Priya Jayachandran

BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: An aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features

The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P=0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60-16.94; and 6.08, 95% CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

Recent literature suggests an increasing incidence of colorectal carcinoma in young patients. We performed a histologic, molecular, and immunophenotypic analysis of patients with sporadic early-onset (≤40 years of age) colorectal carcinoma seen at our institution from the years 2000–2010 and compared these tumors to a cohort of consecutively resected colorectal carcinomas seen in patients >40 years of age. A total of 1160 primary colorectal adenocarcinomas were surgically resected for the years 2000 through 2010. Of these, 75 (6%) were diagnoses in patients ≤40 years of age of which 13 (17%) demonstrated abnormalities in DNA mismatch repair, 4 (5%) were in patients with known germline genetic disorders (two patients with familial adenomatous polyposis, one patient with juvenile polyposis, and one patient with Li-Fraumeni syndrome), and three patients (4%) had long-standing chronic inflammatory bowel disease. The sporadic early-onset colorectal carcinoma group comprised a total of 55 patients (55/1160, 5%) and were compared with a control group comprising 73 consecutively resected colorectal carcinomas with proficient DNA mismatch repair in patients >40 years of age. For the early-onset colorectal carcinoma group, most cases (33/55, 60%) were diagnosed between the age of 35 and 40 years of age. Compared with the control group, the early-onset colorectal carcinoma group was significantly different with respect to tumor location (P<0.007) with 80% (44/55 cases) identified in either the sigmoid colon (24/55, 44%) or rectum (20/55, 36%). Morphologically, early-onset colorectal carcinomas more frequently displayed adverse histologic features compared with the control colorectal carcinoma group such as signet ring cell differentiation (7/55, 13% vs 1/73, 1%, P=0.021), perineural invasion (16/55, 29% vs 8/73, 11%, P=0.009) and venous invasion (12/55, 22% vs 4/73, 6%, P=0.006). A precursor adenomatous lesion was less frequently identified in the early-onset colorectal carcinoma group compared with the control group (19/55, 35% vs 39/73, 53%, P=0.034). Of the early-onset colorectal carcinomas, only 2/45 cases (4%) demonstrated KRAS mutations compared with 11/73 (15%) of the control group colorectal adenocarcinomas harboring KRAS mutations, although this difference did not reach statistical significance (P=0.13). BRAF V600E mutations were not identified in the early-onset colorectal carcinoma group. No difference was identified between the two groups with regard to tumor stage, tumor size, number of lymph node metastases, lymphatic invasion, tumor budding, mucinous histology, or tumor-infiltrating lymphocytes. Both groups had similar recurrence-free (P=0.28) and overall survival (P=0.73). However, patients in the early-onset colorectal carcinoma group more frequently either presented with or developed metastatic disease during their disease course compared with the control colorectal carcinoma group (25/55, 45% vs 18/73, 25%, P=0.014). In addition, 8/55 patients (15%) in the early-onset colorectal carcinoma group developed local recurrence of their tumor while no patients in the control colorectal carcinoma group developed local recurrence (P<0.001), likely due to the increased incidence of rectal carcinoma in the patients with early-onset colorectal carcinoma. Our study demonstrates that colorectal carcinoma is not infrequently diagnosed in patients ≤40 years of age and is not frequently the result of underlying Lynch syndrome or associated with other cancer-predisposing genetic conditions or chronic inflammatory conditions. These tumors have a striking predilection for the distal colon, particularly the sigmoid colon and rectum and are much more likely to demonstrate adverse histologic factors, including signet ring cell differentiation, venous invasion, and perineural invasion.

Interfractional Uncertainty in the Treatment of Pancreatic Cancer With Radiation

PURPOSE To compare the interfractional variation in pancreatic tumor position using bony anatomy and implanted fiducial markers. METHODS AND MATERIALS Five consecutively treated patients with pancreatic adenocarcinoma who received definitive intensity-modulated radiation therapy at Stanford University (Stanford, CA) underwent fiducial seed placement and treatment on the Varian Trilogy system (Varian, Palo Alto, CA) with respiratory gating. Daily orthogonal kilovoltage imaging was performed to verify patient positioning, and isocenter shifts were made initially to match bony anatomy. Next, a final shift to the fiducial seeds was made under fluoroscopic guidance to confirm the location of the pancreatic tumor during the respiratory gated phase. All shifts were measured along three axes, left (+)-right (-), anterior (-)-posterior (+), and superior (+)-inferior (-), and the overall interfractional tumor movement was calculated based on these values. RESULTS A total of 140 fractions were analyzed. The mean absolute shift to fiducial markers after shifting to bony anatomy was 1.6 mm (95th percentile, 7 mm; range, 0-9 mm), 1.8 mm (95th percentile, 7 mm; range, 0-13 mm), and 4.1 mm (95th percentile, 12 mm; range, 0-19 mm) in the anterior-posterior, left-right, and superior-inferior directions, respectively. The mean interfractional vector shift distance was 5.5 mm (95th percentile, 14.5 mm; range, 0-19.3 mm). In 28 of 140 fractions (20%) no fiducial shift was required after alignment to bony anatomy. CONCLUSIONS There is substantial residual uncertainty after alignment to bony anatomy when radiating pancreatic tumors using respiratory gating. Bony anatomy matched tumor position in only 20% of the radiation treatments. If bony alignment is used in conjunction with respiratory gating without implanted fiducials, treatment margins need to account for this uncertainty.

Postchemoradiotherapy Positron Emission Tomography Predicts Pathologic Response and Survival in Patients With Esophageal Cancer

PURPOSE To correlate the prechemoradiotherapy (CRT) and post-CRT metabolic tumor volume (MTV) on positron emission tomography (PET) scanning with the pathologic response and survival in patients receiving preoperative CRT for esophageal cancer. MATERIALS AND METHODS The medical records of 37 patients with histologically confirmed Stage I-IVA esophageal cancer treated with CRT with or without surgical resection were reviewed. Of the 37 patients, 21 received preoperative CRT (57%) and 16 received definitive CRT (43%). All patients had a pre-CRT and 32 had a post-CRT PET scan. The MTV was measured on the pre-CRT PET and post-CRT PET scan, respectively, using a minimum standardized uptake value (SUV) threshold x, where x = 2, 2.5, 3, or the SUV maximum × 50%. The total glycolytic activity (TGA(x)) was defined as the mean SUV × MTV(x). The MTV ratio was defined as the pre-CRT PET MTV/post-CRT MTV. The SUV ratio was defined similarly. A single pathologist scored the pathologic response using a tumor regression grade (TRG) scale. RESULTS The median follow-up was 1.5 years (range, 0.4-4.9). No significant correlation was found between any parameters on the pre-CRT PET scan and the TRG or overall survival (OS). Multiple post-CRT MTV values and post-TGA values correlated with the TRG and OS; however, the MTV(2.5(Post)) and TGA(2.5(Post)) had the greatest correlation. The MTV(2) ratio correlated with OS. The maximum SUV on either the pre-CRT and post-CRT PET scans or the maximum SUV ratio did not correlate with the TRG or OS. Patients treated preoperatively had survival similar compared with those treated definitively with a good PET response (p = 0.97) and significantly better than that of patients treated definitively with a poor PET response (p < 0.0001). CONCLUSION The maximum SUV was not a predictive or prognostic parameter. The MTV(2.5) and TGA(2.5) were useful markers for predicting the response and survival on the post-CRT PET scan. The MTV(2) ratio also correlated with survival. Post-CRT PET can potentially guide therapy after CRT.

Postoperative outcomes following closed head injury and craniotomy for evacuation of hematoma in patients older than 80 years

OBJECT Advances in the management of trauma-induced intracranial hematomas and hemorrhage (epidural, subdural, and intraparenchymal hemorrhage) have improved survival in these conditions over the last several decades. However, there is a paucity of research investigating the relation between patient age and outcomes of surgical treatment for these conditions. In this study, the authors examined the relation between patient age over 80 years and postoperative outcomes following closed head injury and craniotomy for intracranial hemorrhage. METHODS A consecutive population of patients undergoing emergent craniotomy for evacuation of intracranial hematoma following closed head trauma between 2006 and 2009 was identified. Using multivariable logistic regression models, the authors assessed the relation between age (> 80 vs ≤ 80 years) and postoperative complications, intensive care unit stay, hospital stay, morbidity, and mortality. RESULTS Of 103 patients, 27 were older than 80 years and 76 patients were 80 years of age or younger. Older age was associated with longer length of hospital stay (p = 0.014), a higher rate of complications (OR 5.74, 95% CI 1.29-25.34), and a higher likelihood of requiring rehabilitation (OR 3.28, 95% CI 1.13-9.74). However, there were no statistically significant differences between the age groups in 30-day mortality or ability to recover to functional baseline status. CONCLUSIONS The findings suggest that in comparison with younger patients, patients over 80 years of age may be similarly able to return to preinjury functional baselines but may require increased postoperative medical attention in the forms of rehabilitation and longer hospital stays. Prospective studies concerned with the relation between older age, perioperative parameters, and postoperative outcomes following craniotomy for intracranial hemorrhage are needed. Nonetheless, the findings of this study may allow for more informed decisions with respect to the care of elderly patients with intracranial hemorrhage.

Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer

Aims To determine whether expression of Smad4, a tumour suppressor found to be absent in 10% of colorectal cancer (CRC), is associated with outcomes in patients with CRC. Methods Tumour samples from 241 consecutive patients with CRC who underwent upfront colon resection between 2005 and 2009 were obtained. Triplicate tissue cores from resected primary colon tumours and matched normal controls were used to construct the tissue microarrays (TMAs). We examined the expression of Smad4 using immunohistochemistry. Clinicopathological records were obtained for all patients. TMAs were reviewed by two pathologists and scored as either ‘positive’ or ‘negative’ for nuclear staining. In total, 21 of 241 tumours (8.6%) were Smad4 negative. Results Loss of Smad4 expression correlated with significantly worse overall survival (OS) (p=0.011) and disease-free survival (DFS) (p=0.024). Patients with loss of Smad4 expression had a median OS of 31 months compared with 89 months positive Smad4 expression. Loss of Smad4 remained significant on multivariate analysis for OS (p=0.0097). In patients with node-positive disease, loss of Smad4 predicts for worse DFS (p=0.012). In patients with metastatic and recurrent disease, Smad4 loss predicts for worse OS (p=0.012). Of the patients that received capecitabine over the course of their treatment, those with Smad4 loss (n=13) had significantly worse DFS (p=0.003) and OS (p=0.0007). Conclusions Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.

LEF-1 is frequently expressed in colorectal carcinoma and not in other gastrointestinal tract adenocarcinomas: an immunohistochemical survey of 602 gastrointestinal tract neoplasms.

LEF-1 is a DNA-binding protein that interacts with &bgr;-catenin and activates Wnt-responsive target genes. We analyzed the immunohistochemical expression of LEF-1 in 602 gastrointestinal and pancreatobiliary neoplasms in an attempt to (1) investigate the utility of LEF-1 immunohistochemistry as an ancillary marker in gastrointestinal/pancreatobiliary neoplasia, and (2) to perform a clinicopathologic and survival analysis of colorectal carcinoma stratified by LEF-1 expression. LEF-1 nuclear positivity was frequently identified in colorectal carcinoma (89/241, 37%) and only infrequently identified in other neoplasms: 11% esophagus/esophagogastric adenocarcinomas, 7% gastric adenocarcinomas, 1% pancreatic ductal adenocarcinomas, 4% pancreatic intraductal papillary mucinous neoplasms, and in no cases of appendiceal mucinous neoplasms or pancreatic mucinous cystic neoplasms. LEF-1 expression was identified in 35% of colorectal carcinomas that lacked CK20 and CDX2 expression. In colorectal carcinomas, LEF-1-positive tumors more frequently harbored KRAS mutations compared with LEF-1-negative tumors (39% vs. 16%, P=0.005). Patients with moderate/strong LEF-1-positive colorectal carcinoma had a trend of worse overall survival compared with patients with colorectal carcinomas with weak/negative LEF-1 expression (5 y overall survival, 31% vs. 47%, P=0.15). In conclusion, LEF-1 is most commonly expressed in colorectal carcinoma and infrequently observed in the upper gastrointestinal tract and pancreatic adenocarcinoma. LEF-1 Immunohistochemistry may be especially useful as an ancillary diagnostic marker in colorectal carcinomas, which lack the expression of both CK20 and CDX2. LEF-1 expression is associated with the presence of KRAS mutations and may have prognostic value as a trend of worse overall survival is seen in patients with LEF-1-positive colorectal carcinoma.

Immune Reconstitution Inflammatory Syndrome in Patients with AIDS and Disseminated Coccidioidomycosis: A Case Series and Review of the Literature:

Coccidioidomycosis causes substantial morbidity and mortality in endemic areas, and dissemination is frequent in patients with impaired cellular immunity such as AIDS. Immune reconstitution inflammatory syndrome (IRIS) is paradoxical clinical worsening after initiation of antiretroviral therapy (ART) in a patient with HIV and a simultaneous opportunistic infection (OI). Immune reconstitution inflammatory syndrome has been well described for a host of mycobacterial, viral, and fungal OIs and malignancies such as Kaposi sarcoma. To date, only 3 cases of IRIS due to coccidioidomycosis have been reported in the literature. At our institution, we report 4 cases of IRIS in HIV-infected patients with disseminated coccidioidomycosis. Unfortunately, all 4 patients died of worsening coccidioidal infection after initiating ART. The optimal timing of ART in patients with AIDS and coccidioidomycosis remains to be elucidated.

Sex disparities in postoperative outcomes after neurosurgical intervention: findings from the UMEND project.

BACKGROUND: Little is known about the relationship between sex and the risk of complications after neurosurgical intervention. Improved understanding of this relationship may assist clinicians in advising patients of the risks and benefits of neurosurgical intervention and managing their patients after surgery. OBJECTIVE: To determine the independent relationship between sex and morbidity after neurosurgical intervention. METHODS: Data were collected for 918 neurosurgical cases at the University of Michigan Hospitals. Bivariate &khgr;2 tests and analysis of variance were used to assess relationships between sex, demographics, case type, medical comorbidities, postoperative complication risk, and postoperative hospital and intensive care unit stay. We fit a multivariable logistic regression model of 30-day complication risk by sex adjusted for potential confounders and used multifactor analysis of variance to assess the relationship between sex and hospital as well as intensive care unit stay, adjusted for potential confounders. RESULTS: The percentages of patients experiencing complications within 30 days of surgery were 20.3% for male and 11.3% for female patients. In multivariable regression models, male sex predicted postoperative complications compared with female sex (odds ratio: 2.0, 95% confidence interval: 1.4-3.0). By multifactor analysis of variance, male sex was associated with longer hospital stay (P < .01), but was not associated with neurosurgical intensive care unit stay. CONCLUSION: Our findings suggest male sex is an independent predictor of postoperative complication risk and increased hospital stay after neurosurgical intervention. This finding may be used clinically to help identify those patients at increased risk of a complicated recovery. Future research might consider mechanisms relating sex and postoperative outcomes.

Abstract 2068: A genome-wide siRNA screen reveals various modulators of the IRE1-XBP-1 signaling branch of the unfolded protein response

The unfolded protein response (UPR) is an essential cellular mechanism orchestrating endoplasmic reticulum (ER) homeostasis under various cytotoxic stresses. Dysregulation of the UPR signaling pathways is linked to multiple human diseases, including cancer. The inositol requiring kinase 1 (IRE1)-X-box binding protein 1 (XBP-1) pathway is the most evolutionarily conserved signaling branch of the UPR. When activated, the endoribonuclease activity of the IRE1 cleaves the XBP-1 mRNA and generates a spliced form of XBP-1 which transcriptionally regulates cell metabolism, proliferation, survival and apoptosis. Here, we employed a genome-wide siRNA screen to systematically identify genes modulating the IRE1-XBP-1 signaling pathway of the UPR. We induced cellular ER stress with bortezomib, a proteasome inhibitor, and monitored the expression of XBP-1-luciferase fusion protein in which luciferase is fused in-frame with the spliced form of XBP-1. We identified over 100 of genes whose downregulation results in inhibition of bortezomib-induced XBP-1 splicing. These genes include diverse subsets of proteins that are involved in mRNA processing, transcription, cell cycle regulation and cell proliferation and differentiation. Furthermore, the screen reveals a connection of several oncogenes and tumor suppressors, such as Myc, Akt and cyclin K, to the UPR, underlining the important role of the IRE1-XBP-1 signaling branch in human cancers. In summary, our data suggest that the UPR is tightly connected with previously unappreciated pathways regulating various cellular processes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2068. doi:10.1158/1538-7445.AM2011-2068