic diseases. The impact of the COVID-19 pandemic on hospitalizations and outcomes in patients with cirrhosis both before and during different time periods of the pandemic has not been evaluated. AIMS: Describe characteristics of hospitalized patients with cirrhosis and evaluate inpatient mortality and 30-day readmission before and after the start of the COVID-19 pandemic. METHODS: Retrospective single-center cohort study of all hospitalized patients with cirrhosis from 2018 to 2022. Time periods within the COVID-19 pandemic were defined using reference data from the World Health Organization and Centers for Disease Control. Adjusted odds ratios from logistic regression were used to assess differences between periods. RESULTS: 33,926 unique hospitalizations were identified. Most patients were over age 60 years across all time periods of the pandemic. More Hispanic patients were hospitalized during COVID-19 than before COVID-19. Medicare and Medicaid are utilized less frequently during COVID-19 than before COVID-19. After controlling for age and gender, inpatient mortality was significantly higher during all COVID-19 periods except Omicron compared to before COVID-19. The odds of experiencing a 30-day readmission were 1.2 times higher in the pre-vaccination period compared to the pre-COVID-19 period. CONCLUSION: Inpatient mortality among patients with cirrhosis has increased during the COVID-19 pandemic compared to before COVID-19. Although COVID-19 infection may have had a small direct pathologic effect on the natural history of cirrhotic liver disease, it is more likely that other factors are impacting this population.

Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma and Ewing sarcoma.

Rab GTPases are critical regulators of protein trafficking in the cell. To ensure proper cellular localization and function, Rab proteins must undergo a posttranslational modification, termed geranylgeranylation. In the isoprenoid biosynthesis pathway, the enzyme geranylgeranyl diphosphate synthase (GGDPS) generates the 20-carbon isoprenoid donor (geranylgeranyl pyrophosphate [GGPP]), which is utilized in the prenylation of Rab proteins. We have pursued the development of GGDPS inhibitors (GGSI) as a novel means to target Rab activity in cancer cells. Osteosarcoma (OS) and Ewing sarcoma (ES) are aggressive childhood bone cancers with stagnant survival statistics and limited treatment options. Here we show that GGSI treatment induces markers of the unfolded protein response (UPR) and triggers apoptotic cell death in a variety of OS and ES cell lines. Confirmation that these effects were secondary to cellular depletion of GGPP and disruption of Rab geranylgeranylation was confirmed via experiments using exogenous GGPP or specific geranylgeranyl transferase inhibitors. Furthermore, GGSI treatment disrupts cellular migration and invasion in vitro. Metabolomic profiles of OS and ES cell lines identify distinct changes in purine metabolism in GGSI-treated cells. Lastly, we demonstrate that GGSI treatment slows tumor growth in a mouse model of ES. Collectively, these studies support further development of GGSIs as a novel treatment for OS and ES.

Radical surgery for de novo gallbladder carcinoma-Single-center analysis of prognostic factors and survival outcomes from an endemic region.

BACKGROUND AND OBJECTIVE: Gallbladder cancer (GBC) is an aggressive malignancy where curative resection is possible in few and survival is poor. There are limited data on outcomes in patients with de novo GBC from endemic regions undergoing surgery for curative intent. We report survival outcomes in this group of patients from a region with high incidence of disease. METHODS: We reviewed the records of all GBC patients (2014-2018) and included those who underwent radical cholecystectomy (RC) for de novo GBC. Univariable and multivariable analyses were performed to identify factors influencing recurrence and survival. RESULTS: A total of 649 patients with GBC were evaluated for surgery and curative intent surgery was attempted in 246 (38%) patients. Of these 246 patients, RC was performed in 115 patients, with histologically confirmed de novo GBC. Locally advanced disease (≥stage IIIB) was present in 52 (45.2%) patients. Median time to recurrence and overall survival (OS) were 31 and 36 months, respectively. Lymph node positivity (p = 0.005) and grade significantly influenced OS on multivariable analysis. CONCLUSION: Satisfactory survival outcomes are possible after RC for de novo GBC. Extended resections performed in high volume centers combined with appropriate adjuvant treatment can offer significant survival benefits, with acceptable morbidity and mortality rates.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude.

CONTEXT AND PURPOSE: There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. METHODS: IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. RESULTS: To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. CONCLUSIONS: Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. TRAIL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

DNA-gold nanoprobe-based integrated biosensing technology for non-invasive liquid biopsy of serum miRNA: A new frontier in prostate cancer diagnosis.

The low specificity of prostate-specific antigen contributes to overdiagnosis and ov ertreatment of prostate cancer (PCa) patients. Hence, there is an urgent need for inclusive diagnostic platforms that could improve the diagnostic accuracy of PCa. Dysregulated miRNAs are closely associated with the progression and recurrence and have emerged as promising diagnostic and prognostic biomarkers for PCa. Nevertheless, simple, rapid, and ultrasensitive quantification of serum miRNAs is highly challenging. This study designed, synthesized, and demonstrated the practicability of DNA-linked gold nanoprobes (DNA-AuNPs) for the single-step quantification of miR-21/miR-141/miR-375. In preclinical study, the assay differented PCa Pten conditional knockout (PtencKO) mice compared to their age-matched Pten wild-type (PtenWT) control mice. In human sera, receiver operating characteristic (ROC) curve-based correlation analyses revealed clear discrimination between PCa patients from normal healthy controls using training and validation sets. Overall, we established integrated nano-biosensing technology for the PCR-free, non-invasive liquid biopsies of multiple miRNAs for PCa diagnosis.

A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia.

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.

Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL-not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.

Steroidogenesis in patients with adrenal incidentalomas: Extended steroid profile measured by liquid chromatography-mass spectrometry after ACTH stimulation and dexamethasone suppression.

OBJECTIVE: Describe the secretion and profile of adrenal steroids in patients with adrenal incidentalomas compared to control subjects. DESIGN, SETTING AND PARTICIPANTS: A prospective study, 73 patients with adrenal incidentalomas, 21 bilateral and 52 unilateral and 34 matched controls in University Hospital. METHODS: Collect fasting blood sample before and 60 min after ACTH test (250 µg IV). One week later, perform overnight 1 mg dexamethasone test. The following steroids were measured by liquid chromatography-mass spectrometry (LC-MS): pregnenolone, 17-OH pregnenolone, 17-OH progesterone, 11-deoxycorticosterone, 11-deoxyortisol, 21-deoxycortisol, corticosterone, cortisol, androstenedione and aldosterone. RESULTS: Mean baseline serum cortisol was higher in incidentalomas, bilateral 361 ± 124, (range 143-665) nmol/L,(p < .0001), unilateral 268 ± 89 3.2 (range 98-507) nmol/L (p < .019) compared to controls 207 ± 100 (range 72-502) nmol/L. ACTH stimulation showed significantly higher levels in bilateral and unilateral cases compared to controls. After dexamethasone, mean serum cortisol levels suppressed in bilaterals 89 ± 69 (range 30-3) nmol/L (p < .0001), 58 ± 52 (range 16-323) nmol/L in unilateral (p < .01) compared to 26 ± 9 (range 7-46) nmol/L in controls. Mean baseline serum corticosterone was higher in bilateral 9.3 ± 4.8 (range 2.4-18.4) nmol/L (p < .005) and unilateral 7.3 ± 5.7 (range 0.1-30.3) nmol/L (p < .01) compared to controls 4.2 ± 2.4 (range 1.1-10.2) nmol/L, after ACTH stimulation significantly increased to higher levels in bilateral (p < .0002) and unilateral cases (p < .044) compared to controls. After dexamethasone, mean levels were 2.5 ± 2.6 (range 0.5-12.5) nmol/L in bilateral (p < .0006), 1.5 ± 1.6 (range 0.3-9.3) nmol/L in unilateral (p < .09) and 0.75 ± 0.46 (range 0.1-2.1) nmol/L in controls. Mean baseline serum 11-deoxycorticosterone (DOC) was higher in bilaterals 0.32 ± 0.23 (range 0.08-1.1) nmol/L (p < .03) compared to controls 0.15 ± 0.21 (range 0.08-1.1) nmol/L. ACTH stimulation increased levels to 3.27 ± 1.72 (range 0.5-7.4) nmol/L in bilateral cases compared to controls 1.369 ± 1.53 (range 0.1-7.1) nmol/L (p < .0001). Dexamethasone decreased levels to baseline (p ns). There were significant differences in serum 21-deoxycortisol (p < .0002) and serum pregnenolone (p < .004) only after ACTH stimulation. CONCLUSIONS: There is increased activity in several steroid biosynthesis pathways and higher steroid levels in bilateral compared to unilateral cases and evidence of hypercortisolism in 30% unilateral and 62% of bilateral incidentalomas.

In vivo evaluation of combination therapy targeting the isoprenoid biosynthetic pathway.

Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthetic pathway (IBP), produces the isoprenoid (geranylgeranyl pyrophosphate, GGPP) used in protein geranylgeranylation reactions. Our prior studies utilizing triazole bisphosphonate-based GGDPS inhibitors (GGSIs) have revealed that these agents represent a novel strategy by which to induce cancer cell death, including multiple myeloma and pancreatic cancer. Statins inhibit the rate-limiting enzyme in the IBP and potentiate the effects of GGSIs in vitro. The in vivo effects of combination therapy with statins and GGSIs have not been determined. Here we evaluated the effects of combining VSW1198, a novel GGSI, with a statin (lovastatin or pravastatin) in CD-1 mice. Twice-weekly dosing with VSW1198 at the previously established maximally tolerated dose in combination with a statin led to hepatotoxicity, while once-weekly VSW1198-based combinations were feasible. No abnormalities in kidney, spleen, brain or skeletal muscle were observed with combination therapy. Combination therapy disrupted protein geranylgeranylation in vivo. Evaluation of hepatic isoprenoid levels revealed decreased GGPP levels in the single drug groups and undetectable GGPP levels in the combination groups. Additional studies with combinations using 50% dose-reductions of either VSW1198 or lovastatin revealed minimal hepatotoxicity with expected on-target effects of diminished GGPP levels and disruption of protein geranylgeranylation. Combination statin/GGSI therapy significantly slowed tumor growth in a myeloma xenograft model. Collectively, these studies are the first to demonstrate that combination IBP inhibitor therapy alters isoprenoid levels and disrupts protein geranylgeranylation in vivo as well as slows tumor growth in a myeloma xenograft model, thus providing the framework for future clinical exploration.

Stathmin expression in metastatic colorectal cancer.

OBJECTIVES: To evaluate the relationship between stathmin expression and clinical outcome in colorectal cancer (CRC). BACKGROUND: Stathmin is a phosphoprotein involved in the regulation of microtubule dynamics and integration of intracellular signaling pathways. Stathmin has been implicated in the tumorigenesis of several cancers and is a potential therapeutic target. METHODS: Stathmin expression was evaluated in 25 metastatic CRC (mCRC) patients by immunohistochemistry (IHC). Ki67 IHC and TUNEL assay were also evaluated in mCRC for cell proliferation and apoptosis. RESULTS: High expression of stathmin was correlated with CRC metastasis (p = .0084), and significantly worse overall survival (OS) in CRC patients (p = .036). There was a significant increase in cell proliferation and a decrease in apoptosis in liver metastasis compared with CRC primary tumors as determined by Ki67 IHC and TUNEL assay (p < .0001). We also observed a significant positive correlation between stathmin level and cell proliferation in both CRC primary tumor and liver metastasis (p = .0429 to 0.0451; r = .4236 to .4288). CONCLUSION: Stathmin expression correlated with worse patient prognosis in mCRC patients and positively correlated with increased cell proliferation. Together, our findings indicate stathmin as a novel potential marker for increased risk of CRC-specific mortality and identify stathmin as an attractive therapeutic target for the treatment of mCRC.

Preoperative nomogram to predict posthepatectomy liver failure.

BACKGROUND AND OBJECTIVES: Posthepatectomy liver failure (PHLF) is associated with significant morbidity and mortality. However, it is often difficult to predict the risk of PHLF in an individual patient. We aimed to develop a preoperative nomogram to predict PHLF and allow better risk stratification before surgery. METHODS: Data for patients undergoing a partial or major hepatectomy were extracted from the hepatectomy-specific NSQIP database for years 2014-2016. Data set from 2017 was used for validation. Patients with Grade B/C liver failure were compared with patients with no liver failure. RESULTS: A total of 10 808 patients from 2014-2016 data set were included. Of these, 316 patients (2.9%) developed Grade B/C PHLF. In the multivariable model consisting of preoperative variables, the following were predictive of Grade B/C PHLF (all p < 0.05): male gender, biliary stent, neoadjuvant therapy, viral hepatitis B or C, concurrent resections, biliary reconstruction, low sodium, and low albumin (model c statistic-0.78). This model was used to construct a nomogram. In the 2017 validation cohort of 4367 patients the nomogram again demonstrated good c-statistic (0.78). CONCLUSIONS: Our nomogram provides patient-specific probabilities for PHLF, and is easy to use. This is a valuable tool that can be utilized for preoperative patient counseling and selection.

Correlation of PRL3 expression with colorectal cancer progression.

OBJECTIVES: To evaluate the relationship between phosphatase of regenerating liver 3 (PRL3) expression and clinical outcome in colorectal cancer (CRC). BACKGROUND: PRL3, a protein tyrosine phosphatase functions as one of the key regulatory enzymes of various signal transduction pathways. PRL3 is highly expressed in a majority of cancers and is a novel potential therapeutic target. METHODS: PRL3 expression was evaluated by immunohistochemistry in 167 patients with CRC, 37 patients with no disease, and 26 patients with metastatic CRC (mCRC). Phosphorylated Akt at serine 473 (p-Akt S473) expression was also evaluated by immunohistochemistry in mCRC patients. RESULTS: High expression of PRL3 was correlated with CRC progression, and every one unit increase in PRL3 level contributed to an increase in the rate of death by 1%-1.7%. PRL3 expression was significantly higher in liver metastases compared with primary tumors and showed a significant positive correlation with the expression level of p-Akt S473. CONCLUSION: PRL3 expression levels associated with CRC progression and metastasis, and positively correlated with activated Akt level in mCRC. Together, these findings indicated that PRL3 might be a potential marker for increased risk of CRC-specific tumor burden and identify PRL3 as an attractive therapeutic target for mCRC treatment.