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Kenneth Hess - Top 30 Publications

Internal validation of the prognostic index for spine metastasis (PRISM) for stratifying survival in patients treated with spinal stereotactic radiosurgery.

We sought to validate the Prognostic Index for Spinal Metastases (PRISM), a scoring system that stratifies patients into subgroups by overall survival.Methods and materials: The PRISM was previously created from multivariate Cox regression with patients enrolled in prospective single institution trials of stereotactic spine radiosurgery (SSRS) for spinal metastasis. We assess model calibration and discrimination within a validation cohort of patients treated off-trial with SSRS for metastatic disease at the same institution.

Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials.

Immunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT®) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas.

Volumetric response of progressing post-SRS lesions treated with laser interstitial thermal therapy.

We analyzed volumetric response of metastatic brain tumors that progressed despite treatment with stereotactic radiosurgery (SRS) after treatment with laser interstitial thermal therapy (LITT). We retrospectively reviewed consecutive patients treated from 1/2012 to 10/2015 with LITT for metastatic brain tumors demonstrating progression after SRS. Volumes were quantified using MRI with contrast-enhanced T1-weighted (T1W) and fluid-attenuated inversion recovery (FLAIR). Fifty lesions from 36 patients were studied. Lesions were assessed prior to LITT, immediately after LITT, 0-90 days after LITT, 90-180 days after LITT, 180-270 days after LITT, and 270-360 days after LITT. The median T1W volume was 5.05 cc (range 0.54-23.31 cc) before LITT treatment (n = 50), 7.70 cc (range 1.72-38.76 cc) 0-90 days after LITT (n = 47), and 3.68 cc (range 1.282-48.31 cc) 180-270 days after LITT (n = 21). The median FLAIR volume was 43.36 cc (range 3.09-233.01 cc) before LITT treatment (n = 50), 37.13 cc (range 3.48-244.23 cc) 0-90 days after LITT (n = 43), 31.68 cc (range 1.6-248.75 cc) 180-270 days after LITT (n = 18). The 6-month FLAIR volume showed a statistically significant reduction compared to pretreatment (p = 0.04). After selecting for cases where patients had two or more post-operative MRIs, we found that 24 lesions (63%) demonstrated an overall downward trend and 14 lesions (37%) demonstrated an upward trend. The median pre-treatment T1W volume for the patients whose lesions demonstrated volumetric reduction after LITT was 3.54 cc (range 0.539-10.06 cc) and for those who did not demonstrate volumetric reduction after LITT it was 8.81 cc (range 0.926-23.313 cc). The pre-treatment tumor volume plays a significant role in determining response to LITT with smaller tumor volumes responding better to LITT than tumors with larger volumes.

A relative increase in circulating platelets following chemoradiation predicts for poor survival of patients with glioblastoma.

Thrombocytosis is triggered by and promotes tumor growth. The relationship between the change in circulating platelets after chemoradiation therapy (CRT) or adjuvant temozolomide (TMZ) and survival in glioblastoma remains unclear. We hypothesized that an increase in platelets after these treatments would be predictive of a shorter survival.

Real-World Experience with Targeted Therapy for the Treatment of Anaplastic Thyroid Carcinoma.

Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis, despite systemic cytotoxic chemotherapy. The objective of this study was to investigate the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial.

Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.

Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed. Clinical and laboratory parameters were collected to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. Results Ninety eight of 290 patients (34%) experienced any grade irAEs. Among the 15 (5.2%) patients with grade ≥ 3 irAEs, the most common irAEs were dermatitis and enterocolitis. Although 80% of the patients with grade ≥ 3 irAEs required systemic corticosteroids, all the 15 patients recovered from the irAEs. On re-challenge, 4 of the 5 patients who had received systemic corticosteroids for irAE continued to respond. There were no irAE-related deaths. Importantly, patients with grade ≥ 3 irAEs had improved overall response rate (25 vs. 6%; p = 0.039) and longer median time to progression (30 weeks vs. 10 weeks; p = 0.0040) when compared to those without grade ≥ 3 irAEs. Conclusion Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient. Further validation of this association in a large prospective study is warranted.

Outcomes of phase I clinical trials for patients with advanced pancreatic cancer: update of the MD Anderson Cancer Center experience.

In 2011, we reported the outcomes of pancreatic cancer (PC) patients enrolled in phase I trials at our institution from 2004 through 2009. At the time, gemcitabine and erlotinib were the only Food and Drug Administration-approved drugs for PC and median overall survival (OS) from consultation in the phase I clinic was 5 months. We sought to determine the impact of novel therapeutics on PC patients in phase I trials.

Co-occurring Genomic Alterations and Association With Progression-Free Survival in BRAFV600-Mutated Nonmelanoma Tumors.

BRAFV600 mutations occur in multiple nonmelanoma tumors, but no US Food and Drug Administration-approved BRAF-targeted therapies exist for these cancers. BRAF inhibitor vemurafenib was recently found to demonstrate activity across various BRAF-mutated nonmelanoma cancer types. However, most tumors ultimately become resistant to BRAF-targeted monotherapy. To identify whether co-occurring genomic alterations drive resistance to BRAF-targeted therapies, we analyzed next-generation sequencing data from 30 advanced BRAF-mutated nonmelanoma cancers treated with BRAF inhibitor monotherapy. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. All statistical tests were two-sided. We identified a strong association between co-occurring PI3K-mTOR pathway aberrations and primary resistance to BRAF-targeted therapy. PI3K-mTOR pathway aberrations were associated with a statistically significant reduction in progression-free survival (HR = 15.0, 95% CI = 3.6 to 63.0, P < .001) and overall survival (HR = 19.2, 95% CI = 3.7 to 100.0, P < .001). This suggests that co-occurring genomic alterations may predict response and resistance to BRAF inhibitor therapy and identify subgroups of BRAF-mutated nonmelanomas cancers.

Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson Precision Medicine Study.

Genomic profiling is increasingly used in the management of cancer. We have previously reported preliminary results of our precision medicine program. Here, we present response and survival outcomes for 637 additional patients who were referred for phase I trials and were treated with matched targeted therapy (MTT) when available.

Radiomics to predict immunotherapy-induced pneumonitis: proof of concept.

We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes.

Patterns and correlates of treatment failure in relation to isodose distribution in non-small cell lung cancer: An analysis of 1522 patients in the modern era.

To examine the relationship between radiation dose and tumor control in limited stage non-small cell lung cancer (NSCLC).

Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising >46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a, <0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or <0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society.

Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial.

The use of benzodiazepines to control agitation in delirium in the last days of life is controversial.

Ocular toxicities associated with targeted anticancer agents: an analysis of clinical data with management suggestions.

Ocular toxicities are among the most common adverse events resulting from targeted anticancer agents and are becoming increasingly relevant in the management of patients on these agents. The purpose of this study is to provide a framework for management of these challenging toxicities based on objective data from FDA labels and from analysis of the literature. All oncologic drugs approved by the FDA up to March 14, 2015, were screened for inclusion. A total of 16 drugs (12 small-molecule drugs and 4 monoclonal antibodies) were analyzed for ocular toxicity profiles based on evidence of ocular toxicity. Trials cited by FDA labels were retrieved, and a combination search in Medline, Google Scholar, the Cochrane database, and the NIH Clinical Trials Database was conducted. The majority of ocular toxicities reported were low severity, and the most common were conjunctivitis and "visual disturbances." However, severe events including incidents of blindness, retinal vascular occlusion, and corneal ulceration occurred. The frequency and severity at which ocular toxicities occur merits a more multidisciplinary approach to managing patients with agents that are known to cause ocular issues. We suggest a standardized methodology for referral and surveillance of patients who are potentially at risk of severe ocular toxicity.

Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control.

Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear.

A Double-Blind, Randomized, Placebo-Controlled Trial of Panax Ginseng for Cancer-Related Fatigue in Patients With Advanced Cancer.

Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Results: Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; P=.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (P=.0005), Hospital Anxiety and Depression Scale results (P=.032), and sex (P=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; P=.024). Conclusions: Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. Trial Registration: identifier: NCT01375114.

Personalizing prognosis in colorectal cancer: A systematic review of the quality and nature of clinical prognostic tools for survival outcomes.

Integrating diverse types of prognostic information into accurate, individualized estimates of outcome in colorectal cancer is challenging. Significant heterogeneity in colorectal cancer prognostication tool quality exists. Methodology is incompletely or inadequately reported. Evaluations of the internal or external validity of the prognostic model are rarely performed. Prognostication tools are important devices for patient management, but tool reliability is compromised by poor quality. Guidance for future development of prognostication tools in colorectal cancer is needed.

TIE2 Associates with Caveolae and Regulates Caveolin-1 To Promote Their Nuclear Translocation.

DNA repair pathways are aberrant in cancer, enabling tumor cells to survive standard therapies-chemotherapy and radiotherapy. Our group previously reported that, upon irradiation, the membrane-bound tyrosine kinase receptor TIE2 translocates into the nucleus and phosphorylates histone H4 at Tyr51, recruiting ABL1 to the DNA repair complexes that participate in the nonhomologous end-joining pathway. However, no specific molecular mechanisms of TIE2 endocytosis have been reported. Here, we show that irradiation or ligand-induced TIE2 trafficking is dependent on caveolin-1, the main component of caveolae. Subcellular fractionation and confocal microscopy demonstrated TIE2/caveolin-1 complexes in the nucleus, and using inhibitor or small interfering RNAs (siRNAs) against caveolin-1 or Tie2 inhibited their trafficking. TIE2 was found in caveolae and directly phosphorylated caveolin-1 at Tyr14 in vitro and in vivo This modification regulated the generation of TIE2/caveolin-1 complexes and was essential for TIE2/caveolin-1 nuclear translocation. Our data further demonstrate that the combination of TIE2 and caveolin-1 inhibitors resulted in significant radiosensitization of malignant glioma cells, which will guide the development of combinatorial treatment with radiotherapy for patients with glioblastoma.

Patterns of metastatic progression after definitive radiation therapy for early-stage and locally advanced non-small cell lung cancer.

Current preclinical models of metastatic disease (particularly oligometastases) suggest that metastases appear in a hierarchical order. We attempted to identify systematic patterns of metastasis in non-small cell lung cancer (NSCLC) after radiation therapy (XRT). We analyzed 1074 patients treated from 12/21/1998 through 8/20/2012 with ≥60 Gy definitive radiation for initially non-metastatic NSCLC. Location and time of metastases were recorded. Regional nodal failure was noted, as was subsequent distal failure. For further analysis, we considered only the five most common sites of metastasis (bone, brain, liver, adrenal, and lung). Metastatic progression over time was defined and patterns elucidated with Chi square tests. Histologic findings were analyzed with Wilcoxon rank sum tests. A significant multistep linear progression was not apparent. Having a first metastasis in lung or bone was associated with respective 16% (median 2.4 months) and 15% likelihoods (median 7.9 months) of secondary brain metastasis. Initial metastasis in the brain led to metastasis in another organ 29.3% of the time, most often in the lung, bone, and liver (medians 3.6, 7.9, and 3.1 months). Adenocarcinoma was more likely than squamous to metastasize to the brain (18 vs. 9%) and any of the five major sites (41 vs. 27%). We did not appreciate dominant patterns suggesting a multi-step hierarchical order of metastasis. Rather, our findings suggest that certain subgroups may develop different patterns of spread depending on a variety of factors.

Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy.

We evaluated the patterns of progression and determined clinical predictors of survival in patients with castration-resistant prostate cancer (CRPCa) who received sipuleucel-T.

Insurance Clearance for Early-Phase Oncology Clinical Trials Following the Affordable Care Act.

Purpose: The Affordable Care Act (ACA) required that private insurance plans allow clinical trial participation and cover standard-of-care costs, but the impact of this provision has not been well-characterized. We assessed rates of insurance clearance for trial participation within our large early-phase clinical trials program, before and after implementation of the requirement.Experimental Design: We analyzed the departmental database for the Clinical Center for Targeted Therapy (CCTT) at MD Anderson Cancer Center (Houston, TX). Among patients referred for sponsored trials, we described rates of insurance clearance and prolonged time to clearance (at least 14 days) from July 2012 to June 2013 (baseline), July 2013-December 2013 (following CCTT staffing changes in July 2103), and January 2014-June 2015 (following implementation of the ACA). We used multivariable logistic regression models to compare rates across these time periods.Results: We identified 2,404 referrals for insurance clearance. Among privately insured patients, insurance clearance rates were higher for those referred from January 2014 to June 2015 than for those referred from July 2012 to June 2013 (OR, 4.72; 95% CI, 2.96-7.51). There was no association between referral period and clearance rates for Medicare/Medicaid patients (P = 0.25). Referral from January 2014 to June 2015 was associated with lower rates of prolonged clearance among both privately insured (OR 0.57; 95% CI, 0.38-0.86) and Medicare/Medicaid patients (OR 0.39; 95% CI, 0.19-0.83).Conclusion: Within our large early-phase clinical trials program, insurance clearance rates among privately insured patients improved following implementation of the ACA's requirement for coverage of standard-of-care costs. Clin Cancer Res; 23(15); 1-8. ©2017 AACR.

Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial.

After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone.

Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival.

Human mesenchymal stem cells (hMSCs) have been shown to reside as stromal cells in human gliomas as glioma-associated hMSCs (GA-hMSCs), but their biological role remains unclear. Because recent evidence indicates that GA-hMSCs drive tumor cell proliferation and stemness, we hypothesized that a higher percentage of GA-hMSCs in tumors predicts poor patient prognosis.

Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer.

Genetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+/TP53+ mutations.

Prognostic Scoring System to Risk Stratify Parathyroid Carcinoma.

Parathyroid carcinoma is a rare endocrine malignancy that lacks an established system for risk categorization. This study evaluated a prognostic scoring system for recurrence-free survival (RFS) of patients with parathyroid carcinoma.

Outcomes of Patients with Renal Cell Carcinoma and Sarcomatoid Dedifferentiation Treated with Nephrectomy and Systemic Therapies: Comparison between the Cytokine and Targeted Therapy Eras.

We studied overall survival and prognostic factors in patients with sarcomatoid renal cell carcinoma treated with nephrectomy and systemic therapy in the cytokine and targeted therapy eras.

Effect of Mammography on Marker Clip Migration After Stereotactic-Guided Core Needle Breast Biopsy.

To determine whether the type of projection used-same as or orthogonal to the projection used during a stereotactic-guided core needle biopsy procedure-to obtain the first view on a 2-view postbiopsy mammogram affects biopsy marker clip migration.

Use of Expansion Cohorts in Phase I Trials and Probability of Success in Phase II for 381 Anticancer Drugs.

Purpose: Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA.Experimental Design: We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the [email protected] website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II.Results: We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1-4.0; P = 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0-2.9; P = 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5-5.7; P = 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6-5.2; P = 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2-8.8; P < 0.001).Conclusions: The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association. Clin Cancer Res; 23(15); 4020-6. ©2017 AACR.

Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma.

Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category.

Imaging-Concordant Benign MRI-Guided Vacuum-Assisted Breast Biopsy May Not Warrant MRI Follow-Up.

The follow-up of breast lesions with imaging-concordant benign histopathology results on MRI-guided vacuum-assisted biopsy (VAB) is not currently standardized. We determined the false omission rate of breast MRI-guided VAB with benign histopathology (negative results) to assess whether breast MRI follow-up is needed.