Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next-Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers.

Next-generation Sequencing (NGS) of cancer tissues is increasingly being carried out to identify somatic genomic alterations that may guide physicians to make therapeutic decisions. However, a single tissue biopsy may not reflect complete genomic architecture due to the heterogeneous nature of tumors. Circulating tumor DNA (ctDNA) analysis is a robust noninvasive method to detect and monitor genomic alterations in blood in real time. We analyzed 28 matched tissue NGS and ctDNA from gastrointestinal and lung cancers for concordance of somatic genomic alterations, driver, and actionable alterations. Six patients (21%) had at least one concordant mutation between tissue and ctDNA sequencing. At the gene level, among all the mutations (n = 104) detected by tissue and blood sequencing, 7.7% (n = 8) of mutations were concordant. Tissue and ctDNA sequencing identified driver mutations in 60% and 64% of the tested samples, respectively. We found high discordance between tissue and ctDNA testing, especially with respect to the driver and actionable alterations. Both tissue and ctDNA NGS detected actionable alterations in 25% of patients. When somatic alterations identified by each test were combined, the total number of patients with actionable mutations increased to 32%. Our data show significant discordance between tissue NGS and ctDNA analysis. These results suggest tissue NGS and ctDNA NGS are complementary approaches rather than exclusive of each other. When performed in isolation, tissue and ctDNA NGS can each potentially miss driver and targetable alterations, suggesting that both approaches should be incorporated to enhance mutation detection rates. Larger prospective studies are needed to better clarify this emerging precision oncology landscape. Mol Cancer Ther; 17(5); 1123-32. ©2018 AACR.

Transarterial chemoembolization is ineffective for neuroendocrine tumors metastatic to the caudate lobe: a single institution review.

BACKGROUND: Caudate lobe liver metastases occur commonly in patients with neuroendocrine tumors. It is unknown, however, how these lesions respond to regional therapy and how their presence impacts outcomes. We reviewed our experience treating these lesions using transarterial chemoembolization (TACE). METHODS: We reviewed radiographic response to TACE in 86 patients with metastatic neuroendocrine tumors to the liver. We determined the impact of caudate lesions on outcomes in comparison to the cohort of patients without caudate lesions, as well as response of caudate lesions to TACE versus lesions elsewhere in the liver. RESULTS: Caudate lesions were identified in 45 (52%) patients. All patients had disease in other liver segments. Only seven caudate lesions (12.3%) had a radiographic response to TACE, whereas 82% of lesions elsewhere in the liver demonstrated a response. The presence or absence of a caudate lesion did not impact the overall radiographic (82.2% vs. 82.9%), symptomatic (64.4% vs. 56.1%), or biochemical (97.6% vs. 88.9%) response to TACE (P > 0.1 for all). However, median overall survival was reduced in those presenting with caudate lesions (87.1 vs. 45.6 months, P = 0.031). CONCLUSIONS: Metastatic neuroendocrine tumors to the caudate lobe respond poorly to TACE. Symptomatic or threatening caudate lobe lesions should be considered for palliative resection in spite of additional inoperable liver metastases.

An indeterminate nodule in the cirrhotic liver discovered by surveillance imaging is a prelude to malignancy.

BACKGROUND: Surveillance imaging often shows indeterminate lesions in the cirrhotic liver, which may represent early hepatocellular carcinoma (HCC), dysplastic or regenerative nodules, or vascular shunts. The risk of HCC after identification of an indeterminate nodule is not well described. METHODS: We identified 252 patients with cirrhosis and at least one indeterminate nodule discovered on surveillance imaging over a 4-year period. The incidence of HCC development within 2 years of nodule identification was measured along with baseline risk factors associated with developing HCC. RESULTS: The incidence of HCC in this population was 21% (53 of 252), and risk factors associated with HCC included chronic viral hepatitis, male gender, and low platelet count. The median time from identification of an indeterminate nodule to diagnosis of HCC was 2.7 months. Patients with indeterminate nodules who developed HCC were more likely have to have an indeterminate nodule with arterial enhancement. CONCLUSIONS: The 2-year incidence of HCC in the setting of cirrhosis and an indeterminate nodule discovered by surveillance imaging may be as high as one in five persons. Early follow-up imaging, biopsy, or empiric treatment should be considered for those at higher risk. Further, this population is well suited for early detection biomarker and chemoprevention studies.

Extrahepatic disease should not preclude transarterial chemoembolization for metastatic neuroendocrine carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) is often utilized for patients with inoperable neuroendocrine carcinoma liver metastases. Often, metastatic disease is not limited to the liver. The impact of extrahepatic disease (EHD) on outcomes and response after TACE has not been described. METHODS: We reviewed 192 patients who underwent TACE for large hepatic tumor burden, progression of liver metastases, or poorly controlled carcinoid syndrome due to neuroendocrine carcinoma. Demographics, clinicopathologic characteristics, response to TACE, complications, and survival were compared between patients with (n = 123) and without (n = 69) EHD. RESULTS: Demographics, histopathologic characteristics, and complications were similar between groups. As well, those with and without EHD had similar biochemical (85 vs. 88 %) and radiographic response (76 vs. 79 %) to TACE (all p = NS); however, symptomatic responses were improved in those with EHD (79 vs. 60 %, p = 0.01). The group without EHD had better overall survival compared to those with EHD disease at the time of TACE (median 62 vs. 28 months, p = 0.001). DISCUSSION: Although patients with EHD from neuroendocrine carcinoma experience shorter overall survival after TACE compared to those without EHD, they had similar symptomatic, biochemical, and radiographic response to TACE. Meaningful response to TACE is still possible in the presence of EHD and should be considered, particularly in those with carcinoid syndrome.

Concomitant dysregulation of microRNAs miR-151-3p and miR-126 correlates with improved survival in resected cholangiocarcinoma.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding genes which become dysregulated in cancer and may predict survival. The role of miRNAs in outcomes in cholangiocarcinoma (CC) has not been reported. METHODS: RNA was extracted from 32 resected CCs along with adjacent uninvolved bile duct epithelium. A total of 43 miRNAs were quantified using NanoString™. Clinicopathologic characteristics and outcomes were captured and compared. Overall survival curves were created using the Kaplan-Meier method; factors, including miRNA expression, were compared by log-rank, chi-squared or Cox regression analyses. RESULTS: Absolute expression of each miRNA was compared with overall survival after excluding perioperative deaths (n= 3). One upregulated (miR-151-3p; P= 0.003) and one downregulated (miR-126; P= 0.023) miRNA in resected CC relative to adjacent normal bile duct epithelium correlated with survival on univariate analysis. Clinical factors and these miRNAs were compared. Dysregulated miR-151-3p and miR-126, respectively, were the only factors that correlated with improved overall survival [41.5 months vs. 12.3 months (P= 0.002) and 21.9 months vs. 15.1 months (P= 0.02), respectively]. In eight patients, both miRNAs were dysregulated. In the remainder, only one or neither showed dysregulation. Concomitant dysregulation correlated with the best overall survival (58.7 months vs. 15.1 months; P < 0.000; n= 8); clinicopathologic factors in these groups were otherwise similar. CONCLUSIONS: In resected CC, the concomitant dysregulation of both miR-151-3p and miR-126 was the factor related to the greatest improvement in overall survival. Further analysis of the targets of these miRNAs may yield potential therapeutic targets or prognostic biomarkers.

Inflammatory markers are associated with outcome in patients with unresectable hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND: The serum neutrophil-lymphocyte ratio (NLR) is associated with outcomes in several solid organ cancers, including hepatocellular carcinoma (HCC). METHODS: We reviewed our experience in patients with HCC who underwent transarterial chemoembolization (TACE) as the initial treatment. Serum complete blood counts were used to calculate the NLR before and after TACE. The Kaplan-Meier method was used to determine survival and significant differences between groups by the log-rank test. RESULTS: There were 103 patients identified who underwent TACE for HCC. The median age was 60.5 years. Median overall survival was 12.6 (95% confidence interval 8.3-17) months. Median survival in patients with a high preprocedural NLR was 4.2 months compared to 15 months in those with a normal NLR (p = 0.021). In those whose NLR either rose 1 month after treatment or remained elevated, survival was worse compared to those who normalized or remained normal (18.6 vs. 10.6 months, p = 0.026). The same was true at 6 months (21.3 vs. 9.5 months, p = 0.002). An unresponsive NLR was associated with very poor outcome (median survival 3.7 months). Multivariate analysis of clinicopathologic factors showed that presence of extrahepatic disease and high NLR were independent factors associated with worse survival. CONCLUSIONS: Our study demonstrates that periprocedural trends of serum NLR are associated with outcome in unresectable HCC undergoing TACE. Serum NLR is easy to calculate from a routine complete blood count with differential. Along with liver function, serum NLR may be helpful to clinicians in providing prognostic information and monitoring response to therapy.

Perioperative mortality in patients with myelodysplastic syndrome.

INTRODUCTION: Myelodysplastic syndrome (MDS) is a conglomerate of diseases in which bone marrow-derived cells die before or shortly after entering circulation. We sought to define the perioperative mortality in MDS patients. METHODS: We reviewed our experience of all persons treated for MDS at our institution over the past 15 years. Demographic and survival information were collected, and those who underwent any procedure requiring general anesthesia were defined as the operative subgroup. RESULTS: Of 169 patients identified, 39 (23%) were in the operative subgroup. The median survival was 17.8 months. The mortality rate for the operative group was 23% (N = 9) and 30.8% (N = 12) at 30 and 60 days post-procedure. Twenty-three patients (59%) had an urgent/emergent indication for operation, which was associated with higher 60-day mortality (N = 12, 48%) compared to those with elective indications (N = 1, 7%) (P = 0.037, Chi-square). Several other factors (age, gender, International Prognostic Score, MDACC score, and major/minor procedure type) were not associated with perioperative mortality. CONCLUSION: Outcomes in MDS patients are poor with expected survival less than 2 years and high postoperative mortality in the setting of urgent/emergent operations. While maybe not prohibitive, we believe it is an imperative part of the informed consent process particularly for urgent/emergent procedures.

Repeat hepatectomy for metastatic colorectal cancer is safe but marginally effective.

BACKGROUND: Although hepatectomy for metastatic colorectal cancer (mCRC) offers prolonged survival in up to 40% of people, recurrence rates are high, approaching 70%. Many patients experience recurrent disease in the liver after initial hepatectomy. We examined our experience with repeat hepatectomy for mCRC. METHODS: After Institutional Review Board approval, we reviewed the records of all patients at a single institution who underwent hepatectomy for mCRC. Repeat hepatectomy was defined as partial liver resection any time after the initial hepatectomy for recurrent mCRC. We estimated time to recurrence and survival by using the Kaplan-Meier method and compared outcomes between groups by using the log-rank test. RESULTS: From 1998 to 2008, 405 patients underwent hepatectomy for mCRC, and 215 (53%) experienced disease recurrence at a median of 13 months. Of 150 patients with liver-only or liver-predominant recurrence, 52 (35%) underwent repeat hepatectomy. The median time to recurrence after repeat hepatectomy was 10 months, and median overall survival was 19 months. There was one (1.9%) perioperative death, and there were 14 (27%) major complications. The median overall survival in the repeat hepatectomy group from the time of recurrence after initial hepatectomy was 22 months, compared with 15 months in the 98 patients with liver recurrence who were not selected for repeat hepatectomy (P=0.02). CONCLUSIONS: Repeat hepatectomy for mCRC is feasible in highly selected patients, with acceptable perioperative morbidity and mortality. Although repeat hepatectomy should be considered, recurrence rates are high. Although the initial hepatectomy for mCRC is potentially curative, recurrence of metastatic disease in the liver is unlikely to be cured.

Occult Breast Cancer Presenting as Leptomeningeal Carcinomatosis.

Leptomeningeal carcinomatosis (LC) is a rare and devastating metastatic manifestation of both liquid and solid tumors consisting of dissemination of malignant cells with invasion into the meninges. Few options exist in most clinical situations, especially when LC is the presenting sign of occult malignancy. The prognosis is often poor with limited survival. Aims of palliation must be considered the primary goal for most patients. We report a case in which occult metastatic breast cancer presented with neurological symptoms from LC. We discuss diagnosing the primary malignancy when LC is the presenting manifestation as well as treatment, both palliative and cytoreductive. We also focus on those patients with breast cancer that are at highest risk of developing LC.

Single-incision laparoscopic colectomy for malignant disease.

BACKGROUND: Laparoscopic colectomy has been shown to confer equivalent disease-free and overall survival compared to traditional open colectomy. Patients experience benefit in length of hospital stay as well as diminished narcotic use. Single-incision laparoscopic colectomy (SIL-C) may offer additional benefit compared to traditional laparoscopic colectomy without compromising oncologic principles. METHODS: We retrospectively reviewed records of patients who underwent SIL-C and traditional laparoscopic colectomy (TLC) for potentially malignant and malignant disease performed by a single surgeon. SIL-C consisted of a single-port access device with traditional lateral-to-medial laparoscopic technique. RESULTS: Between January and October 2009, 27 SIL-C procedures were performed. Forty-six TLC patients from the prior year were used as controls. Median age was 70 years and 54% were female, with no differences between the groups. The median body mass index (BMI) was 27 kg/m(2) (range = 18.3-39.9) and 26 kg/m(2) (16.6-71.4) for SIL-C and TLC, respectively. The median lymph node harvest was 15 (range = 3-32) and 17 (0-35) for SIL-C and TLC, respectively. The median operative time was 114 min (range = 59-268) and 135 min (45-314) for SIL-C and TLC, respectively. Five SIL-C required additional ports while six TLC required conversion to open technique. The median length of stay was 3 days (range = 2-17) and 5 days (range = 2-11) for SIL-C and TLC, respectively (p = 0.079). There were five significant postoperative complications in the SIL-C group and 16 in the TLC group, including four postoperative ileus and one leak. There were no postoperative deaths in the SIL-C group and two in the TLC group. CONCLUSIONS: SIL-C can be used safely in selected colon cancer patients with no difference in blood loss, OR time, or lymph node retrieval. SIL-C patients may have a shorter LOS.

Mixed ductal-endocrine carcinoma of the pancreas with synchronous papillary carcinoma-in-situ of the common bile duct: a case report and literature review--synchronous pancreatic and bile duct tumors.

This report is a case of a 58-year-old woman with a mixed ductal-endocrine carcinoma of the pancreas and a synchronous carcinoma-in-situ of the common bile duct. She presented with intractable itching from obstructive jaundice. Magnetic resonance imaging scan showed dilated intrahepatic biliary and common bile ducts. Endoscopic retrograde cholangiopancreatography revealed an ulcerated lesion of the ampulla. Biopsies from this lesion showed adenocarcinoma. Subsequently, pancreatoduodenectomy was performed for the diagnosis of peri-ampullary carcinoma. Gross examination revealed a 2-cm irregular, ulcerated lesion obstructing the distal 0.5 cm of the common bile duct within the head of the pancreas. On histopathological examination, it was discovered that this lesion contained two separate neoplasms: papillary carcinoma-in-situ of the intraparenchymal portion of the common bile duct and a mixed ductal-endocrine carcinoma of the pancreas. Mixed ductal-endocrine carcinoma of the pancreas is very rare. Finding it in conjunction with a synchronous, overlying papillary carcinoma carcinoma-in-situ of the common bile duct has not been previously described.

The effects of race and age on axillary lymph node involvement in breast cancer patients at a Midwestern safety-net hospital.

BACKGROUND: Black and premenopausal patients have been shown to have poorer stage for stage survival than the overall population. The purpose of this study was to define the effects of age and race on axillary lymph node involvement at a Midwestern safety-net hospital. The hypothesis was that black patients under the age of 50 would be found to have increased rates of axillary involvement in breast cancer. METHODS: A retrospective case review was performed of 184 breast cancer patients from 2000 to 2005. Statistical analysis was performed by race and age. Patients under 50 years of age were defined as premenopausal. RESULTS: The overall rate of axillary involvement was 47.8%. Black patients had an overall rate of axillary involvement of 52.9%. However, premenopausal black patients had a 70.8% rate of axillary involvement (P < .05). Premenopausal white patients had a 46.3% rate of axillary involvement. Logistic regression analysis was performed, and premenopausal age and tumor size were found to be independent predictors of positive lymph node status in black patients. CONCLUSION: In our study, premenopausal black patients had a much higher rate of axillary lymph node involvement than any other group. This finding was consistent even when tumor size was taken into account. More research needs to be done to better define this difference and to detect this disease at an earlier stage.