An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone). CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

Gastroduodenal Artery Pseudoaneurysm Causing Obstructive Jaundice.

Background: Visceral artery aneurysms and pseudoaneurysms are uncommon phenomena with a high mortality rate in cases of rupture. These rare vascular pathologies are usually asymptomatic and are therefore generally discovered incidentally on computed tomography or magnetic resonance imaging examination. Current therapeutic options have trended toward a minimally invasive approach because of evolving endovascular treatment options, with open operations typically reserved for cases of intraabdominal hemorrhage. Case Report: We describe a case of gastroduodenal artery pseudoaneurysm manifesting as obstructive jaundice and pancreatitis because of extrahepatic compression of the common bile duct and pancreatic duct by mass effect. Open repair was ultimately required secondary to arterial anatomy that was not amenable to any endovascular treatment approach. Conclusion: While endovascular options are the preferred treatment modality for visceral artery aneurysms and pseudo-aneurysms, some cases require definitive open repair for a variety of reasons, including unsuitable anatomy.

15-Year Experience with Multimodality Therapy Including Esophagectomy for Elderly Patients with Locoregional Esophageal Cancer.

BACKGROUND: Optimal curative therapy for locally advanced esophageal and esophagogastric junction (EGJ) cancer might not be offered to elderly patients due to patient and treating physician perception of the high risk of therapy. To understand the risk of multimodality curative therapy, including surgical resection in the elderly population, we studied our experience with curative therapy in this patient population and compared the risks and outcomes with those in a younger population. STUDY DESIGN: Between January 1, 2004 and December 31, 2019, four hundred and five consecutive patients with esophageal or EGJ cancer underwent primary treatment at our institution, including esophagectomy. Data collected included demographic information, tumor stage, preoperative Charlson Comorbidity Index scores, treatment variables, and short- and long-term outcomes. Patients who were 70 years or older were classified as the "older" group and patients younger than 70 years were "younger." RESULTS: One hundred and eighty-eight younger (mean age 59 years) and 94 older (mean age 74 years) patients received neoadjuvant chemoradiotherapy and surgical resection for stage II and higher cancer. Preoperative American Society of Anesthesiologist and Charlson Comorbidity Index scores were significantly worse in the older group. Postoperative atrial fibrillation and urinary retention developed more often in the older group. Despite this, the rate of postoperative Clavien-Dindo complication severity scores of 3 or higher, perioperative mortality rates, and lengths of stay were similar. Long-term age-adjusted survival rate was 44.8% at 5 years for the group 70 years or older and 39% for the group younger than 70 years (NS). CONCLUSIONS: Patients 70 years and older with locally advanced esophageal or EGJ cancer should be evaluated for optimal curative therapy including neoadjuvant chemoradiotherapy and surgical resection. Although preoperative risk scoring and postoperative atrial arrythmias are higher in the older group, short- and long-term outcomes are not inferior in these patients.

Multiagent neoadjuvant chemotherapy and tumor response are associated with improved survival in pancreatic cancer.

BACKGROUND: Neoadjuvant therapy (NT) for borderline resectable pancreatic cancer (BRPC) has evolved to include multi-agent regimens and chemoradiation. We report our experience and compare outcomes of initially resectable pancreatic cancer (IRPC) vs BRPC receiving NT across two eras of chemotherapy regimens. METHODS: Data were collected retrospectively on pancreaticoduodenectomy patients between January 2008 and October 2015. Outcomes and survival were compared based on patient, laboratory and treatment factors. RESULTS: 195 patients were included and 133 had IRPC and 62 BRPC. IRPC operations were shorter (449 min vs 520 min, p = 0.003), had less blood loss (663 ml vs 954 ml, p = 0.002) and involved fewer vascular resections (29% vs 76%, p = 0.002). The rate of R0 resection was identical (82%, p = 1) and the IRPC group had higher node-positive ratio (19.3% vs 7.2% p < 0.0001). 15 patients received a single agent regimen while 47 received multi-agent regimens with 90% receiving radiation.Survival was similar between BRPC and IRPC (log-rank p = 0.7). Histopathologic response (CAP grade 0 or 1) was not associated with survival (p = 0.13), but completion of ≥4 cycles of multi-agent pre-operative chemotherapy (p = 0.001) and complete response to NT (p = 0.04) were significant predictors of survival. CONCLUSIONS: BRPC patients treated with NT have similar morbidity and survival to their IRPC counterparts. Pathologic response and modern NT are associated with improved survival.

Long-Term Cancer Outcomes From Study NRG Oncology/RTOG 9517: A Phase 2 Study of Accelerated Partial Breast Irradiation With Multicatheter Brachytherapy After Lumpectomy for Early-Stage Breast Cancer.

PURPOSE: To examine 10-year rates of local, regional, and distant recurrences, patterns of recurrence, and survival rates for breast cancer patients enrolled on Study NRG Oncology/Radiation Therapy Oncology Group 9517, a multi-institutional prospective trial that studied one of the earliest methods of accelerated partial breast irradiation (APBI), multicatheter brachytherapy (MCT). METHODS AND MATERIALS: Eligibility included stage I/II unifocal breast cancer <3 cm in size after lumpectomy with negative surgical margins and 0 to 3 positive axillary nodes without extracapsular extension. The APBI dose delivered was 34 Gy in 10 twice-daily fractions over 5 days for high-dose-rate (HDR); and 45 Gy in 3.5 to 5 days for low-dose-rate (LDR) brachytherapy. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on long-term ipsilateral breast recurrence (IBR), contralateral breast cancer events (CBE), regional recurrence (RR), and distant metastases (DM), disease-free, and overall survival. RESULTS: The median follow-up was 12.1 years. One hundred patients were accrued from 1997 to 2000; 98 were evaluable; 65 underwent HDR and 33 LDR MCT. Median age was 62 years; 88% had T1 tumors; 81% were pN0. Seventy-seven percent were estrogen receptor and/or progesterone receptor positive; 33% received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 4 isolated IBRs and 1 IBR with RR, for 5.2% 10-year IBR without DM. There was 1 isolated RR, 1 with IBR, and 1 with a CBE, for 3.1% 10-year RR without DM. The 10-year CBE rate was 4.2%, with 5 total events. Eleven patients have developed DM, 8 have died of breast cancer, and 22 have died from other causes. The 10-year DFS and OS rates are 69.8% and 78.0%, respectively. CONCLUSION: This multi-institutional, phase 2 trial studying MCT-APBI continues to report durable in-breast cancer control rates with long-term follow-up.

Planned delay of oral intake after esophagectomy reduces the cervical anastomotic leak rate and hospital length of stay.

Cervical anastomotic leak rates are high after esophagectomy. We examined the effect of a purposeful delay in institution of oral diet after esophagectomy on the leak rate and hospital length of stay. A retrospective analysis of 120 patients submitted to esophagectomy with cervical esophagogastric anastomosis was conducted. Eighty-seven resumed diet within 7 days of surgery (early eaters), and 33 had delayed diet until a mean of 12 days after surgery (late eaters). Mean age was 62.3 years; 98 patients were male. One hundred one resections were for cancer, and 49 % of cancer patients received neoadjuvant therapy. The overall leak rate was 17.5 %, and hospital length of stay was 10.9 days. Anastomotic leak rate was 3 % for late eaters versus 23 % for early eaters (OR of 9.57, p = 0.010). Hospital length of stay was 6 days for late eaters versus 11.8 days for early eaters (p < 0.001). Anastomotic leak was significantly associated with increased length of stay (p < 0.001), adding an average of 7.6 days to hospital stay. Respiratory complications (p < 0.001) and delayed gastric emptying (p = 0.014) were also independent predictors of increased length of stay, but early eater status was not. Delayed resumption of oral diet after esophagectomy significantly reduces cervical anastomotic leak rate and avoids the increased length of stay associated with leak.

The evolution in management of patients with subcentimeter, node-negative, triple-negative breast cancer.

BACKGROUND: The aim of this study was to determine the evolution in treatment recommendations and outcomes for patients with subcentimeter, node-negative, triple-negative disease. METHODS: Patients were divided into a remote (diagnosed from 1997 to 2003) and a recent (diagnosed from 2004 to 2011) group. Demographics, tumor size, surgical treatment, use of adjuvant chemotherapy, survival, and disease recurrence were evaluated. RESULTS: Thirty patients were placed in the remote group and 31 in the recent group. Demographics, tumor sizes, and surgical treatment were similar between groups. The use of adjuvant chemotherapy increased from 7% to 42% in the recent group (P < .002). Disease-free survival and recurrence (7%) was not influenced by the use of chemotherapy. CONCLUSIONS: This study demonstrates that adjuvant chemotherapy is increasingly used in patients with the triple-negative phenotype, regardless of other favorable prognostic variables. The value of adjuvant chemotherapy for the subgroup of patients in our study is unclear and mandates further investigation.

Use of a sestamibi-only approach to routine minimally invasive parathyroidectomy.

We performed this study to compare a sestamibi-only radio-guided approach (MIBI) versus using intraoperative parathyroid hormone monitoring (IOPTH) in the performance of minimally invasive parathyroidectomy (MIP) in patients with a clearly positive preoperative sestamibi scan from January 2000 to June 2010. Five of 81 patients in the MIBI group required additional surgery, three at the time of MIP when the intraoperative findings were in conflict with the preoperative sestamibi scan and two required a second operation as a result of an undiscovered second adenoma. In the IOPTH group, five patients had an unnecessary bilateral neck exploration as a result of an inadequate drop in PTH levels, whereas six had their disease cured because the PTH levels predicted additional pathology. One patient in the IOPTH group remains hypercalcemic and represents the only surgical failure in this study. The MIBI group had a shortened operating room time and less cost (P < 0.001). No deaths or complications, including recurrent laryngeal nerve injuries, occurred in this study. Although both strategies are effective in managing hyperparathyroidism, a MIBI-only approach is less expensive and has shorter operative times with an occasional need for reoperation, whereas the IOPTH group results in more extensive surgery that will occasionally be unnecessary.

Hepatic arterial infusion and systemic chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic to the liver: a North Central Cancer Treatment Group (NCCTG) phase II study, 92-46-52.

BACKGROUND: Patients with multiple liver metastases from colorectal cancer are at high risk of recurrence after resection. Hepatic artery infusion (HAI) alternating with systemic therapy after surgical resection may improve survival after surgery. METHODS: Patients with liver-only metastases from colorectal cancer amenable to resection/cryoablation were eligible. Previous adjuvant chemotherapy for a completely resected primary tumor was allowed. Alternating courses of HAI and systemic therapy included floxuridine (FUDR) by HAI. Systemic chemotherapy consisted of bolus leucovorin (LV) plus 5-fluorouracil (5-FU). RESULTS: Forty-nine patients had complete resection of their liver metastases, with 44% having more than 4 hepatic metastases and 78% having bilobar disease. Thirty-six patients had HAI FUDR alternating with systemic therapy. Patients received a median of 3.5 cycles (range, 1-4) and 3 cycles (range, 0-6) of therapy with HAI FUDR and systemic therapy, respectively. At the time of final analysis the estimated median disease-free survival and hepatic disease-free survival was 1.2 years (95% confidence interval [CI], 0.9-2.1) and 1.8 years (95% CI, 1.8-not available), respectively. Eleven patients (31%) were alive at this writing. All surviving patients had a minimum of 5.5 years of follow-up. CONCLUSION: This trial of adjuvant chemotherapy in patients who underwent complete resection with unfavorable characteristics demonstrates apparent improvement in outcome compared with historical series treated with surgery alone. However the results of this trial and other randomized trials of HAI do not appear to support its use at this time because of the development of more effective systemic options.

Postgastrectomy syndromes.

The first postgastrectomy syndrome was noted not long after the first gastrectomy was performed. The indications for gastric resection have changed dramatically over the past 4 decades, and the overall incidence of gastric resection has decreased. This article focuses on the small proportion of patients with severe, debilitating symptoms; these symptoms can challenge the acumen of the surgeon who is providing the patient's long-term follow-up and care. The article does not deal with the sequelae of bariatric surgery.

Extracorporeal gastric stapling reduces the incidence of gastric conduit failure after minimally invasive esophagectomy.

Esophageal cancer resection is associated with significant morbidity and mortality. To date, no standardized technique exists. In this study, we analyze our short-term results in 92 minimally invasive resections performed over the past 10 years in an attempt to identify technical factors, which contribute to improved short-term outcomes. A retrospective review of 92 minimally invasive esophagectomies was performed at the Ochsner Clinic Foundation from 1999 through 2009. Data collected included preoperative stage, whether or not preoperative chemoradiation was used, technique of minimally-invasive resection, technique of esophagogastric anastomosis, margin status, anastomotic leak, conduit necrosis, gastric conduit failure of any type, and operative mortality. Gastric stapling was done either laparoscopically (intracorporeal) or through a minilaparotomy (extracorporeal). Ninety-two patients met criteria for this study. There was a significant difference in the incidence of positive gastric margins (P = 0.04), anastomotic leak (P = 0.045), conduit necrosis (P = 0.03), and any gastric conduit failure (P = 0.02) favoring the extracorporeal group. The overall short-term morbidity and operative mortality with minimally invasive esophagectomy is comparable to the results obtained with open techniques. A relatively simple modification of the operative technique-performing extracorporeal stapling of the gastric conduit-led to a significant reduction in the incidence of gastric conduit failures when compared with the intracorporeal stapling technique.

Alternating systemic and hepatic artery infusion therapy for resected liver metastases from colorectal cancer: a North Central Cancer Treatment Group (NCCTG)/ National Surgical Adjuvant Breast and Bowel Project (NSABP) phase II intergroup trial, N9945/CI-66.

PURPOSE Prior trials have shown that surgery followed by hepatic artery infusion (HAI) of floxuridine (FUDR) alternating with systemic fluorouracil improves survival rates. Oxaliplatin combined with capecitabine has demonstrated activity in advanced colorectal cancer. Based on this observation a trial was conducted to assess the potential benefit of systemic oxaliplatin and capecitabine alternating with HAI of FUDR. The primary end point was 2-year survival. PATIENTS AND METHODS Patients with liver-only metastases from colorectal cancer amenable to resection or cryoablation were eligible. HAI and systemic therapy was initiated after metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m(2)/d FUDR and dexamethasone, day 1 through 14 weeks 1 and 2. Systemic therapy included oxaliplatin 130 mg/m(2) day 1 with capecitabine at 1,000 mg/m(2) twice daily, days 1 through 14, weeks 4 and 5. Two additional 3-week courses of systemic therapy were given. Capecitabine was reduced to 850 mg/m(2) twice daily after interim review of toxicity. Results Fifty-five of 76 eligible patients were able to initiate protocol-directed therapy and completed median of six cycles (range, one to six). Three postoperative or treatment-related deaths were reported. Overall, 88% of evaluable patients were alive at 2 years. With a median follow-up of 4.8 years, a total of 30 patients have had disease recurrence, 11 involving the liver. Median disease-free survival was 32.7 months. CONCLUSION Alternating HAI of FUDR and systemic capecitabine and oxaliplatin met the prespecified end point of higher than 85% survival at 2 years and was clinically tolerable. However, the merits of this approach need to be established with a phase III trial.

5-year follow-up after sentinel node mapping for breast cancer demonstrates better than expected treatment outcomes.

We conducted this study to provide one of the initial assessments of treatment outcomes for breast cancer patients evaluated with sentinel node mapping. All patients diagnosed with breast carcinoma, evaluated with sentinel node mapping, and followed for 5 years were divided into three groups depending on sentinel node(s) status. Group I (node negative) included 91 patients, 77 with invasive cancer, and 7 lost to follow-up. Of the remaining 70 patients, 3 (4.3%) suffered a distant recurrence and died, 1 developed an in-breast recurrence, and 9 (12.9%) developed a contralateral cancer during the study. Group II (IHC positive) included 28 patients. One (3.6%) developed a distant recurrence and died of breast cancer, and one developed a contralateral cancer during follow. Group III (H&E positive) included 36 patients with 1 lost to follow-up. Five patients (14.3%) died of breast cancer and two (5.7%) developed contralateral carcinomas during follow-up. The most striking observation was a lower than expected rate of distant recurrences in these patients followed for 5 years after a diagnosis of breast cancer and staging with sentinel node mapping. The ability to identify subtle nodal metastasis and design appropriate systemic therapeutic strategies may explain this finding.

Initial experience with surgical treatment planning in the newly diagnosed breast cancer patient at high risk for BRCA-1 or BRCA-2 mutation.

Despite an abundance of information available for dealing with patients with BRCA-1 and BRCA-2 mutations, little guidance is available to assist the surgeon in dealing with the genetically high-risk patient recently diagnosed with breast cancer. A retrospective review was undertaken of 170 patients who underwent genetic counseling and testing over a 3-year period from March 2000 to March 2003. Forty-three of the 170 patients tested were diagnosed with breast cancer prior to genetic testing. Nine patients (20.9%) tested positive for a deleterious mutation. Fifty-eight percent underwent genetic counseling prior to definitive cancer surgery. Five of the 25 patients who underwent lumpectomy tested positive for a deleterious mutation. Testing results became available during systemic therapy or radiation was delayed until results were known. After counseling, all five patients testing positive went on to bilateral prophylactic mastectomy and reconstruction. None had radiation therapy. Because of a strong family history, eight patients elected to undergo prophylactic mastectomy and reconstruction prior to obtaining genetic test results; and despite compelling histories, all eight tested negative for a mutation. Treatment algorithms are developed to manage patients that are first discovered to be at high risk for a BRCA-1 or BRCA-2 mutation at the time they are diagnosed with breast cancer. Patients diagnosed with breast cancer who are discovered to be at high risk for a genetic mutation should undergo counseling prior to definitive surgery. This maximizes the time that patients have to consider options for prophylaxis and monitoring should their test be positive. It also prevents women who would otherwise be candidates for breast preservation from undergoing unnecessary radiation therapy should they chose prophylactic mastectomy in the face of a positive test.

Transthoracic or transhiatal esophagectomy for cancer of the esophagus--does it matter?

Despite the ongoing controversy between proponents of TTE and THE, in the hands of experienced surgeons, both approaches provide excellent results for patients with carcinoma of the esophagus and EG junction. Ideally, surgeons dealing with esophageal carcinoma should be expert in both approaches and should select the best approach for the individual patient. The transhiatal approach appears to have a slightly lower operative mortality, and this advantage may be significant for the older, higher-risk surgical patient. Nevertheless, the transhiatal approach has a slightly higher risk of anastomotic complications and recurrent laryngeal nerve injury. Recent studies suggest, however, that the volume of experience of the surgeon is probably a more important factor in predicting operative mortality and complication rates than is the choice between TTE and THE. Cancer-related survival appears to be similar after the two procedures.

A comparison of methylene blue and lymphazurin in breast cancer sentinel node mapping.

BACKGROUND: When lymphazurin became unavailable to our institution, we elected to employ methylene blue to perform sentinel node mapping for patients with breast cancer. The purpose of this study was to compare methylene blue and lymphazurin for performing sentinel node mapping for breast cancer. METHODS: We evaluated our sentinel node mapping experience from April 1, 2001 to March 31, 2002. Patients were divided into two groups based on the dye used for lymphatic mapping. The two groups were compared to evaluate the results of the sentinel node mapping procedure. RESULTS: During the study period a total of 199 patients were evaluated with sentinel node mapping, 87 with lymphazurin and 112 with methylene blue. The two groups were similar in demonstrating the success of the sentinel node procedure, nodes identified per case, and technique used for node identification (colloid or dye, or both). CONCLUSIONS: In our initial experience, methylene blue appears to be equivalent to lymphazurin for sentinel node mapping in breast cancer.