Smoking history is associated with reduced efficacy of neoadjuvant therapy in pancreatic adenocarcinoma.

BACKGROUND: Differential responses to neoadjuvant therapy (NAT) exist in pancreatic ductal adenocarcinoma (PDAC); however, contributing factors are poorly understood. Tobacco smoke is a common risk factor for PDAC, with nicotine-induced chemoresistance observed in other cancers. This study aimed to explore the potential association between tobacco use and NAT efficacy in PDAC. METHODS: A single-center, retrospective analysis was conducted that included all consecutive patients with PDAC who underwent surgical resection after NAT with a documented smoking history (N = 208). NAT response was measured as percentage fibrosis in the surgical specimen. Multivariable models controlled for covariates and survival were modeled using the Kaplan-Meier method. RESULTS: Postoperatively, major responses to NAT (>95% fibrosis) were less frequently observed in smokers than in nonsmokers (13.7% vs 30.4%, respectively; P = .021). Pathologic complete responses were similarly less frequent in smokers than in nonsmokers (2.1% vs 9.9%, respectively; P = .023). On multivariate analysis controlling for covariates, smoking history remained independently associated with lower odds of major fibrosis (odds ratio [OR], 0.25; 95% CI, 0.10-0.59; P = .002) and pathologic complete response (OR, 0.21; 95% CI, 0.03-0.84; P = .05). The median overall survival was significantly longer in nonsmokers than in smokers (39.1 vs 26.6 months, respectively; P = .05). CONCLUSION: Tobacco use was associated with diminished pathologic responses to NAT. Future research to understand the biology underlying this observation is warranted and may inform differential NAT approaches or counseling among these populations.

Type of neoadjuvant treatment strategy is associated with differential pathologic responses in pancreatic ductal adenocarcinoma.

BACKGROUND: Tumor fibrosis after neoadjuvant treatment (NAT) for pancreatic ductal adenocarcinoma (PDAC) correlates with treatment response. Herein we assessed how different NAT strategies influence pathologic responses and survival. METHODS: Patients with surgically resected PDAC who received NAT (1991-2020) were included. Descriptive statistics compared outcomes amongst fibrosis groups (none, minor <50 â€‹%, partial 51%-94 â€‹%, major ≥95 â€‹%) and NAT (chemotherapy alone, chemoradiation, or chemotherapy â€‹+ â€‹chemoradiation (total neoadjuvant therapy, TNT)). RESULTS: Patients with major fibrosis most often received TNT (65.8 â€‹%, p â€‹< â€‹0.001). Major fibrosis was associated with the greatest rate of downstaging (77.8 â€‹%, p â€‹< â€‹0.001), highest R0 margin rate (100 â€‹%, p â€‹< â€‹0.01), and lowest mean positive lymph node ratio (0.80, p â€‹< â€‹0.01). Amongst complete responders, 11/14 (78.6 â€‹%) received TNT. Median overall (66.3 months, p â€‹= â€‹0.003) and disease-free (54.7months, p â€‹= â€‹0.05) survival were highest with major fibrosis. CONCLUSIONS: Major fibrosis and complete pathologic responses after NAT are most frequent with a TNT strategy and are associated with improved outcomes.

Total Neoadjuvant Treatment for Pancreatic Ductal Adenocarcinoma Is Associated With Limited Lymph Node Yield but Improved Ratio.

INTRODUCTION: The lymph node yield (LNY) and lymph node ratio (LNR) of nodal metastases following pancreatoduodenectomy (PD) have been reported as prognostic parameters in patients with pancreatic ductal adenocarcinoma (PDAC). However, they have not been compared in the setting of various neoadjuvant therapy modalities. METHODS: A single institutional retrospective study identified 134 patients diagnosed with resectable, BLR- and LA-PDAC who underwent PD at Fox Chase Cancer Center between 2010 and 2019. Patients were categorized based on first-line treatment as follows: surgery first (SF), total neoadjuvant therapy (TNT), and single modality neoadjuvant therapy (SMNT). The histopathological reports of the surgical specimens were examined to obtain LNY and determine the counts of lymph nodes with metastases. Subsequently, LNR was calculated as the number of positive lymph nodes divided by the number of lymph nodes examined. RESULTS: Overall, 49, 38, 27, 12, and 8 patients underwent SF approach, SMNT, incomplete TNT, induction TNT, and consolidation TNT, respectively. There was no difference in R0 resection and vascular resection between the groups (P = 0.096 and 0.794, respectively). The median counts of LNY were 22, 15, 21, 11.5, and 10, respectively (P < 0.001). The average LNR was 0.16, 0.07, 0.03, 0.02, and 0.02, respectively (P < 0.001). There were statistically significant differences in overall survival in the TNT groups (log-rank test P = 0.030). CONCLUSIONS: PDAC patients who undergo the TNT modality exhibit lower LNY and improved LNR compared with the SF approach and SMNT neoadjuvant therapy groups. This is likely explained by the increased treatment response and lymph node obliteration associated with the TNT approach. Our results question the minimal requirement of 11-18 harvested lymph nodes for PD following TNT.

Total neoadjuvant therapy is associated with improved overall survival and pathologic response in pancreatic adenocarcinoma.

BACKGROUND: Few studies have evaluated outcomes of total neoadjuvant therapy (TNT) compared with single modality neoadjuvant therapy (SMNT) or surgery first (SF) for pancreatic ductal adenocarcinoma (PDAC). METHODS: A single-institution retrospective review of PDAC patients who underwent pancreatectomy was conducted (1993-2019). Overall survival (OS) estimates from diagnosis and from surgery were determined using Kaplan-Meier methods; Cox proportional hazards models adjusted for covariates. RESULTS: Surgery was performed upfront (SF) in 168 (46.9%), while 111 (31.0%) had chemotherapy or chemoradiation before resection (SMNT), and 79 (22.1%) underwent TNT (chemotherapy and chemoradiation). Resection margins were more frequently R0 in the TNT group (86.1%) compared with SMNT (64.0%) and SF (72%) (p < 0.001). Complete pathologic response was more common in the TNT group (10.1%) compared with SMNT (3.6%) or SF (0.6%) (p = 0.001), resulting in prolonged survival (median OS = 100.2 months). TNT patients demonstrated longer median OS from surgery (33.6 months) compared with SF (19.1 months) and SMNT (17.4 months) (p = 0.010), which persisted after controlling for covariates. CONCLUSIONS: TNT is associated with more frequent complete pathologic response, a higher rate of margin negative resection, and prolonged OS as compared with SF or SMNT. Additional studies to identify subgroups that derive the greatest benefit are warranted.

Total neoadjuvant therapy for pancreatic adenocarcinoma increases probability for a complete pathologic response.

BACKGROUND: Multiple neoadjuvant therapy protocols have been proposed in the treatment of pancreatic adenocarcinoma, including chemotherapy (CT), chemoradiation (CRT), and total neoadjuvant therapy (TNT), defined as a CT plus CRT. A pathologic complete response (pCR) can be achieved in a minority of cases. We hypothesize that TNT is more likely to confer pCR than other neoadjuvant therapies, which may improve overall survival (OS). METHODS: A retrospective review of the National Cancer Database (NCDB) from 2006 to 2016 was performed, identifying patients who underwent any neoadjuvant therapy followed by definitive pancreatic resection for locally advanced or borderline resectable pancreatic adenocarcinoma. A pathologic complete response was defined as down-staging from any clinical stage to pathologic stage 0. RESULTS: A total of 5402 patients who received neoadjuvant therapy followed by resection were identified. 177 patients (3.3%) achieved a pCR. Of the patients who achieved a pCR, 57 received CT, 41 CRT and 79 received TNT. On multivariate analysis, TNT was more likely to confer a pCR than CRT (OR 1.67, CI 1.13-2.46, p = 0.0103) or CT (OR 2.61, CI 1.83-3.71, p < 0.0001). Patients who achieved pCR had a significantly higher OS, with median survival of 64.9 months, compared to 21.6 months in patients who did not achieve pCR (p < 0.0001). CONCLUSION: TNT may be more likely to achieve a pCR than CT or CRT. Patients who achieve a pCR have a significant OS benefit as compared to those who have residual disease. TNT should be considered for patients requiring neoadjuvant therapy, as it may increase the likelihood of achieving a pCR, thus potentially improving OS.

Appendiceal tumors with glandular and neuroendocrine features exhibiting peritoneal metastases - Critical evaluation of outcome following cytoreductive surgery with perioperative chemotherapy.

BACKGROUND: A rare appendiceal malignancy is characterized by both glandular and neuroendocrine histology. It often presents with dissemination of the perforated tumor to peritoneal surfaces. Current treatments involve systemic chemotherapy, cytoreductive surgery and perioperative intraperitoneal chemotherapy. METHODS: The impact of clinical, histological and treatment-related characteristics on survival were evaluated and subjected to univariate statistical analyses. All patients had stage IV disease and were treated by a uniform treatment strategy. Survival was determined from onset of disease until death or most recent follow-up. RESULTS: There were 47 patients available for study of whom 17 were male. Median age was 48 with a range of 27-65. None or a single symptom vs. 2 or more symptoms had a significant effect on survival. Median survival of the entire cohort was 45 months and 34.88% and 8.72% of patients survived 5 and 10 years, respectively. The use of neoadjuvant chemotherapy showed no impact on survival. Patients with a peritoneal cancer index (PCI) of 0-20 as compared to PCI > 20 survived longer (p = 0.012). The survival of patients able to have a complete resection as compared to an incomplete resection of disease was significant (p = 0.0087). The type of perioperative chemotherapy did not alter survival. CONCLUSIONS: These data show that patients with a lesser extent of disease with a complete cytoreduction had an improved prognosis. No benefit from systemic or perioperative regional chemotherapy was apparent. With long-term follow-up, patients with the combined glandular and neuroendocrine histology exhibiting peritoneal metastases have a guarded prognosis.

Robot-assisted combined pancreatectomy/hepatectomy for metastatic pancreatic acinar cell carcinoma: case report and review of the literature.

Acinar cell carcinoma (ACC) of the pancreas is a rare neoplasm with less aggressive behavior than ductal carcinoma. As a result, surgical resection for metastatic ACC is a therapeutic option which can result in long-term survival. There is a paucity of data describing institutional approaches to these challenging patients, and therefore, we herein describe our institution's approach to a patient with a distal pancreatic ACC and isolated liver metastasis. The patient underwent neoadjuvant chemotherapy (FOLFIRINOX), followed by a robot-assisted distal pancreatectomy/splenectomy and non-anatomic segment 6 resection. He was discharged to home post-operative day 2. Final pathology revealed complete tumor response of the liver metastasis and a margin negative resection of the primary tumor. He remains disease free and without complications at 3 months. We highlight that combined modality therapy for metastatic ACC can yield long-term survival in selected patients. Similarly, the robotic platform enables performance of complex multivisceral resections with rapid recovery. Future research investigating precision medicine for metastatic ACC is warranted given widely variable tumor biology in this disease.

Disparities in Risk Reduction Therapy Recommendations for Young Women With Lobular Carcinoma In-Situ.

BACKGROUND: Endocrine therapy (ET) significantly reduces the risk of breast cancer development in high-risk patients diagnosed with lobular carcinoma in situ (LCIS). However, the variables impacting recommendation and use of ET in young adults (YAs) is not well-studied. We examined the role of provider recommendation and patient acceptance for ET for YAs with LCIS. MATERIALS AND METHODS: The National Cancer Database was queried for women aged < 40 years with primary LCIS between 2000 and 2012. Socioeconomic, demographic, and treatment variables were examined to determine their impact on ET provider recommendation and initial patient acceptance of risk-reducing therapy. RESULTS: Among 1650 YA patients with LCIS, only 749 (45.4%) were recommended ET. On multivariable analysis, women > 30 years of age were more likely recommended ET than women < 30 years (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.10-2.47), African Americans more than other ethnicities (OR, 1.48; 95% CI, 1.1-2.0), and YAs treated in New England were more likely than those in the rest of the country (OR, 3.26; 95% CI, 2.0-5.2). Among YA women recommended ET, only 20.2% had a documented refusal. Only geography appeared to independently impact the likelihood of refusal, with YAs in the Southeastern-Central United States being most likely to refuse ET (OR, 5.4; 95% CI, 1.2-24.0). CONCLUSION: ET is underutilized for risk-reduction in YAs with LCIS. This underuse appears dependent on disparities in provider recommendation practices rather than non-acceptance of therapy. This may reflect regional practice patterns, community standards of care, or provider bias regarding the significance of LCIS as a risk factor for development of invasive cancer.

The Immune Microenvironment Impacts Survival in Western Patients with Gastric Adenocarcinoma.

BACKGROUND: Expression of CD3+ T cells, CD8+ cytotoxic T cells, CD45RO+ memory T cells, and FOXP3+ regulatory T cells at the invasive margin (IM) and tumor center (TC) has correlated with survival in gastric adenocarcinoma (GA) patients from East Asia, independent of anatomic staging. The reason for improved survival in East Asians compared with Western patients is a subject of debate. This study examined the immune profiles of a cohort of Western patients with GA, and their association with overall survival (OS). METHODS: Immunohistochemistry (IHC) using antibodies to CD3, CD4, CD8, CD45RO, and FOXP3 was performed on a randomly selected resected GA specimens from 88 Western patients. Cutoffs for high or low expression of each marker were determined with maximally selected rank statistics, and multivariable Cox proportional-hazards models constructed to evaluate the relationship between OS and expression of each marker at the IM and TC. RESULTS: Immune cell density was independent of anatomic staging. High expression of CD3, CD4, CD8, and CD45RO at the IM along with CD4 and FOXP3 at the TC were associated with improved OS. A combined marker of CD3, CD8, CD45RO, and FOXP3 associated with OS in East Asian GA was also validated. DISCUSSION: This is the first report in US patients to demonstrate that high expression of multiple subsets of T lymphocytes in GA is associated with better OS independent of clinical factors and anatomic stage. Further evaluation of immune-modulating mechanisms may explain survival differences between Western and Eastern patients and provide opportunity for novel treatments.

Regionalization of Retroperitoneal Sarcoma Surgery to High-Volume Hospitals: Missed Opportunities for Outcome Improvement.

PURPOSE: Surgery continues to be the dominant therapy for the management of retroperitoneal soft-tissue sarcoma (RPS). Many groups advocate performing these resections at high-volume hospitals (HVHs), given their complexity. We therefore sought to explore whether RPS surgery has indeed begun to regionalize to HVHs in the same manner as pancreatic cancer (PC) surgery during the last decade. METHODS: We identified 70,763 patients who underwent surgical resection for RPS or PC using the National Cancer Database (2004 to 2015). Patients were stratified by hospital surgical volume. We performed an adjusted time trend analysis to compare trends in performance of surgery at HVHs for RPS versus PC. Multivariable logistic analyses were then performed, controlling for covariables, to elucidate relationships between patient-, hospital-, and treatment-related variables that may contribute to these observed trends. RESULTS: Only 9.6% of patients underwent RPS surgery at HVHs. During this time period, the odds ratio of undergoing RPS compared with pancreatectomy at HVHs was 0.65 ( P < .05). Time trend analysis estimated that whereas both procedures are regionalizing, the rate of RPS regionalization grew at 30.5% of the rate of PC (1.017 v 1.056; P < .001) and remained consistent after using several hospital volume thresholds and hospital volume as a continuous variable. CONCLUSION: Results from this retrospective multi-institutional analysis uncovered a lag in the regionalization of surgery for RPS compared with PC surgery. These findings reinforce the call to regionalize surgery for RPS to HVHs in a manner that is similar to that of other procedures in complex cancer surgery.

Survival from a 75% TBSA thermal injury complicated by bowel ischemia presenting with pneumatosis intestinalis.

Thermal injury is associated with an increased risk of abdominal complications such as ischemia, infarction and pneumatosis intestinalis (PI). PI is characterized by gas in the intestinal wall and, when diagnosed it can signify the presence of a life-threatening condition. We present a case of a patient who survived 75% total body surface area burns complicated by ischemic bowel that initially presented as extensive PI. This patient was emergently taken to the operating room and underwent a subtotal colectomy and small bowel resection for ischemic bowel. Prompt diagnosis and successful management of the underlying condition ultimately contributed to the patient's survival. The presence of peritonitis or abdominal distension, portomesenteric venous gas and lactic acidosis should prompt immediate surgical intervention in the post-burn period.

The potential for liquid biopsies in the precision medical treatment of breast cancer.

Currently the clinical management of breast cancer relies on relatively few prognostic/predictive clinical markers (estrogen receptor, progesterone receptor, HER2), based on primary tumor biology. Circulating biomarkers, such as circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) may enhance our treatment options by focusing on the very cells that are the direct precursors of distant metastatic disease, and probably inherently different than the primary tumor's biology. To shift the current clinical paradigm, assessing tumor biology in real time by molecularly profiling CTCs or ctDNA may serve to discover therapeutic targets, detect minimal residual disease and predict response to treatment. This review serves to elucidate the detection, characterization, and clinical application of CTCs and ctDNA with the goal of precision treatment of breast cancer.

EpCAM based capture detects and recovers circulating tumor cells from all subtypes of breast cancer except claudin-low.

PURPOSE: The potential utility of circulating tumor cells (CTCs) as liquid biopsies is of great interest. We hypothesized that CTC capture using EpCAM based gating is feasible for most breast cancer subtypes. RESULTS: Cancer cells could be recovered from all intrinsic subtypes of breast cancer with IE/FACS, however, claudin-low cell lines showed very low capture rates compared to the four other groups (p = 0.03). IE/FACS detection of CTC mimic cells was time sensitive, emphasizing controlling for pre-analytic variables in CTC studies. Median fluorescent intensity for flow cytometry and RNA flow cell type characterization were highly correlated, predicting for CTC isolation across molecular subtypes. RNA-Seq of IE/FACS sorted single cell equivalents showed high correlation compared to bulk cell lines, and distinct gene expression signatures compared to PB. MATERIALS AND METHODS: Ten cell lines representing all major subtypes of breast cancer were spiked (as CTC mimics) into and recovered from peripheral blood (PB) using immunomagnetic enrichment followed by fluorescence-activated cell sorting (IE/FACS). Flow cytometry and RNA flow were used to quantify the expression of multiple breast cancer related markers of interest. Two different RNA-Seq technologies were used to analyze global gene expression of recovered sorted cells compared to bulk cell lines and PB. CONCLUSIONS: EpCAM based IE/FACS detected and captured a portion of spiked cells from each of the 10 cell lines representing all breast cancer subtypes, including basal-like but not claudin-low cancers. The assay allows for the isolation of high quality RNA suitable for accurate RNA-Seq of heterogeneous rare cell populations.

Chronic spontaneous idiopathic spleen hematoma presenting as a large cystic tumor: a case report with review of the literature.

Spontaneous idiopathic splenic hematomas occur very rare. Hematomas of the spleen are usually associated with trauma, or infectious, neoplastic, or hematologic diseases. They present a diagnostic challenge as they can be easily confused with other more common entities. We report a case of atraumatic idiopathic splenic hematoma in a patient with no underlying systemic or local disease and discuss the approach to diagnosis and treatment.