Metastatic Ductal Adenocarcinoma Research Articles

Gemcitabine and nab-paclitaxel combined with afatinib in metastatic pancreatic cancer – Results of a phase 1b clinical trial

PurposeThe combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC. MethodsTreatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m2 / 125 mg/m2 (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy. ResultsTwelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3–5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months. ConclusionsIn this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m2 / 125 mg/m2) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.

Nanoscopy on drug-encapsulating nanosystems by phasor-based fluorescence lifetime analysis.

Understanding the supramolecular organization of active compounds (drugs) encapsulated within standard formulations is becoming increasingly important in nanomedicine. In fact, the synthetic identity of a drug-encapsulating nanosystem is supposed to change throughout its journey, from administration to final fate within the target tissue/cell. Here we addressed this issue by exploiting phasor-based fluorescence lifetime imaging (FLIM) of a drug intrinsic fluorescence signal. As case-study, we selected Irinotecan (CPT-11), a chemotherapy medication used to treat colon cancer, small lung cancer and pancreatic cancer, and focused on its liposomal formulation Onivyde®, launched in 2015 as an orphan drug for the treatment of metastatic ductal adenocarcinoma (mPDAC). After measuring the FLIM signature of the drug's individual physical states, we extracted the fractional intensities of each coexisting physical state of the active principle within the nanoparticle. Our analysis was boosted by means of dedicated custom algorithms based on preliminary data processing and multi-dimensional histogram inference to identify regions of interest in the phasor plot. Whereas, in the case of biological samples, we achieved autonomous cell segmentation by means of computer vision algorithms. Onivyde® in commercial vials was found to coexist in multiple physical states (i.e. gelated/precipitated, free and membrane-associated) and undergo extensive leakage in media mimicking complex biological environments. Moreover, we identified multiple mechanism of cellular uptake and were able to investigate subcellular localization and supramolecular organization of irinotecan in a model of pancreatic cells. In conclusion, we believe that Phasor-FLIM represents a useful platform to quantitatively address the synthetic identity of encapsulated fluorescent drugs, both in cuvette and cellular environments. In this context, we envision many potential applications ranging from batch-to-batch analysis, at the production level, to drug development optimization.

PCN27 Real-World Characteristics and Outcomes of Patients with Metastatic Ductal Adenocarcinoma (MPDAC) Treated with Liposomal Irinotecan-Based Regimens By Race

Racial disparities persist in outcomes for patients with pancreatic cancer in the United States, with Black or African American patients having higher age-adjusted incidence and mortality than White patients. Similarly, results from the pivotal phase 3 study, NAPOLI-1, and recent literature suggest that participants of East Asian ethnic origin experience better outcomes than other ethnic groups with liposomal irinotecan+5-fluorouracil/leucovorin following gemcitabine. This study seeks to describe clinical characteristics and treatment outcomes based on race. This retrospective observational study utilized the Flatiron Health EHR-derived de-identified database from over 280 cancer clinics in the US. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan-based regimens between January 2015 and February 2020. Patients were stratified based on their self-reported race. Median overall survival (OS) from treatment initiation was derived using Kaplan-Meier analysis. Of the included 608 patients (median age 68 years (y), IQR: 61-74) with mPDAC and treated with a liposomal irinotecan-based regimen, 448 patients (73.7%) were White, 48 patients (7.9%) were Black or African American, 13 (2.1%) were Asian, and 99 (16.3%) were of other race or the data were missing. White patients had a median age at metastatic diagnosis of 69y (IQR: 61–74), Black patients, 64y (60-71), and Asian patients 65y (63-72). ECOG scores of 0-1 were reported for 61.6% of White patients, 58.3% of Black patients, and 61.5% of Asian patients. Overall, median OS was 4.7 months (95% CI: 4.2–5.4). Median OS was 4.6 months 4.1–5.6) among White patients, 3.8 months (3.1–5.6) among Black patients, and 12 months (3.4–NR) among Asian patients. This analysis found racial disparities may persist in survival outcomes among patients with mPDAC treated with liposomal irinotecan-based regimens. Further studies are needed to characterize and understand the biological and socio-economic factors contributing to these disparate outcomes.

PCN17 Real-World Impact of Prior Surgery on Outcomes of Patients with Metastatic Ductal Adenocarcinoma (mPDAC) Treated with Liposomal Irinotecan-Based Regimens

This study seeks to describe demographic and clinical characteristics and treatment outcomes based on prior surgery in a real-world setting among patients with mPDAC treated with liposomal irinotecan-based regimens.

CT Simplified Radiomic Approach to Assess the Metastatic Ductal Adenocarcinoma of the Pancreas.

The aim of this study was to perform a simplified radiomic analysis of pancreatic ductal adenocarcinoma based on qualitative and quantitative tumor features and to compare the results between metastatic and non-metastatic patients. A search of our radiological, surgical, and pathological databases identified 1218 patients with a newly diagnosed pancreatic ductal adenocarcinoma who were referred to our Institution between January 2014 and December 2018. Computed Tomography (CT) examinations were reviewed analyzing qualitative and quantitative features. Two hundred eighty-eight patients fulfilled the inclusion criteria and were included in this study. Overall, metastases were present at diagnosis in 86/288 patients, while no metastases were identified in 202/288 patients. Ill-defined margins and a hypodense appearance on portal-phase images were significantly more common among patients with metastases compared to non-metastatic patients (p < 0.05). Metastatic tumors showed a significantly larger size and significantly lower arterial index, perfusion index, and permeability index compared to non-metastatic tumors (p < 0.05). In the management of pancreatic ductal adenocarcinoma, early detection and correct staging are key elements. The study of computerized tomography characteristics of pancreatic ductal adenocarcinoma showed substantial differences, both qualitative and quantitative, between metastatic and non-metastatic disease.

Pretreatment platelet to lymphocyte ratio is predictive of overall survival in metastatic pancreatic ductal adenocarcinoma

Background: This study aimed to investigate whether the pretreatment platelet to lymphocyte ratio (PLR) is a significant prognostic factor in metastatic pancreatic ductal adenocarcinoma (PDAC). Methods: A total of 134 histologically confirmed PDAC patients were included in our retrospective study. The data included treatment regimens, Karnofsky Performance Status (KPS), and PLR. Kaplan-Meier curves and univariate and multivariate Cox proportional hazards regression analyses were applied to identify the prognostic factors associated with overall survival (OS). Results: We used the receiver operating characteristic (ROC) curve to set the cut-off value of the PLR. For the Kaplan-Meier analysis, the median overall survival in PDAC patients with a PLR of 123 or less was 19.7 months, whereas the values in those with a PLR greater than 123 was 13.7 months (P=0.014). PLR was a significant prognostic marker in the multivariate Cox model [hazard ratio (HR) =1.721, 95% CI: 1.162–2.550, P=0.007]. Conclusions: The PLR pretreatment had potential as prognostic indicator in patients with metastatic PDAC.

Obstructive jaundice secondary to pancreatic head adenocarcinoma in a young teenage boy: a case report

IntroductionPancreatic adenocarcinoma is extremely rare in childhood. We report a case of metastatic pancreatic adenocarcinoma in a 13-year-old boy, revealed by jaundice.Case presentationA 13-year-old Moroccan boy was admitted with obstructive jaundice to the children's Hospital of Rabat, Department of Pediatric Oncology. Laboratory study results showed a high level of total and conjugated bilirubin. Computerized tomography of the abdomen showed a dilatation of the intra-hepatic and extra-hepatic bile ducts with a tissular heterogeneous tumor of the head of the pancreas and five hepatic lesions. Biopsy of a liver lesion was performed, and a histopathological examination of the sample confirmed the diagnosis of metastatic ductal adenocarcinoma of the pancreas. Our patient underwent a palliative biliary derivation. After that, chemotherapy was administered (5-fluorouracil and epirubicin), however no significant response to treatment was noted and our patient died six months after diagnosis.ConclusionMalignant pancreatic tumors, especially ductal carcinomas, are exceedingly rare in the pediatric age group and their clinical features and treatment usually go unappreciated by most pediatric oncologists and surgeons.

INTRAMEDULLARY SPINAL CORD AND CAUDA EQUINA METASTASIS OF BREAST CARCINOMA: CASE REPORT

We present a case report of a female patient with metastasis of breast carcinoma to the medullary conus and cauda equina. A 48-year-old woman with a history of breast tumor, suddenly felt severe weakness and numbness of the lower extremities. MRI of the spine disclosed a mass lesion within the medullary conus, with leptomeningeal involvement of cauda equina at the spinal level L1. Laminectomy was performed and partial resection of the medullary conus tumor and especially release of nerve roots of cauda equina was achieved using microsurgical techniques. Her clinical status, especially right leg weakness and sensory loss in the lower extremities have immediately improved but bladder dysfunction remained and she was unable to walk. The histological picture and immunophenotype indicates the presence of metastatic ductal adenocarcinoma of the mammary gland. Patient died 4 months after the spinal cord and cauda equina surgery. To our knowledge, this is the first report of successful surgical treatment of metastatic leptomeningeal infiltration of breast carcinoma.

Endoscopic Ultrasound–Guided Fine-Needle Aspiration of Ascites

The aim of this study is to report a large single-center experience with endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) of ascites. Consecutive patients at our institution in whom EUS-guided paracentesis was performed between January 1997 and July 2005 were identified retrospectively. All procedures were performed by or under the supervision of 1 of 5 experienced endosonographers with available on-site cytopathology. Sixty consecutive patients (33 men; mean age, 67 y) were identified. Previously attempted percutaneous paracentesis was unsuccessful in 3 of 6 patients. Ascites confirmed by EUS FNA was visible in 28 of 54 (52%) computerized tomography, 3 of 11 (27%) transabdominal ultrasound, and 4 of 8 (50%) magnetic resonance imaging examinations before EUS. Transgastric (n = 55) or transduodenal (n = 5) EUS-guided paracentesis (mean, 8.9; range, 1-40 mL) revealed malignancy in 16 (27%) from primary pancreatic (n = 9), gastric (n = 2), urothelial (n = 1), esophageal (n = 1), gallbladder (n = 1), bile duct (n = 1) cancer, and lymphoma (n = 1). The cytology from 2 patients was atypical (1 suspicious for malignancy and 1 considered reactive) and the remaining 42 were benign. Potential complications occurred in 2 of 60 (3%) patients with self-limited fever. Of the 8 of 60 (13%) patients who underwent subsequent surgery, 3 had metastatic pancreatic adenocarcinoma (n = 2) and metastatic small intestinal carcinoid (n = 1) to the peritoneum after negative EUS-FNA cytology. EUS frequently identifies ascites missed by other imaging studies. EUS-guided paracentesis may identify malignancy in a subset of patients. Negative ascitic fluid cytology from EUS FNA does not exclude possible peritoneal carcinomatosis.

Metastatic Ductal Adenocarcinoma of the Prostate: Cytologic Features and Clinical Findings

We retrospectively reviewed the cytologic features of metastatic prostatic ductal carcinoma (PDC) in 23 cases, clinical manifestations, and clinical outcomes. Cytologic smears typically showed tumor cells with abundant cytoplasm and oval nuclei arranged in papillary groups or flat and folded sheets, some of which showed peripheral nuclear palisading. However, these features could be focal, subtle, and even indistinguishable from those of acinar carcinoma, particularly when the ductal component was predominantly of a cribriform and solid pattern or coexisted with acinar carcinoma. A determination of a prostatic origin of a metastatic PDC, based on cytomorphologic features alone, could be difficult. Immunostaining for prostate-specific antigen and prostatic acid phosphatase proved helpful in determining a definitive diagnosis. The median followup of patients was 82 months, the median overall survival was 77 months, and the 5-year overall survival rate was 72%. Tumor growth pattern did not correlate with prognosis, but visceral metastasis conveyed a poor prognosis. The correlation with clinical and radiologic findings, a high index of suspicion, and the use of immunoperoxidase studies are important in making an accurate diagnosis.

Metastatic Ductal Adenocarcinoma of the Prostate

Metastatic Ductal Adenocarcinoma of the Prostate

C-MYC Activation in Primary and Metastatic Ductal Adenocarcinoma of the Pancreas: Incidence, Mechanisms, and Clinical Significance

Amplification and overexpression of c-MYC is a common event in various neoplasias. Recently, comparative genomic hybridization (CGH) of primary pancreatic adenocarcinomas revealed a distinct high-level amplification of 8q23-qter, suggesting that c-MYC located on 8q24 may be a candidate oncogene. To evaluate the biological significance and prognostic value of c-MYC activation in pancreatic carcinoma, we performed interphase fluorescence in situ hybridization (FISH) and immunohistochemistry on a series of 69 primary pancreatic adenocarcinomas, 19 corresponding lymph node metastases, and 5 pancreatic intraductal lesions. Dual color FISH using a probe for c-MYC (8q24) and a centromeric probe for chromosome 8 revealed amplification of c-MYC in 32.3% and 29.4% of primary and metastatic tumors, respectively. Immunostaining identified c-MYC protein overexpression in 43.5% of primaries and 31.6% of metastases. Low concordance between positive FISH and immunostaining (13.4%) suggests multiple independent regulatory pathways of c-MYC activation. Statistical evaluation revealed significant correlation (α = 0.033) between c-MYC protein overexpression and histopathological tumor grade but absence of correlation with tumor stage or lymph node status. Analysis of pancreatic intraductal lesions showed c-MYC amplification and protein overexpression in two of five cases in which invasive carcinoma exhibited identical aberrations. We conclude that deregulation of c-MYC protein is common in pancreatic cancer and that it may be involved in early neoplastic development and progression rather than in locoregional spread of invasive cancer.