698 Background: Lymphovascular invasion (LVI) has been shown to be associated with nodal involvement and higher rates of local recurrence in rectal cancer. In some studies, the presence of LVI has also been associated with worse overall survival; however, these have been mostly smaller, single institution studies or incomplete data sets. Our goal was to examine the effect of LVI on prognosis in a large and inclusive database. Methods: Outcomes of patients with clinical stage II and stage III rectal adenocarcinoma in the National Cancer Data Base (NCDB) from 2011 to 2015, in whom LVI data was available, were included. Exclusion criteria incorporated patients who did not receive neoadjuvant radiation and chemotherapy, neoadjuvant or adjuvant. Overall survival was compared in patients with and without LVI, controlling for age, sex, race, comorbidities, socioeconomic factors, and T and N stages using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Median overall survival and hazard ratios with 95% confidence intervals are reported where available. Results: The dataset included 9206 patients with stage II and 12640 patients with stage III rectal adenocarcinoma for which LVI data were available and who received the study’s previously defined standard of care. The proportion of patients with LVI was 11% in stage II and 16% in stage III rectal cancer. After adjusting for age, sex, race, T or N stage, and other clinical and demographic variables, LVI was associated with worse overall survival in stage II HR 1.87 (1.62-2.16, p < 0.001) and in stage III HR 1.8 (1.61-2.02, p < 0.001) rectal cancer. The median overall survival was not reached in stage II rectal cancer patients without LVI versus 5.73 years with LVI. In stage III rectal cancer, the median overall survival was 6.91 years without LVI versus 6.21 years with LVI. Conclusions: Lymphovascular invasion is an independent risk factor of mortality in stage II and III rectal cancer. Stage II rectal cancer patients without LVI have comparatively good survival of the groups studied, potentially identifying a group of patients that may benefit from de-escalated therapy. Further studies will be guided at identifying if benefits with chemotherapy are associated with LVI status.
Abstract Somatic PTEN mutations are common and have driver function in some cancer types. However, in colorectal cancers (CRCs), somatic PTEN -inactivating mutations occur at a low frequency (~8–9%), and whether these mutations are actively selected and promote tumor aggressiveness has been controversial. Analysis of genomic data from ~53,000 CRCs indicates that hotspot mutation patterns in PTEN partially reflect DNA-dependent selection pressures, but also suggests a strong selection pressure based on protein function. In microsatellite stable (MSS) tumors, PTEN alterations co-occur with mutations activating BRAF or PI3K , or with TP53 deletions, but not in CRC with microsatellite instability (MSI). Unexpectedly, PTEN deletions are associated with poor survival in MSS CRC, whereas PTEN mutations are associated with improved survival in MSI CRC. These and other data suggest use of PTEN as a prognostic marker is valid in CRC, but such use must consider driver mutation landscape, tumor subtype, and category of PTEN alteration.
<div>AbstractPurpose:<p>The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.</p>Experimental Design:<p>DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established.</p>Results:<p>Overall genomic alteration rates in the younger (<40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, <i>TP53</i> (FDR < 0.01) and <i>CTNNB1</i> (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and <i>APC</i> (FDR < 0.01), <i>KRAS</i> (FDR < 0.01), <i>BRAF</i> (FDR < 0.01), and <i>FAM123B</i> (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in <i>APC</i> (FDR < 0.01), <i>BRAF</i> (FDR < 0.01), and KRAS (FDR < 0.01).</p>Conclusions:<p>Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.</p></div>
678 Background: Improved outcomes have been demonstrated with the use of neoadjuvant fluoropyrimidine-based chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer. The addition of oxaliplatin in the adjuvant setting has also resulted in improved disease-free survival (DFS). A meta-analysis was performed to evaluate DFS and overall survival (OS) with the addition of oxaliplatin to standard neoadjuvant chemoradiation for locally advanced rectal cancer. Methods: A systematic literature review was performed. Randomized-controlled trials (RCTs) comparing the addition of oxaliplatin in the neoadjuvant setting (oxaliplatin group) to fluoropyrimidine-based chemoradiation (standard group) were included. The primary outcomes were DFS and OS; secondary outcomes were short-term surgical results, morbidity, and mortality. Results were combined using meta-analysis via linear mixed-effects models. Calculations were performed using R. Results: Of 73 studies identified, 4 reported DFS (n=3829) and 3 reported OS (n=2680). There was no difference in DFS between the standard and oxaliplatin groups amongst RCTs [HR 0.90 (0.64-1.26), p=0.5313]. There was no difference in OS [HR 0.93 (0.59-1.47), p=0.9894]. There was no significant heterogeneity between RCTs for primary outcomes. There was also no difference in pathologic complete response rate [OR 0.93 (0.77-1.14), p=0.4923), resection margin (R0) status [OR 1.01 (0.59-1.72), p=0.9846], circumferential resection margin status [OR 0.84 (0.50-1.41), p=0.5079], sphincter saving surgery rate [OR 0.87 (0.74-1.03), p=0.1103], grade 3-4 toxicity [OR 1.60 (0.88-2.92), p=0.1251], and 60-day mortality [OR 1.27 (0.50-3.25), p=0.6148]. There was significant heterogeneity between RCTs for R0 status, circumferential margin status, and grade 3-4 toxicity. Adjuvant treatment varied across studies. Conclusions: There are no short-term or long-term survival benefits with the addition of oxaliplatin to fluoropyrimidine-based chemoradiation in the neoadjuvant setting for locally advanced rectal cancer.
Introduction: Squamoid eccrine carcinoma is a very rare carcinoma with few reported cases in the literature. As a result, there islimited guidance on management and follow-up of these cases.Case Presentation: We describe the case of a 39 year-old male with a large painful squamoid eccrine carcinoma of the right lowerabdominal wall with inguinal nodal involvement. He underwent radical resection, superficial groin dissection, transposition of asartorius muscleflap, anda pedicled anterolateral thigh perforatorflapfor reconstruction. The postoperative coursewasuneventfulapart from a postoperative seroma which was treated with aspiration. He underwent adjuvant radiation following full recoveryfrom his procedure.Conclusions: Our case study represents a rare, large squamoid eccrine carcinoma of the abdominal wall treated with radical resection,superficial groin dissection, transposition of a sartorius muscle flap, and a pedicled anterolateral thigh perforator flap forreconstruction. Due to the limited number of reported cases, there are no guidelines for management of squamoid eccrine carcinomas.With this case report we aim to increase awareness of this rare carcinoma, and to summarize the existing literature onmanagement of squamoid eccrine carcinoma.
From 1974 to 1983, 112 patients were treated at the Chirurgische Universitätsklinik Münster according to the procedure first published by Whipple in 1935. 40 patients (35.7%) were operated for chronic pancreatitis, 39 for (34.8%) ampullary cancer and 33 (29.5%) for pancreatic cancer. As to operative mortality which amounted to 10.7% (12/112) for all patients, figures of 10.0% (4/40) could be found for relapsing pancreatitis and 7.7% or 15.2% respectively for cancer patients. The underlying cause was circulatory arrest in 6 cases, anastomotic leakage in 4 cases, liver failure and gas gangrene in 1 case each. Altogether eight relaparotomies were performed (7.1%). As non-letal complications, pancreatic fistula, rise of liver enzymes, wound healing disturbances, and pleural effusion were the most frequent non-letal complications. By using the Ethibloc for pancreatic duct occlusion the rate of complications could be lowered. Hardly ever, glucose-metabolism was markedly affected by this extensive procedure.
Purpose: In the past few years there have been numerous proposals for 3D dose reconstruction from the PET-CT imaging of patients undergoing radioembolization treatment of the liver with yttrium-90 microspheres. One of the most promising techniques uses convolution of the measured PET activity distribution with a pre-calculated Monte Carlo dose deposition kernel. The goal of the present study is to experimentally verify the accuracy of this method and to analyze the significance of various error sources. Methods: Optically stimulated luminescence detectors (OSLD) were used (NanoDot, Landauer) in this experiment. Two detectors were mounted on the central axis of a cylinder filled with water solution of yttrium-90 chloride. The total initial activity was 90mCi. The cylinder was inserted in a larger water phantom and scanned on a Siemens Biograph 16 Truepoint PET-CT scanner. Scans were performed daily over a period of 20 days to build a calibration curve for the measured absolute activity spanning 7 yttrium-90 half-lives. The OSLDs were mounted in the phantom for a predetermined period of time in order to record 2Gy dose. The measured dose was then compared to the dose reconstructed from the activity density at the location of each dosimeter. Results: Thorough error analysis of the dose reconstruction algorithm takes into account the uncertainties in the absolute PET activity, branching ratios, and nonlinearity of the calibration curve. The measured dose for 105-minute exposure on day 10 of the experiment was 219(11)cGy, while the reconstructed dose at the location of the detector was 215(47)cGy. Conclusion: We present the first experimental verification of the accuracy of the convolution algorithm for absolute dose reconstruction of yttrium-90 microspheres. The excellent agreement between the measured and calculated point doses will encourage the broad clinical adoption of the convolution-based dose reconstruction algorithm, making future quantitative dose/outcome studies possible.
682 Background: Pancreatic ductal adenocarcinoma (PDAC) features a distinctive tumor microenvironment comprising cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix (ECM), forming functional CAF units (CAF u). The current total neoadjuvant therapy (TNT), involving conventional chemoradiotherapy (CRT), yields suboptimal responses while promoting a tumor-permissive CAF u state. To address this, we explored pulsed low dose rate radiation (PLDR)-based TNT, as an alternative to CRT, to treat three-dimensional in vivo-like human PDAC CAF u cultures. We assessed gemcitabine combined with PLDR versus CRT using theHOST Factor, a “harmonized output of stroma traits” factor, comprising several established CAF u functional indicators, which inform on the functional status of the PDAC microenvironment. Methods: The unique CAF u functional values used corresponded to: i) ECM anisotropy; ii) persistent cell-ECM signaling; iii) sustained cytokine-induced activation; iv) cytoskeletal bundling; and v) systemic features of fibroblastic activation. The validity of the resultant HOST factor was assessed using the unit’s ECM ability to elicit fibroblastic activation, indicated by a high αSMA/F-actin ratio value. Results: Ex-vivo CRT led to a HOST factor that was 2-fold greater than chemotherapy alone (p=0.6), which was functionally gauged as a tumor-permissive CAF u. In contrast, PLDR averted CRT-induced tumor-permissive response and established a 6-fold lower HOST factor, suggestive of a “normalized” CAF u, when compared to the HOST factor value established when using conventional TNT (P=0.0016 vs. CRT, and P= 0.0086 vs. gemcitabine alone). The multi-parameter HOST factor validity was confirmed as CRT treated CAF u’s ECM activated human pancreatic fibroblasts (αSMA/F-actin = 70% ± 29) while PLDR-treated CAF u's ECM failed to do so (αSMA/F-actin = 32% ± 26), reaching a 30% mean rank difference (P <0.0001). Conclusions: PLDR mitigates conventional CRT-based TNT-induced tumor-permissive responses, restoring the fibroblastic units' tumor-suppressive function. These results lend support to a phase 1 trial designed to evaluate whether radiation with PLDR-based TNT, constitutes a safe and more effective treatment for PDAC patients. The novel HOST factor is being used to appraise specimens from NCT04452357.
