Impact of KRAS status on tumor response and survival after neoadjuvant treatment of locally advanced rectal cancer.

BACKGROUND: Mutation of the KRAS oncogene (mKRAS) in colorectal cancer has been associated with aggressive tumor biology, resistance to epidermal growth factor inhibitors, and decreased overall survival (OS). The aim of the current study was to analyze the association of mKRAS with pathologic complete response (pCR) and neoadjuvant rectal (NAR) score, and its impact on the survival of patients with locally advanced rectal cancer who were managed with multimodality therapy. METHODS: The National Cancer Database was queried for stage II-III rectal cancer patients with a known KRAS status who underwent neoadjuvant chemoradiation therapy (nCRT) and proctectomy between 2004 and 2015. RESULTS: In total, 1886 patients were identified; 12% had pCR and 36% had mKRAS. Patients with mKRAS were more likely to have advanced pathologic T stage, tumor deposits, perineural invasion, and elevated carcinoembryonic antigen levels (all p ≤ .05). After adjustment for available confounders, mKRAS status was not associated with pCR or NAR score. In multivariable analysis, patients with pCR and lower NAR score had better OS, whereas mKRAS was independently associated with a worse prognosis. CONCLUSION: In this cohort of locally advanced rectal cancer patients who underwent proctectomy after nCRT, mKRAS was not associated with lower pCR rates or NAR scores; however, these patients experienced worse survival.

The Role of Definitive Radiation and Surgery in Metastatic Esophageal Cancer: An NCDB Investigation.

BACKGROUND: Approximately 40% of patients with esophageal cancer present with metastatic disease. Survival with palliative treatment is poor, and the benefit of aggressive focal therapies is unclear. This study aimed to identify a subset of patients with metastatic esophageal cancer with favorable outcomes after curative doses of radiation therapy, esophagectomy, or both. METHODS: Between 2004 and 2015, the study investigators found 28,101 patients with metastatic esophageal cancer in the National Cancer Database and identified those who underwent chemotherapy and definitive radiation therapy with or without surgery over the study period. The study compared the estimated median overall survival (OS) of all patients with metastatic esophageal cancer with the estimated median OS of patients with metastatic esophageal cancer who underwent radiation therapy with or without surgery. Multivariable analysis was used to examine clinical and pathologic factors associated with OS. RESULTS: At a median follow-up of 11.1 months, 3219 patients with a median age of 64 years and a radiation dose of 50.4 Gy were identified. Only 202 (6.2%) patients undergoing definitive-dose radiation therapy underwent esophagectomy, with a median age of 60 years. The median OS durations for all patients, for patients treated with radiation, and for patients treated with radiation therapy in combination with esophagectomy were 6.6, 11.5, and 30.2 months, respectively. Among patients undergoing surgery, median OS after surgery was 23.7 months. Patients with lung, liver, or bone metastases were less likely to undergo esophagectomy. On multivariable analysis, esophagectomy and low tumor grade were associated with higher OS, whereas liver and bone metastases at diagnosis were associated with worse OS. CONCLUSIONS: This analysis suggests that select subsets of patients with primarily nonvisceral, nonosseous metastatic esophageal cancer have favorable survival and may potentially benefit from aggressive local therapies.

The Impact of KRAS Mutation on the Presentation and Prognosis of Non-Metastatic Colon Cancer: an Analysis from the National Cancer Database.

INTRODUCTION: Approximately 40% of colorectal cancers have a KRAS mutation. The prognostic significance of KRAS mutations in patients with non-metastatic colon cancer has not been well elucidated. The National Cancer Database (NCDB) was used to analyze factors associated with KRAS mutation as well as its impact on the presentation and survival of patients with stages I-III colon cancer. METHODS: The NCDB was queried to identify patients diagnosed with stages I-III adenocarcinoma of the colon from 2004 to 2015. RESULTS: A total of 19,877 patients with known KRAS status were identified: mutation rates were 33% in stage I, 35% in stage II, and 38% in stage III patients (p < 0.01). On multivariable analysis, black race and right-sided location were independently associated with KRAS-mutated cancers (all p < 0.01). On univariate analysis for overall survival (OS), KRAS mutation was not significantly associated with a worse 5-year OS for stages I and II patients (p = 0.60 and 0.88, respectively). However, stage III KRAS-mutated colon cancers had a lower OS as compared with KRAS wild type cancers both on univariate and multivariable analysis. Right-sided colon cancers were independently associated with a worse prognosis compared with left-sided lesions (p < 0.01). CONCLUSIONS: KRAS-mutated colon cancers were more frequently observed in black patients, right-sided locations, and higher-stage tumors. These mutations had a negative prognostic impact for stage III patients, suggesting that the incorporation of genotypic data into colon cancer staging may help to guide systemic therapy and prognostication of colon cancer patients.

Positive circumferential resection margins following locally advanced colon cancer surgery: Risk factors and survival impact.

BACKGROUND: While the prognostic implications of positive circumferential resection margins (CRM) have been established for rectal cancer, its significance in colon cancer has not been well defined. The aim of the current study was to determine national rates for positive CRM in locally advanced colon cancer, associated factors, and survival impact. METHODS: The National Cancer Database was queried to identify patients with stage II-III adenocarcinoma of the colon (2004-2015). RESULTS: Positive CRM was identified in 9% of stage II and 12% of stage III patients. Factors associated with negative CRM included surgery in a high-volume facility, adequate lymph-node harvest, and negative distal/proximal margins. No difference in CRM rates was observed between surgical approaches, although having a positive CRM was significantly associated with higher conversion rates. Positive CRM was associated with significantly lower overall survival on both univariate and multivariable analysis. CONCLUSIONS: Positive CRM rates exceeded 10% nationally and have an adverse impact on survival. While several tumor characteristics were identified as independent risk factors, oncologic resections and surgery at high-volume centers were associated with lower rates of positive CRM. These findings emphasize the need for process improvement initiatives targeting modifiable factors, including adoption of appropriate oncologic techniques, standardized pathology reporting, and potential neoadjuvant strategies.

Timing of surgery following neoadjuvant chemoradiation in rectal cancer: a retrospective analysis from an academic medical center.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) has been shown to achieve decreased local recurrence (LR) with lower toxicity in rectal cancer patients, but data confirming the optimal timing of surgery following this therapy is less robust. METHODS: The University of Iowa Cancer Registry was queried to identify all patients with stages II-III rectal cancer who received nCRT and surgery from 2000 through 2012. Primary endpoints were time interval to surgery (TI), and overall survival (OS). Secondary endpoints included pathologic outcomes, perioperative morbidities and postoperative complications. Patient characteristics and treatment regimens were compared. Univariate Cox proportional hazard models were used to study the association between TI and OS. Associations of TI with secondary endpoints were tested using Chi-square tests of association. RESULTS: Eighty-seven patients presented with stages II-III rectal cancer. Mean TI was 9.92 weeks. There was no significant association between TI and OS when comparing <8 to ≥8 weeks (P=0.23) or when considering the interval as a continuous variable (P=0.85). Increased LOS [median 7.00 days, P=0.05, HR 1.03 (1.00-1.06)] did correlate with worse survival outcomes. Delaying surgery beyond 8 weeks was associated with increased risk for wound infection (P=0.05). CONCLUSIONS: OS was not influenced by longer intervals between nCRT and surgery. Delaying surgery beyond 8 weeks was associated with increased risk for wound infection.

RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth.

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

Using Smaller-Than-Standard Radiation Treatment Margins Does Not Change Survival Outcomes in Patients with High-Grade Gliomas.

PURPOSE: The number of studies that evaluate treatment margins for high grade gliomas (HGG) are limited. We hypothesize that patients with HGG who are treated with a gross tumor volume (GTV) to planning tumor volume (PTV) expansion of ≤1 cm will have progression-free survival (PFS) and overall survival (OS) rates similar to those treated in accordance with standard protocols by the Radiation Therapy Oncology Group or European Organisation for Research and Treatment of Cancer. Furthermore, the PFS and OS of subgroups within the study population will have equivalent survival outcomes with GTV1-to-PTV1 margins of 1.0 cm and 0.4 cm. METHODS AND MATERIALS: Treatment plans and outcomes for patients with pathologically confirmed HGG were analyzed (n = 267). Survival (PFS and OS) was calculated from the time of the first radiation treatment and a χ2 test or Fisher exact test was used to calculate the associations between margin size and patient characteristics. Survival was estimated using Kaplan-Meier and compared using the log-rank test. All analyses were performed on the univariate level. RESULTS: The median PFS and OS times were 10.6 and 19.1 months, respectively. By disease, the median PFS and OS times were 8.6 and 16.1 months for glioblastoma and 26.7 and 52.5 months for anaplastic glioma. The median follow-up time was 18.3 months. The treatment margin had no effect on outcome and the 1.0 cm GTV1-PTV1 margin subgroup (n = 212) showed median PFS and OS times of 10.7 and 19.1 months, respectively, and the 0.4 cm margin subgroup (n = 55) 10.2 and 19.3 months, respectively. In comparison with the standard treatment with 2 cm to 3 cm margins, there was not a significant difference in outcomes. CONCLUSIONS: There is no apparent difference in survival when utilizing smaller versus larger margins as defined by the guidelines of the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer. Although there remains no class I evidence that outcomes after treatment with smaller margins are identical to those after treatment with larger margins, this large series with long-term follow up suggests that a reduction of the margins is safe and further investigation is warranted.

Independent Predictors of Prognosis Based on Oral Cavity Squamous Cell Carcinoma Surgical Margins.

Objective To conduct a multivariate analysis of a large cohort of oral cavity squamous cell carcinoma (OCSCC) cases for independent predictors of local recurrence (LR) and overall survival (OS), with emphasis on the relationship between (1) prognosis and (2) main specimen permanent margins and intraoperative tumor bed frozen margins. Study Design Retrospective cohort study. Setting Tertiary academic head and neck cancer program. Subjects and Methods This study included 426 patients treated with OCSCC resection between 2005 and 2014 at University of Iowa Hospitals and Clinics. Patients underwent excision of OCSCC with intraoperative tumor bed frozen margin sampling and main specimen permanent margin assessment. Multivariate analysis of the data set to predict LR and OS was performed. Results Independent predictors of LR included nodal involvement, histologic grade, and main specimen permanent margin status. Specifically, the presence of a positive margin (odds ratio, 6.21; 95% CI, 3.3-11.9) or <1-mm/carcinoma in situ margin (odds ratio, 2.41; 95% CI, 1.19-4.87) on the main specimen was an independent predictor of LR, whereas intraoperative tumor bed margins were not predictive of LR on multivariate analysis. Similarly, independent predictors of OS on multivariate analysis included nodal involvement, extracapsular extension, and a positive main specimen margin. Tumor bed margins did not independently predict OS. Conclusion The main specimen margin is a strong independent predictor of LR and OS on multivariate analysis. Intraoperative tumor bed frozen margins do not independently predict prognosis. We conclude that emphasis should be placed on evaluating the main specimen margins when estimating prognosis after OCSCC resection.

Reduction of applicator displacement in MR/CT-guided cervical cancer HDR brachytherapy by the use of patient hover transport system.

PURPOSE: To quantify the reduction of relative displacement between the implanted intracavitary applicator and the patient bony anatomy, due to the use of a hover transport system during the patient transports between the imaging table and the treatment table. MATERIAL AND METHODS: The displacement of the applicator inside the patient was measured by comparing the distance between the tip of the tandem and the pubic bone on X-ray radiography images taken before and after moving a patient to magnetic resonance/computed tomography imaging. Displacements were evaluated for 27 fractions of treatment using hover transport and 185 fractions of treatment using manual transport. RESULTS: The use of hover transport system reduced the percentage of fractions with displacements greater than 5 mm from 22.7% to 7.4%. The reduction of applicator displacement using hover transport is statistically significant, compared to the manual transport method (p-value 0.0086; mean displacement 3.41 mm [95% CI: 2.96-3.97] for manual transport, and 2.27 mm [95% CI: 1.71-2.97] for hover transport fractions). CONCLUSIONS: This study indicates that the hover transport system is effectively reducing displacement between tandem and patient bony anatomy during patient transports. The potential improvement in dosimetric accuracy due to this reduction warrants further study.

Flow cytometric aberrancies in plasma cell myeloma and MGUS - correlation with laboratory parameters.

BACKGROUND: Multiparametric flow cytometry is a useful tool for diagnosis of plasma cell (PC) dyscrasias and assessment of minimal residual disease in plasma cell myeloma (PCM). However, the immunophenotypic differences between the clonal PCs of PCM and those of monoclonal gammopathy of undetermined significance (MGUS) as well as the correlation of these flow cytometric markers with pertinent laboratory parameters have not been evaluated. METHODS: We retrospectively identified all newly diagnosed treatment-naive PCM and MGUS patients between 09/2014 and 06/2015 who underwent 10-color flow-cytometric evaluation: CD45, CD38, CD138, cKappa, cLambda, CD19, CD27, CD28, CD56, CD117. FACSDiva analysis was used to identify antigenic aberrancies and associations with pertinent laboratory parameters were evaluated. RESULTS: All cases demonstrated at least two aberrancies. There was a trend toward a greater number of aberrancies in PCM, with 68% showing >/= 4 aberrancies compared with 44% in MGUS (P = 0.11). The only marker more frequently aberrant in one disease class was CD19, aberrant in 68% of PCM and 25% of MGUS (P < 0.01). In PCM, significant associations were found for CD56 non-aberrancy (P = 0.05) and the presence of amyloid and CD27 aberrancy and normal serum albumin (P = 0.05). In MGUS, CD117 expression was associated with normal hemoglobin (P = 0.03). CONCLUSIONS: The PCs of PCM show a trend toward more antigenic aberrancy than those of MGUS. There is significant association between the antigenic profiles of PCM/MGUS and clinical parameters including amyloidosis, albumin level, and hemoglobin. © 2018 International Clinical Cytometry Society.

Utility of 3-Month Surveillance F-18 FDG PET/CT in Surgically Resected Oral Squamous Cell Carcinoma.

OBJECTIVES: To evaluate the performance of surveillance F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) 1 year after imaging in oral squamous cell carcinoma (OSCC) patients treated with definitive surgery and adjuvant (chemo)radiotherapy (RT). METHODS AND MATERIALS: Surveillance PET/CT accuracy was retrospectively evaluated in OSCC patients receiving surgical resection and (chemo)RT. Pathologic risk factors were assessed for influence on accuracy of the post-RT PET/CT. RESULTS: Fifty-four patients with median follow-up of 3.8 years met inclusion criteria. A PET/CT obtained a median of 3.4 months after RT revealed 11 (20.4%) instances of true disease recurrence: 4 locoregional alone, 6 distant alone, and 1 patient with locoregional and distant disease. Locoregional detection sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 55.6%, 75.0%, 33.3%, and 88.2%, respectively. For distant recurrence, the respective values were 100%, 95.2%, 77.8%, and 100%. Absence of bone invasion, absence of pT4 disease, and disease within the tongue were independently associated with higher sensitivity ( P = .048). Perineural invasion was associated with increased specificity ( P = .027), and tumor location in the tongue was associated with a higher PPV ( P = .007) on surveillance PET/CT. CONCLUSIONS: Post-RT PET/CT accuracy information for surgically managed OSCC patients demonstrates significant associations with pathologic factors.

Rapid and Sensitive Detection of Breast Cancer Cells in Patient Blood with Nuclease-Activated Probe Technology.

A challenge for circulating tumor cell (CTC)-based diagnostics is the development of simple and inexpensive methods that reliably detect the diverse cells that make up CTCs. CTC-derived nucleases are one category of proteins that could be exploited to meet this challenge. Advantages of nucleases as CTC biomarkers include: (1) their elevated expression in many cancer cells, including cells implicated in metastasis that have undergone epithelial-to-mesenchymal transition; and (2) their enzymatic activity, which can be exploited for signal amplification in detection methods. Here, we describe a diagnostic assay based on quenched fluorescent nucleic acid probes that detect breast cancer CTCs via their nuclease activity. This assay exhibited robust performance in distinguishing breast cancer patients from healthy controls, and it is rapid, inexpensive, and easy to implement in most clinical labs. Given its broad applicability, this technology has the potential to have a substantive impact on the diagnosis and treatment of many cancers.

68Ga-DOTATOC Imaging of Neuroendocrine Tumors: A Systematic Review and Metaanalysis.

68Ga-DOTATOC, a somatostatin receptor-targeted ligand, has been used clinically in Europe over the past decade for imaging neuroendocrine tumors (NETs). It appears to be quite sensitive and effective for clinical management decision making. This metaanalysis summarizes the efficacy of 68Ga-DOTATOC for several distinct indications and is intended to support approval of this agent by the U.S. Food and Drug Administration. Methods: The major electronic medical databases were searched for relevant papers over the period from January 2001 to November 2015. Papers were selected for review in 3 categories: clinical trials that reported sensitivity and specificity, comparison studies with 111In-octreotide, and change of management studies. All the eligible papers underwent Quality Assessment of Diagnostic Accuracy Studies (QUADAS) assessment, which was useful in the final selection of papers for review. Results: The initial search yielded 468 papers. After detailed evaluation, 17 papers were finally selected. Five types of studies emerged: workup of patients with symptoms and biomarker findings suggestive of NET, but with negative conventional imaging (3 papers, yield was only 13%); sensitivity (12 papers; sensitivity, 92%) and specificity (7 papers; specificity, 82%); identification of site of unknown primary in patients with metastatic NET (4 papers, yield was 44%); impact on subsequent NET patient management (4 papers, change in management in 51%); and comparison with 111In-octreotide (2 papers, sensitivity of DOTATOC on a per-lesion basis was 100%, for 111In-octreotide it was 78.2%; specificity was not available). Safety was not explicitly addressed in any study, but there were no reports of adverse events. Conclusion:68Ga-DOTATOC is useful for evaluating the presence and extent in disease for staging and restaging and for assisting in treatment decision making for patients with NET. It is also effective in locating the site of an unknown primary in NET patients who present with metastatic NET, but no known primary tumor. It also appears to be more accurate than 111In-octreotide. Although 68Ga-DOTATOC would seem to be useful in evaluating patients with suggestive symptoms and biomarker findings, it does not perform well in this setting and has low yield. Overall, it appears to be an excellent imaging agent to assess patients with known NET and frequently leads to a change in management.

Localization of Unknown Primary Site with 68Ga-DOTATOC PET/CT in Patients with Metastatic Neuroendocrine Tumor.

Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent 68Ga-DOTATOC PET/CT in a single-site prospective study. The 68Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the 68Ga-DOTATOC-positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if 68Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion:68Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET.

Prediction of chemo-response in serous ovarian cancer.

BACKGROUND: Nearly one-third of serous ovarian cancer (OVCA) patients will not respond to initial treatment with surgery and chemotherapy and die within one year of diagnosis. If patients who are unlikely to respond to current standard therapy can be identified up front, enhanced tumor analyses and treatment regimens could potentially be offered. Using the Cancer Genome Atlas (TCGA) serous OVCA database, we previously identified a robust molecular signature of 422-genes associated with chemo-response. Our objective was to test whether this signature is an accurate and sensitive predictor of chemo-response in serous OVCA. METHODS: We first constructed prediction models to predict chemo-response using our previously described 422-gene signature that was associated with response to treatment in serous OVCA. Performance of all prediction models were measured with area under the curves (AUCs, a measure of the model's accuracy) and their respective confidence intervals (CIs). To optimize the prediction process, we determined which elements of the signature most contributed to chemo-response prediction. All prediction models were replicated and validated using six publicly available independent gene expression datasets. RESULTS: The 422-gene signature prediction models predicted chemo-response with AUCs of ~70 %. Optimization of prediction models identified the 34 most important genes in chemo-response prediction. These 34-gene models had improved performance, with AUCs approaching 80 %. Both 422-gene and 34-gene prediction models were replicated and validated in six independent datasets. CONCLUSIONS: These prediction models serve as the foundation for the future development and implementation of a diagnostic tool to predict response to chemotherapy for serous OVCA patients.