Treatment landscape of metastatic pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.

Increased zinc and albumin but lowered copper in children with transfusion-dependent thalassemia.

BACKGROUND: Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results. AIM OF THE STUDY: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. METHODS: This study recruited 60 children with TDT and 30 healthy controls aged 3-12 years old. RESULTS: Zinc was significantly higher in TDT children than in controls, while copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. CONCLUSION: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.

Adjuvant FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Pancreatic Cancer: A Brown University Oncology Research Group Phase II Study (BrUOG295).

OBJECTIVES: Multiple clinical trials have established a role for adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Adjuvant FOLFIRINOX increases survival as compared with gemcitabine but with increased toxicity. FOLFOX+nab-paclitaxel (FOLFOX-A) was developed by the Brown University Oncology Research Group (BrUOG) as an alternative to FOLFIRINOX. This phase II trial explored the feasibility and toxicity of adjuvant FOLFOX-A in patients who have completed resection for pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: Patients with resected pancreatic ductal adenocarcinoma were eligible. The primary objective was to determine the feasibility of adjuvant FOLFOX-A. Patients experiencing grade 2 neuropathy received a 20% reduction of oxaliplatin. Secondary end points were disease-free survival, and overall survival. RESULTS: Between June 2014 and October 2018, 25 patients were enrolled following surgical resection. The median number of cycles completed was 9.5. Median disease-free survival was 19.7 months (95% confidence interval, 10.3 to not reached) and median overall survival was 53.5 months (95% confidence interval, 24.2 to not reached). The most common treatment-related grade 3 or greater adverse events were fatigue (58%), nausea (13%), and neutropenia (26%). Fourteen patients had grade 2 neuropathy (58%) and 1 patient (4%) had grade 3 neuropathy. Only 2 patients (8%) had grade 3 diarrhea. CONCLUSIONS: Adjuvant FOLFOX-A is a feasible multi-agent adjuvant treatment regimen and, with further validation, could be an alternative to FOLFIRINOX.

Neoadjuvant-modified FOLFIRINOX vs nab-paclitaxel plus gemcitabine for borderline resectable or locally advanced pancreatic cancer patients who achieved surgical resection.

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)-modified FOLFIRINOX (mFOLF) vs nanoparticle albumin-bound paclitaxel plus gemcitabine (nab-P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan-Meier method and log-rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy-two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab-P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab-P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis-free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab-P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186-0.987) and abnormal postoperative CA 19-9 (hazard ratio, 2.47; 95% CI, 1.06-5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab-P/G.

Role of Conversion Surgery for Unresectable Pancreatic Cancer After Long-Term Chemotherapy.

BACKGROUND: Unresectable pancreatic cancer (UR-PC) has a poor prognosis. Although conversion surgery has been considered a promising strategy for improving prognosis in UR-PC, the clinical benefit offered to patients with UR-PC remains controversial. This study aimed to investigate the clinical benefits of conversion surgery in patients with UR-PC. METHODS: We evaluated patients with UR-PC referred to our department for possible surgical resection between January 2008 and June 2017. Resectability was evaluated using multimodal imaging in patients who underwent chemotherapy for more than 6 months. Conversion surgery was performed only in patients who were judged eligible for R0 resection. RESULTS: In total, 90 patients were evaluated. Among them, only 22 (24.4%) could actually undergo conversion surgery, and the R0 resection rate was 72.7% (16/22). Although Evans grade ≥ IIB was noted in six patients (27.3%), none achieved complete response (CR). The median survival time was significantly longer among patients who underwent conversion surgery than in the unresected patients who underwent chemotherapy (21.3 months vs. 12.6 months; p < 0.001). Multivariate and Kaplan-Meier analyses revealed microvascular invasion to have a significant adverse effect on recurrence-free survival (RFS: 7 months vs. not reached, p = 0.004) and overall survival (OS: 21 months vs. 85 months, p = 0.047). CONCLUSIONS: After long-term chemotherapy, conversion surgery for UR-PC is associated with long-term survival. Microvascular invasion is predictive of poor prognosis in these patients; adjuvant protocols are therefore needed for patients with microvascular invasion.

Preclinical Assessment with Clinical Validation of Selinexor with Gemcitabine and Nab-Paclitaxel for the Treatment of Pancreatic Ductal Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models. EXPERIMENTAL DESIGN: We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial. RESULTS: SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin-bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient-derived (PDX) subcutaneous xenografts. Selinexor-GEM-nab-paclitaxel blocked PDX and orthotopic tumor growth. In a phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1,000 mg/m2 i.v.) and nab-paclitaxel (125 mg/m2 i.v.) on days 1, 8, and 15 of 28-day cycle. Two patients showed partial response, and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression-free survival of 16 months and overall survival of 22 months. CONCLUSIONS: Our preclinical and ongoing clinical study lends support to the use of selinexor-GEM-nab-paclitaxel as an effective therapy for metastatic PDAC.

Molecular Targeting-Mediated Mild-Temperature Photothermal Therapy with a Smart Albumin-Based Nanodrug.

Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin-based tumor microenvironment-responsive nanoagent is designed via the self-assembly of human serum albumin (HSA), dc-IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting-mediated mild-temperature PTT. The formed HSA/dc-IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near-infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia-induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc-IR825/GA NPs show pH-responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild-temperature PTT and chemotherapy. Taken together, the NIR-activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild-temperature PTT-based combination strategies.

Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer: Results of the PANOVA phase 2 study.

BACKGROUND: Tumor Treating Fields (TTFields), low intensity alternating electric fields with antimitotic activity, have demonstrated survival benefit in patients with glioblastoma. This phase 2 PANOVA study was conducted to examine the combination of TTFields plus chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Forty patients with newly-diagnosed, locally advanced or metastatic PDAC received continuous TTFields (150 KHz for ≥18 h/day) plus gemcitabine (1000 mg/m2), or gemcitabine plus nab-paclitaxel (125 mg/m2). The primary endpoint was safety and secondary endpoints included compliance to TTFields, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventeen patients (85%) in each cohort reported Grade ≥3 adverse events (AEs). No increase in serious AEs (SAEs) was observed compared to that anticipated with systemic chemotherapy alone. Twenty-one patients reported TTFields-related skin toxicity, of which 7 were Grade 3; all resolved following temporary reduction of daily TTFields usage. No TTFields-related SAEs were reported. Compliance to TTFields was 68-78% of the recommended average daily use in both cohorts. Median PFS was 8.3 months (95% CI 4.3, 10.3) and median OS was 14.9 months (95% CI 6.2, NA) in the TTFields + gemcitabine cohort. In the TTFields + gemcitabine + nab-paclitaxel cohort, the median PFS was 12.7 months (95% CI 5.4, NA); median OS has not been reached. CONCLUSION: The PANOVA trial demonstrated that the combination of TTFields and systemic chemotherapy is safe and tolerable in patients with advanced PDAC. Based on the safety and preliminary efficacy results of this phase 2 study, a randomized phase 3 study (PANOVA-3) is underway.

Use of some nutritional supplements in drinking water of growing turkeys during 1st month of age and their effect on performance, meat quality, blood profile and antioxidant status.

The management practices implemented by the poultry sector as using some nutritional additives in the early stage of a bird's life can potentially detect other challenges to production development in the poultry farms. Many potential supplements can be included in the early feeding as which are added to drinking water. In this study, 180 1-day-old chicks were randomly distributed into six groups to investigate the use of some nutritional supplements in drinking water of growing turkeys during 1st month of age and their effect on growth performance, carcass traits, meat quality, leg problems, blood profile and oxidative status. Birds that were supplied with tap water were considered the control group (C), whereas the birds that received the 1st, 2nd, 3rd, 4th and 5th treatments (T1, T2, T3, T4 and T5, respectively) were supplied with drinking water containing 10% sugar syrup, molasses, lemon juice, skim milk and fresh egg albumin respectively. The different water additives significantly (p < 0.05) affected the body weight (BW) and body weight gain (BWG) at all studied ages except for the BW at 4 weeks old and BWG at 0-4 weeks old and 8-12 weeks old. Significant effects of the treatments on the feed consumption (FC) and feed conversion ratio (FCR) were not observed during the experiment, and the treatments did not cause significant differences (p < 0.05) in the carcass cut-up traits, bone measurements, body temperature, plumage conditions, mortality rates and blood parameters except for IgA (p = 0.043). The activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) was improved in the treatment groups with 10% molasses and lemon juice respectively. The total antioxidant capacity (T-AOC) and catalase (CAT) activities were enhanced in the treatments compared with the control group. The plasma malondialdehyde (MDA) levels were decreased with the sugar syrup, molasses and lemon juice treatments compared with those in the control and other groups. Supplementation of molasses or lemon juice to drinking water of turkeys during the 1st month of age resulted in a higher profit margin in comparison with the control group. The results showed that birds supplied with water containing 10% molasses or lemon juice during the growing period presented an improved growth performance, immune response, antioxidant status and economic efficiency.

FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel for Neoadjuvant Treatment of Resectable and Borderline Resectable Pancreatic Head Adenocarcinoma.

BACKGROUND: Both FOLFIRINOX and gemcitabine/nab-paclitaxel (G-nP) are used increasingly in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA). This study aimed to compare neoadjuvant FOLFIRINOX and G-nP in the treatment of resectable (R) and borderline resectable (BR) head PDA. METHODS: A single-institution retrospective review of R and BR patients undergoing pancreaticoduodenectomy after NAT with FOLFIRINOX or G-nP was performed. Comparative analysis was performed using inverse-probability-weighted (IPW) estimators. The end points of the study were overall survival (OS) and an 80% reduction in CA19-9 with NAT. RESULTS: In this study, 193 patients were analyzed, with 73 patients receiving FOLFIRINOX and 120 patients receiving G-nP. The median OS was 38.7 months for FOLFIRINOX versus 28.6 months for G-nP (p = 0.214). The patients who received FOLFIRINOX were younger and had fewer comorbidities, more BR disease, and larger tumors than those treated with G-nP (all p < 0.05). The two regimens were equally effective in achieving an 80% decline in CA19-9 (p = 0.8). The R0 resection rates were similar (80%), but FOLFIRINOX was associated with a reduction in pN1 disease (56% vs. 72%; p = 0.028). The receipt of adjuvant therapy was similar (74 vs. 75%; p = 0.79). In the Cox regression analysis with adjustment for baseline and treatment-related variables (FOLFIRINOX vs. G-nP, age, gender, computed tomography (CT) tumor size, BR vs. R, pre-NAT CA19-9), regimen type was not associated with a survival benefit. In the IPW analysis of 166 patients, however, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months compared with G-nP (p = 0.012). CONCLUSIONS: Both FOLFIRINOX and G-nP are viable options for neoadjuvant treatment of PDA. In this study, neoadjuvant FOLFIRINOX was associated with a 4.9-month improvement in survival compared with G-nP after adjustment for covariates.

Effects of ω-3 Fatty Acid Supplementation in Patients with Bile Duct or Pancreatic Cancer Undergoing Chemotherapy.

BACKGROUND/AIM: Omega-3 fatty acids may improve cancer cachexia, but only in patients with pancreatic and bile duct cancer. Patients with pancreatic cancer commonly suffer from exocrine pancreatic insufficiency, and the ingestion of digestive enzyme supplements may improve absorption. PATIENTS AND METHODS: Racol®, an enteral nutrient formulated with omega-3 fatty acids, was administered to patients with unresectable pancreatic and bile duct cancer. The skeletal muscle mass and blood test data were taken pre-administration and at 4 and 8 weeks after. Patients with pancreatic cancer were given the digestive enzyme supplement LipaCreon® from the fifth week after the start of administration. RESULTS: In all 27 patients, skeletal muscle mass was significantly increased at both 4 and 8 weeks after the start of administration versus pre-administration (p=0.006, p=0.002, respectively). CONCLUSION: Omega-3 fatty acid supplementation in patients with unresectable pancreatic and bile duct cancer may improve cancer cachexia.

Feasibility Study of Weekly Nanoparticle Albumin-Bound Paclitaxel (150 mg/m2) Followed by Fluorouracil, Epirubicin, and Cyclophosphamide Therapy as Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer.

BACKGROUND: Although several studies have shown efficacy of nanoparticle albumin-bound (nab) paclitaxel use as a neoadjuvant treatment in breast cancer, dosage and schedules were varied or used in combination and the data are still limited for weekly regimens. We evaluated the feasibility of weekly nab-paclitaxel followed by FEC (5-FU [fluorouracil], epirubicin, and cyclophosphamide) treatment feasibility as neoadjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Thirty-three patients with no previous chemotherapy were enrolled to receive nab-paclitaxel 150 mg/m2 the first 3 of 4 weeks (3q4w) followed by FEC as neoadjuvant treatment. The trial was powered for analyses of feasibility. RESULTS: Twenty-five patients completed the treatment as per protocol, and the completion rate was 75.8% (95% confidence interval, 59.0-87.2; P = .44). The regimen completion group was younger than those with regimen incompletion (average 45.1 vs. 56.6 years). The pathological complete response (ypT0-is/N0) rate was 30.3% in 33 patients, which was higher in triple-negative patients (58.3%). Grade 3/4 neutropenia was seen in 48.5%, although there was no febrile neutropenia. Grade 3 peripheral neuropathy was seen in 33.3%. CONCLUSION: Our study showed that weekly nab-paclitaxel 150 mg/m2 3q4w followed by FEC as neoadjuvant regimen might be sufficient in efficacy, although with a relatively high severe adverse event occurrence rate.

Management of Nephrotic Syndrome: A Case Report from Lao PDR.

We report the case of a 23-year-old woman with a 2-week history of swelling around the eyes and both legs, and generalized body swelling. She had a history of chronic constipation and poor diet but no fever, recent illnesses, or hematuria. Examination revealed bilateral pedal edema and mild ascites. Laboratory investigations showed low hemoglobin 79 g/L, low mean corpuscular volume 53 fL, thrombocytosis 973 × 109/L, and marked hypochromia and microcytosis, with low iron and ferritin. She had hypoalbuminemia and reduced serum protein (albumin 1.9 g/dL, globulin 2.8 g/dL) with elevated triglycerides (454 mg/dL). Although kidney biopsy could not be performed due to a lack of facilities in the country, we made a diagnosis of idiopathic nephrotic syndrome (NS) with iron deficiency anemia secondary to poor diet based on clinical and laboratory findings. The patient was admitted and treated with intravenous methylprednisolone and iron supplements. Antiplatelet therapy was instituted with dipyridamole to prevent thromboembolism from the combination of nephrotic syndrome and thrombocytosis. She was later treated with albumin and furosemide due to elevated blood pressure and worsened edema. The edema resolved and her general condition improved. She was discharged to follow up and has remained stable, requiring no further treatment as of 18 months after admission. Kidney biopsy is important for diagnosis of NS. Diagnosis may be made from clinical and laboratory findings alone in some cases; however, biopsy is required to determine the type of NS and improve further management and treatment outcomes for patients.

Size-Tunable Gd2O3@Albumin Nanoparticles Conjugating Chlorin e6 for Magnetic Resonance Imaging-Guided Photo-Induced Therapy.

Protein nanoparticles as nanocarriers are of particular interest in the field of cancer therapy. Nevertheless, so far a facile fabrication of theranostic protein nanoparticles have been explored with limited success for cancer imaging and therapy. In this work, we demonstrate the controllable synthesis of size-tunable Gd2O3@albumin conjugating photosensitizer (PS) (GA-NPs) using hollow albumin as the nanoreactor for magnetic resonance imaging (MRI)-guided photo-induced therapy. The growth of Gd2O3 nanocrystals within the hollow nanoreactors is well regulated through reaction time, and a typical PS (e.g. chlorin e6) is further conjugated with the protein corona of the nanoreactor through facile chemical coupling, followed by the formation of theranostic GA-NPs. GA-NPs exhibit good longitudinal relaxivity, ideal photostability, enhanced cellular uptakes, and preferable size-dependent tumor accumulation. Moreover, GA-NPs effectively generate remarkable photothermal effect, intracellular reactive oxygen species from Ce6, and subsequent cytoplasmic drug translocation, thereby leading to severe synergistic photothermal and photodynamic cell damages. Consequently, GA-NPs exhibit an in vivo size-dependent MRI capacity with enhanced imaging contrast for effective tumor localization, and also generate a potent synergistic photodynamic therapy/photothermal therapy efficacy under irradiation owing to their enhanced tumor accumulation and strong photo-induced cytotoxicity. These results suggest that GA-NPs can act as a promising theranostic protein nanoplatform for cancer imaging and photo-induced therapy.

Does radiologic response correlate to pathologic response in patients undergoing neoadjuvant therapy for borderline resectable pancreatic malignancy?

BACKGROUND AND OBJECTIVES: In patients with borderline resectable pancreas cancers, clinicians frequently consider radiographic response as the primary driver of whether patients should be offered surgical intervention following neoadjuvant therapy (NT). We sought to determine any correlation between radiographic and pathologic response rates following NT. METHODS: Between 2005 and 2015, 38 patients at a tertiary care referral center underwent NT followed by pancreaticoduodenectomy for borderline resectable pancreas cancer. Radiographic response after the completion of NT and pathologic response after surgery were graded according to RECIST and Evans' criteria, respectively. RESULTS: Preoperatively, 50% of patients underwent chemotherapy alone and 50% underwent chemotherapy and chemoradiation. Radiographically, one patient demonstrated a complete radiologic response, 68.4% (n = 26) of patients had stable disease (SD), 26.3% (n = 10) demonstrated a partial response, and one patient had progressive. Among patients without radiographic response, 77.7% (n = 21) achieved a R0 resection. Of patients with SD on imaging, 26.9% (n = 7) had Evans grade IIB or greater pathologic response. CONCLUSIONS: Our data indicate that approximately one-fourth of patients who did not have a radiologic response had a grade IIB or greater pathologic response. In the absence of metastatic progression, lack of radiographic down-staging following NT should not preclude surgery.

The Value of Survival Gains in Pancreatic Cancer from Novel Treatment Regimens.

BACKGROUND: Metastatic pancreatic cancer (mPC) is associated with low survival, with less than 10% of patients surviving 5 years. Recent therapies improve survival outcomes where few alternative therapies exist, but few economic analyses measure the value of survival gains attributable to new therapies. OBJECTIVE: To estimate the value of survival gains in advanced or mPC attributable to the introduction of novel treatment regimens. METHODS: Multivariate Cox proportional hazards models were used to estimate real-world survival gains associated with the introduction of gemcitabine (GEM) for patients diagnosed with stage IV or unstaged mPC in the Surveillance, Epidemiology, and End Results Program cancer registries. Then, evidence from clinical trials was used to evaluate the survival gains associated with nab-paclitaxel + gemcitabine (nP +GEM) and FOLFIRINOX (FFX) relative to GEM. The survival estimates and clinical trial evidence were used to calibrate an economic model and assess the cumulative value of survival gains in mPC to patients. Costs of treatment were calculated based on published cost-effectiveness studies. RESULTS: We estimated that the introduction of GEM in 1996 was associated with a hazard ratio of 0.920 (P < 0.05) and an increase in median survival from 3.1 to 4.5 months. Results suggested that the value of survival gains attributable to GEM equaled about $71,000 per patient, while the value attributable to nP + GEM was an additional $56,700. Estimates for the value of survival gains per patient, net of total incremental lifetime treatment costs (drugs, adverse events, and other costs), were $50,294 for GEM and an additional $31,900 for nP + GEM. Clinical trials and cost-effectiveness studies reported an overall survival gain from FFX that was larger than, but statistically similar to, nP + GEM and had greater risk of adverse events and total incremental costs. We estimated that the total value of survival gains to mPC patients, net of total costs, associated with GEM was up to $47.6 billion, and the additional values attributable to nP+GEM and FFX were up to $39.0 billion and $26.3 billion, respectively. CONCLUSIONS: Historically, mPC patients have faced high disease burden and had few treatment options. Treatments introduced since 1996 have led to improved survival, with varying costs associated with treatment and adverse events. Accounting for total incremental costs, the majority of the value of survival gains from GEM and nP+GEM was retained by mPC patients, highlighting the value of innovation in settings where survival is low and few alternative therapies exist. DISCLOSURES: Support for this research was provided by Celgene. Precision Health Economics was compensated by Celgene for work on this study. MacEwan is an employee of, and Yin is a consultant to, Precision Health Economics. Kaura and Khan are employees of Celgene. Study concept and design were contributed primarily by Yin and MacEwan, along with Kaura and Khan. MacEwan collected the data, and data interpretation was performed primarily by MacEwan and Yin, along with Kaura and Khan. The manuscript was written and revised by MacEwan, Yin, Kaura, and Khan.

Near-infrared photoimmunotherapy with galactosyl serum albumin in a model of diffuse peritoneal disseminated ovarian cancer.

Near-infrared photoimmunotherapy (NIR-PIT) is a highly cell-selective cancer therapy based on an armed antibody conjugated with a phthalocyanine-based photo-absorber, IRDye700DX (IR700). NIR-PIT can quickly kill target cells that express specific proteins on the cellular membrane but only when the antibody-IR700 conjugate binds to the cell membrane and is then exposed to NIR light. NIR-PIT is highly selective based on the specificity of the antibody. Galactosyl serum albumin (GSA) is composed of albumin decorated with galactose molecules conjugated to the carboxyl groups of albumin. GSA binds to beta-D-galactose receptors, a surface lectin, which are overexpressed on the cell surface of many cancers, including ovarian cancers and is quickly internalized after binding. Here, we demonstrate the feasibility of NIR-PIT in a model of disseminated peritoneal ovarian cancer (SHIN3 cells) using GSA-IR700 that binds to beta-D-galactose receptors. GSA-IR700 bound quickly to SHIN3 cells, then accumulated in the endo-lysosomes. Cell-specific killing was observed in vitro, yet a relatively large dose of NIR light exposure was required for cell killing compared to antibody-IR700 conjugates. To evaluate in vivo therapeutic effects of GSA-IR700 NIR-PIT, peritoneal disseminated SHIN3 tumor-bearing mice were separated into four groups: no treatment; NIR light only; GSA-IR700 only; and GSA-IR700 NIR-PIT. Repeated NIR-PIT showed significant suppression of tumor based on bioluminescence compared to the other groups (p < 0.05). Thus, repeated NIR-PIT using GSA-IR700 can achieve efficient antitumor effects, although GSA-IR700 NIR-PIT was less effective than antibody-IR700 NIR-PIT conjugates likely due to the rapid internalization of GSA-IR700.

Half-life extended biotherapeutics.

INTRODUCTION: Many of the biotherapeutics approved or under development suffer from a short half-life necessitating frequent applications in order to maintain a therapeutic concentration over an extended period of time. The implementation of half-life extension strategies allows the generation of long-lasting therapeutics with improved pharmacokinetic and pharmacodynamic properties. AREAS COVERED: This review gives an overview of the different half-life extension strategies developed over the past years and their application to generate next-generation biotherapeutics. It focuses on srategies already used in approved drugs and drugs that are in clinical development. These strategies include those aimed at increasing the hydrodynamic radius of the biotherapeutic and strategies which further implement recycling by the neonatal Fc receptor (FcRn). EXPERT OPINION: Half-life extension strategies have become an integral part of development for many biotherapeutics. A diverse set of these strategies is available for the fine-tuning of half-life and adaption to the intended treatment modality and disease. Currently, half-life extension is dominated by strategies utilizing albumin binding or fusion, fusion to an immunoglobulin Fc region and PEGylation. However, a variety of alternative strategies, such as fusion of flexible polypeptide chains as PEG mimetic substitute, have reached advanced stages and offer further alternatives for half-life extension.

Pancreatic cancer.

Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status.