Spleen Volume Reduction Is a Reliable and Independent Biomarker for Long-Term Risk of Leukopenia Development in Peptide Receptor Radionuclide Therapy.

177Lu-DOTATATE therapy is an effective treatment for advanced neuroendocrine tumors, despite its dose-limiting hematotoxicity. Herein, the significance of off-target splenic irradiation is unknown. Our study aims to identify predictive markers of peptide receptor radionuclide therapy-induced leukopenia. Methods: We retrospectively analyzed blood counts and imaging data of 88 patients with histologically confirmed, unresectable metastatic neuroendocrine tumors who received 177Lu-DOTATATE treatment at our institution from February 2009 to July 2021. Inclusion criterium was a tumor uptake equivalent to or greater than that in the liver on baseline receptor imaging. We excluded patients with less than 24 mo of follow-up and those patients who received fewer than 4 treatment cycles, additional therapies, or blood transfusions during follow-up. Results: Our study revealed absolute and relative white blood cell counts and relative spleen volume reduction as independent predictors of radiation-induced leukopenia at 24 mo. However, a 30% decline in spleen volume 12 mo after treatment most accurately predicted patients proceeding to leukopenia at 24 mo (receiver operating characteristic area under the curve of 0.91, sensitivity of 0.93, and specificity of 0.90), outperforming all other parameters by far. Conclusion: Automated splenic volume assessments demonstrated superior predictive capabilities for the development of leukopenia in patients undergoing 177Lu-DOTATATE treatment compared with conventional laboratory parameters. The reduction in spleen size proves to be a valuable, routinely available, and quantitative imaging-based biomarker for predicting radiation-induced leukopenia. This suggests potential clinical applications for risk assessment and management.

Nanoliposomal irinotecan and fluorouracil plus leucovorin versus fluorouracil plus leucovorin in patients with cholangiocarcinoma and gallbladder carcinoma previously treated with gemcitabine-based therapies (AIO NALIRICC): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: There is an unmet need for effective therapies in pretreated advanced biliary tract cancer. We aimed to evaluate the efficacy of nanoliposomal irinotecan and fluorouracil plus leucovorin compared with fluorouracil plus leucovorin as second-line treatment for biliary tract cancer. METHODS: NALIRICC was a multicentre, open-label, randomised, phase 2 trial done in 17 German centres for patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, metastatic biliary tract cancer, and progression on gemcitabine-based therapy. Patients were randomly assigned (1:1) to receive intravenous infusions of nanoliposomal irinotecan (70 mg/m2), fluorouracil (2400 mg/m2), and leucovorin (400 mg/m2) every 2 weeks (nanoliposomal irinotecan group) or fluorouracil (2400 mg/m2) plus leucovorin (400 mg/m2) every 2 weeks (control group). Randomisation was by permutated block randomisation in block sizes of four, stratified by primary tumour site. Investigator-assessed progression-free survival was the primary endpoint, which was evaluated in all randomly assigned patients. Secondary efficacy outcomes were overall survival, objective response rate, and quality of life. Safety was assessed in all randomly assigned patients who received at least one dose of the study treatment. Enrolment for this trial has been completed, and it is registered with ClinicalTrials.gov, NCT03043547. FINDING: Between Dec 4, 2017, and Aug 2, 2021, 49 patients were randomly assigned to the nanoliposomal irinotecan group and 51 patients to the control group. Median age was 65 years (IQR 59-71); 45 (45%) of 100 patients were female. Median progression-free survival was 2·6 months (95% CI 1·7-3·6) in the nanoliposomal irinotecan group and 2·3 months (1·6-3·4) in the control group (hazard ratio [HR] 0·87 [0·56-1·35]). Median overall survival was 6·9 months (95% CI 5·3-10·6) in the nanoliposomal irinotecan group and 8·2 months (5·4-11·9) in the control group (HR 1·08 [0·68-1·72]). The objective response rate was 14% (95% CI 6-27; seven patients) in the nanoliposomal irinotecan group and 4% (1-14; two patients) in the control group. The most common grade 3 or worse adverse events in the nanoliposomal irinotecan group were neutropenia (eight [17%] of 48 vs none in the control group), diarrhoea (seven [15%] vs one [2%]), and nausea (four [8%] vs none). In the control group, the most common grade 3 or worse adverse events were cholangitis (four [8%] patients vs none in the nanoliposomal irinotecan group) and bile duct stenosis (four [8%] vs three [6%]). Treatment-related serious adverse events occurred in 16 (33%) patients in the nanoliposomal irinotecan group (grade 2-3 diarrhoea in five patients; one case each of abdominal infection, acute kidney injury, pancytopenia, increased blood bilirubin, colitis, dehydration, dyspnoea, infectious enterocolitis, ileus, oral mucositis, and nausea). One (2%) treatment-related serious adverse event occurred in the control group (worsening of general condition). Median duration until deterioration of global health status, characterised by the time from randomisation to the initial observation of a score decline exceeding 10 points, was 4·0 months (95% CI 2·2-not reached) in the nanoliposomal irinotecan group and 3·7 months (2·7-not reached) in the control group. INTERPRETATION: The addition of nanoliposomal irinotecan to fluorouracil plus leucovorin did not improve progression-free survival or overall survival and was associated with higher toxicity compared with fluorouracil plus leucovorin. Further research is necessary to define the role of irinotecan-based combinations in second-line treatment of biliary tract cancer. FUNDING: Servier and AIO-Studien.

HDAC2 Facilitates Pancreatic Cancer Metastasis.

The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multistep process that is incompletely understood in this disease. Although genetic drivers of PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. The epigenetic eraser histone deacetylase 2 (HDAC2) has been connected to less differentiated PDAC, but the function of HDAC2 in PDAC has not been comprehensively evaluated. Using genetically defined models, we show that HDAC2 is a cellular fitness factor that controls cell cycle in vitro and metastasis in vivo, particularly in undifferentiated, mesenchymal PDAC cells. Unbiased expression profiling detected a core set of HDAC2-regulated genes. HDAC2 controlled expression of several prosurvival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRα, PDGFRß, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFß pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. These data identify HDAC2 as a tractable player in the PDAC metastatic cascade. The complexity of the function of epigenetic regulators like HDAC2 implicates that an increased understanding of these proteins is needed for implementation of effective epigenetic therapies. SIGNIFICANCE: HDAC2 has a context-specific role in undifferentiated PDAC and the capacity to disseminate systemically, implicating HDAC2 as targetable protein to prevent metastasis.

[Diagnostics and therapy of pancreatic carcinoma]. / Diagnostik und Therapie des Pankreaskarzinoms.

Ductal pancreatic carcinoma is expected to become one of the most common malignant diseases worldwide in the coming decades. However, the prognosis of the disease remains very poor and has improved only slightly over the last decade. The 5-year survival rate of all patients with ductal adenocarcinoma has been increased to approximately 10 percent. The reasons for the very poor prognosis are the advanced stage of the disease at diagnosis with metastases already present in many cases, the anatomical location of the pancreas and the tumor biology. Therapeutically, chemotherapy remains the basis of systemic therapy. Intensive combinations with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin/5-FU) and nanoparticel albumin bound (nab)paclitaxel/gemcitabine lead to an improvement in overall survival in the palliative situation; used preoperatively, they can increase the rate of secondary resections. Targeted therapies and immune checkpoint inhibitors could not be established. In patients with a proven germline mutation in the BRCA gene, a therapy with the PARP inhibitor olaparib is in the approval process.This article provides an overview of differential diagnoses, meaningful diagnostics, therapeutic concepts to improve surgical treatment, possibilities of palliative chemotherapy and targeted therapy in the presence of a BRCA mutation.

Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer.

BACKGROUND: Mutations in the KRAS gene can be detected in about 70-90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. METHODS: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS. RESULTS: One hundred and seventy-eight tumour samples were collected from prospective clinical studies and successfully analysed for the extended RAS status: 37 tumours were KRAS wild-type (21%), whereas 141 (79%) carried a KRAS mutation; 132 of these mutations were found in KRAS exon 2 (74%), whereas only 9 mutations (5%) were detected in KRAS exon 3. Within KRAS exon 4 and NRAS exons 2-4, no mutations were apparent. There was no significant difference in overall survival for KRAS wild-type vs mutant patients (9.9 vs 8.3 months, P=0.70). CONCLUSIONS: Together with the results of the AIO-PK-0104-trial, the present analysis supports the notion that KRAS mutation status is rather predictive than prognostic in advanced PC.

The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when liver metastases already emerged. This study elucidated the impact of hepatic stromal cells on growth behavior of premalignant and malignant pancreatic ductal epithelial cells (PDECs). Liver sections of tumor-bearing KPC mice comprised micrometastases displaying low proliferation located in an unobtrusive hepatic microenvironment whereas macrometastases containing more proliferating cells were surrounded by hepatic myofibroblasts (HMFs). In an age-related syngeneic PDAC mouse model livers with signs of age-related inflammation exhibited significantly more proliferating disseminated tumor cells (DTCs) and micrometastases despite comparable primary tumor growth and DTC numbers. Hepatic stellate cells (HSC), representing a physiologic liver stroma, promoted an IL-8 mediated quiescence-associated phenotype (QAP) of PDECs in coculture. QAP included flattened cell morphology, Ki67-negativity and reduced proliferation, elevated senescence-associated ß galactosidase activity and diminished p-Erk/p-p38-ratio. In contrast, proliferation of PDECs was enhanced by VEGF in the presence of HMF. Switching the micromilieu from HSC to HMF or blocking VEGF reversed QAP in PDECs. This study demonstrates how HSCs induce and maintain a reversible QAP in disseminated PDAC cells, while inflammatory HMFs foster QAP reversal and metastatic outgrowth. Overall, the importance of the hepatic microenvironment in induction and reversal of dormancy during PDAC metastasis is emphasized.

Resectability After First-Line FOLFIRINOX in Initially Unresectable Locally Advanced Pancreatic Cancer: A Single-Center Experience.

BACKGROUND: FOLFIRINOX is an active but relatively toxic chemotherapeutic regimen for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The increased frequency of responding tumors shift interest to neoadjuvant approaches. We report our institutional experience with FOLFIRINOX for therapy-naïve patients with locally advanced and initially unresectable PDAC. METHODS: All patients with unresectable locally advanced PDAC who underwent treatment with FOLFIRINOX at a single center between 2011 and 2014 were identified and evaluated retrospectively regarding chemotherapy response, toxicity, conversion to resectability, and survival. Resectability, response to chemotherapy, and postoperative complications were reported according to NCCN-guidelines, RECIST-criteria, and Clavien-Dindo-classification, respectively. RESULTS: Overall, 14 patients received FOLFIRINOX as first-line therapy for locally advanced and unresectable PDAC. Fifty-seven percent of the patients had severe tumor-related comorbidities at the time of diagnosis, and in 86 %, dose reduction due to toxicity was necessary during a median of seven cycles. Nevertheless, only one patient had progressive disease during FOLFIRINOX, whereas the others experienced stable disease (n = 6) or partial remission (n = 6; no restaging in one patient). Oncological tumor resection was possible in 4 patients (29 % of all patients) with no postoperative mortality and only one grade 2 surgical complication. After a median follow-up of 10 months, 4 of the 14 patients were still in remission, 5 were alive with stable disease under ongoing systemic chemotherapy, and 5 died tumor-related. CONCLUSIONS: FOLFIRINOX is a powerful first-line regimen that leads to resectability in a substantial portion of patients with initially unresectable pancreatic cancer.

Increased incidence of extrapancreatic neoplasms in patients with IPMN: Fact or fiction? A critical systematic review.

BACKGROUND: To identify potential associations between intraductal papillary mucinous neoplasm of the pancreas (IPMN) and extrapancreatic neoplasms (EPN), a systematic review of the literature has been performed. METHODS: A systematic search of Medline/Pubmed was performed according to the PRISMA guidelines for reporting systematic reviews and meta-analysis for the following search terms: "extrapancreatic", "non pancreatic", "additional pancreatic", "additional primary" and alternatively matched with "neoplasms/tumours/cancers/malignancies/lesions". The results obtained specifically for IPMN were examined one by one by two independent investigators for further data selection and extraction. RESULTS: Fifteen studies were identified to be suitable and included for systematic review. Fourteen reported an elevated risk for extrapancreatic malignancy, particularly gastric and colon cancer, while the largest and only prospective study did not find any association. Most studies were retrospective with a weak level of evidence that was not substantially enhanced even by a recent multicentre case series. CONCLUSIONS: The available data on this clinically relevant question remain inconclusive. Due to lacking evidence on extrapancreatic neoplasms in IPMN patients, only a standard surveillance can be advised.

Association between pancreatic intraductal papillary mucinous neoplasms and extrapancreatic malignancies.

BACKGROUND & AIMS: The association between pancreatic intraductal papillary mucinous neoplasms (IPMNs) and extrapancreatic neoplasms (EPNs) is controversial. We performed a multicenter observational study to assess the incidence of EPNs after an IPMN diagnosis. METHODS: 1340 patients with IPMNs were evaluated from 2000 through 2013 at 4 academic institutions in Europe for development of EPN. To estimate the actual incidence of EPN, we excluded patients with an EPN previous or synchronous to the IPMN, and patients who had been followed for less than 12 months, resulting in a study population of 816 patients. The incidence of EPN was compared with sex-specific, age-adjusted European cancer statistics; the standardized incidence ratio (SIR), and the 5- and 10-year cumulative incidence rates were calculated. RESULTS: A total of 290/1340 patients had a history of EPN (prevalence of 21.6%). In this subgroup of patients, the IPMN was discovered incidentally in 241. Among the 816 patients included in the incidence analysis, 50 developed an EPN after a median time of 46 months from study enrollment. The incidence of any EPN was not greater in patients with than without IPMN with a SIR of 1.48 (95% confidence interval, 0.94-2.22) in males and of 1.39 (95% CI 0.90-2.05) in females. The 5- and 10-year cumulative incidence rates for development of EPN in patients with IPMN were 7.9% and 16.6% in men, and 3.4% and 23.1% in women. CONCLUSIONS: Patients with IPMN do not have a significantly higher incidence of EPNs than the general European population. It might not be necessary to screen patients with IPMN for EPN.

Efemp1 and p27(Kip1) modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models.

Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease with a poor prognosis and targeted therapies have failed in the clinic so far. Several evidences point to the phosphatidylinositol 3-kinase (PI3K)-mTOR pathway as a promising signaling node for targeted therapeutic intervention. Markers, which predict responsiveness of PDAC cells towards PI3K inhibitors are unknown. However, such markers are needed and critical to better stratify patients in clinical trials. We used a large murine Kras(G12D)- and PI3K (p110α(H1047R))-driven PDAC cell line platform to unbiased define modulators of responsiveness towards the dual PI3K-mTOR inhibitor Bez235. In contrast to other tumor models, we show that Kras(G12D)- and PI3K (p110α(H1047R))-driven PDAC cell lines are equally sensitive towards Bez235. In an unbiased approach we found that the extracellular matrix protein Efemp1 controls sensitivity of murine PDAC cells towards Bez235. We show that Efemp1 expression is connected to the cyclin-dependent kinase inhibitor p27(Kip1). In a murine Kras(G12D)-driven PDAC model, p27(Kip1) haploinsufficiency accelerates cancer development in vivo. Furthermore, p27(Kip1) controls Bez235 sensitivity in a gene dose-dependent fashion in murine PDAC cells and lowering of p27(Kip1) decreases Bez235 responsiveness in murine PDAC models. Together, we define the Efemp1-p27(Kip1) axis as a potential marker module of PDAC cell sensitivity towards dual PI3K-mTOR inhibitors, which might help to better stratify patients in clinical trials.