TRUST-II: a global phase II study of taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors.

Crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer. However, unmet needs remain, including treatment of patients with resistance mutations, efficacy in brain metastasis and avoidance of neurological side effects. Taletrectinib was designed to: improve efficacy; overcome resistance to first-generation ROS1 inhibitors; and address brain metastasis while conferring fewer neurological adverse events. All of these features are demonstrated and supported by the interim data from the regional phase II TRUST-I clinical study. Here we describe the rationale and design of TRUST-II, a global phase II study of taletrectinib in patients with locally advanced/metastatic ROS1+ non-small-cell lung cancer and other ROS1+ solid tumors. The primary end point is confirmed objective response rate. Secondary end points include duration of response, progression-free survival, overall survival and safety. This trial is enrolling patients in North America, Europe and Asia.

The targeted therapies crizotinib and entrectinib are the first options available to treat a type of lung cancer called ROS1 fusion-positive non-small-cell lung cancer (ROS1⁺ NSCLC). However, not all patients with ROS1⁺ NSCLC respond to these drugs. In addition, most patients who take these drugs find their cancer eventually develops resistance and begins to grow again. Patients with disease that has spread (metastasized) to the brain have worse outcomes. Taletrectinib is a new type of targeted therapy that is being developed to treat people who have metastatic ROS1⁺ NSCLC. Data from a regional phase II clinical trial showed that taletrectinib is well tolerated, effective for patients who have never taken a ROS1 targeted therapy and inhibits ROS1⁺ NSCLC for patients whose cancer has developed some types of resistance to these drugs. It has also been shown to treat ROS1⁺ NSCLC tumors that have spread to the brain. This article discusses the rationale and design of a new trial called TRUST-II, which is a global phase II clinical trial looking at how well taletrectinib works and how safe it is. TRUST-II is actively enrolling patients in North America, Europe and Asia. Clinical Trial Registration: NCT04919811 (ClinicalTrials.gov).

Real-world characteristics and outcomes of advanced non-small-cell lung cancer patients with EGFR exon 19 deletions or exon 21 mutations.

Aim: To estimate real-world (rw) outcomes for first-line therapy in patients with advanced EGF receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), focusing on specific mutation types. Patients & methods: Retrospective observational study (n = 244 patients). Results: Univariate/multivariate analyses showed longer rw progression-free survival (rwPFS) and rwPFS2 in patients with ex19del versus Leu858Arg mutations. Median overall survival was 12.3 months longer with ex19del versus Leu858Arg mutations (HR: 1.47 [95% CI: 0.96-2.25]; p = 0.074). With EGFR-tyrosine kinase inhibitor monotherapy, unadjusted rwPFS for ex19del mutations was longer than for Leu858Arg mutations (HR: 1.62 [95% CI: 1.03-2.56]; p = 0.036). Conclusion: In this rw cohort of patients with advanced EGFR+ NSCLC, ex19del mutations conferred a prognostic advantage over Leu858Arg mutations, with significantly better rwPFS and rwPFS2.

Drone vs. Bird Detection: Deep Learning Algorithms and Results from a Grand Challenge.

Adopting effective techniques to automatically detect and identify small drones is a very compelling need for a number of different stakeholders in both the public and private sectors. This work presents three different original approaches that competed in a grand challenge on the "Drone vs. Bird" detection problem. The goal is to detect one or more drones appearing at some time point in video sequences where birds and other distractor objects may be also present, together with motion in background or foreground. Algorithms should raise an alarm and provide a position estimate only when a drone is present, while not issuing alarms on birds, nor being confused by the rest of the scene. In particular, three original approaches based on different deep learning strategies are proposed and compared on a real-world dataset provided by a consortium of universities and research centers, under the 2020 edition of the Drone vs. Bird Detection Challenge. Results show that there is a range in difficulty among different test sequences, depending on the size and the shape visibility of the drone in the sequence, while sequences recorded by a moving camera and very distant drones are the most challenging ones. The performance comparison reveals that the different approaches perform somewhat complementary, in terms of correct detection rate, false alarm rate, and average precision.

Granulomatosis with polyangiitis in a patient treated with dabrafenib and trametinib for BRAF V600E positive lung adenocarcinoma.

BACKGROUND: Dabrafenib and trametinib combination therapy is approved for the treatment of patients with BRAF V600E positive tumors including melanoma and lung cancer. The effect of BRAF and MEK inhibitors on the immune system is not fully understood although a number of case reports indicate autoimmune side effects related to the use of these drugs. Here, we discuss a case of a patient diagnosed with granulomatosis with polyangiitis (GPA) shortly after starting treatment with dabrafenib and trametinib for BRAF V600E positive metastatic lung adenocarcinoma. CASE PRESENTATION: A 57 years old female patient was diagnosed with recurrent lung adenocarcinoma following initial lobectomy for early stage disease. A BRAF V600E mutation was identified at the time of recurrence and she received combination dabrafenib and trametinib therapy. Shortly after commencement of treatment, she developed persistent fevers necessitating withholding both drugs. Pyrexia continued and was followed by left vision loss and acute kidney injury. Further rheumatological workup led to the unifying diagnosis of GPA. The patient was then treated with rituximab for GPA to the present date while all antineoplastic drugs were held. Lung cancer oligoprogression was addressed with radiation therapy and has not required further systemic treatment whereas GPA has been controlled to-date with rituximab. CONCLUSIONS: This case report raises awareness among clinicians treating patients with lung cancer for the possibility of triggering a flare of autoimmune diseases like GPA in patients with BRAF V600E positive lung cancer receiving treatment with BRAF directed therapy.

Implicit and Explicit Regularization for Optical Flow Estimation.

In this paper, two novel and practical regularizing methods are proposed to improve existing neural network architectures for monocular optical flow estimation. The proposed methods aim to alleviate deficiencies of current methods, such as flow leakage across objects and motion consistency within rigid objects, by exploiting contextual information. More specifically, the first regularization method utilizes semantic information during the training process to explicitly regularize the produced optical flow field. The novelty of this method lies in the use of semantic segmentation masks to teach the network to implicitly identify the semantic edges of an object and better reason on the local motion flow. A novel loss function is introduced that takes into account the objects' boundaries as derived from the semantic segmentation mask to selectively penalize motion inconsistency within an object. The method is architecture agnostic and can be integrated into any neural network without modifying or adding complexity at inference. The second regularization method adds spatial awareness to the input data of the network in order to improve training stability and efficiency. The coordinates of each pixel are used as an additional feature, breaking the invariance properties of the neural network architecture. The additional features are shown to implicitly regularize the optical flow estimation enforcing a consistent flow, while improving both the performance and the convergence time. Finally, the combination of both regularization methods further improves the performance of existing cutting edge architectures in a complementary way, both quantitatively and qualitatively, on popular flow estimation benchmark datasets.

Predictive value of oncogenic driver subtype, programmed death-1 ligand (PD-L1) score, and smoking status on the efficacy of PD-1/PD-L1 inhibitors in patients with oncogene-driven non-small cell lung cancer.

BACKGROUND: This multicenter, retrospective study explored the value of oncogene driver subtype, programmed death-1 ligand (PD-L1) status, and smoking status for predicting which patients with oncogene-driven non-small cell lung cancer (NSCLC) would benefit from treatment with programmed death-1 (PD-1)/PD-L1 inhibitors. METHODS: The clinical features, PD-L1 tumor proportion scores, and PD-1/PD-L1 inhibitor (PDi) outcomes (objective response rate and progression-free survival) of patients who had advanced NSCLC with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations or common, actionable oncogenic drivers were captured. RESULTS: In total, 189 oncogene-positive patients were analyzed. Of these, 104 received a PDi, and 108 had undergone prior PD-L1 testing. The frequency of PD-L1 positivity (≥1%) was higher in patients who had KRAS mutations (P = .031), smokers (P = .006), and non-Asian patients (P = .002). Multivariable analysis indicated that smoking status (P < .001) was the only factor associated significantly with KRAS mutation. The objective response rate to PDi treatment was 16.9% (11 of 65 patients) among smokers (17.3% in the KRAS-mutant and 15.4% in the non-KRAS-mutant smoker subgroups), which was significantly higher than the 0% rate (0 of 26 patients; P = .019) among never-smokers. In subgroup analyses, progression-free survival was influenced by KRAS mutation status (median, 4.57 vs 1.63 months; P = .004), smoking status (4.07 vs 1.73 months; P = .004), PD-L1 positivity (3.8 vs 1.2 months; P = .040), and non-Asian race (3.0 vs 1.97 months; P = .046). In multivariable analysis, only smoking status (P = .008) remained a significant predictor when a PD-L1 level ≥1% was used. However, both smoking status (P = .001) and PD-L1 status (P = .028) were independent predictors when a PD-L1 level ≥50% was used. CONCLUSIONS: Among associated clinical features among patients who have NSCLC with oncogenic drivers, smoking status potentially was the most important, easily available predictor of single PDi efficacy.

New Developments in Neoadjuvant Therapy for Lung Cancer.

Lung cancer is the leading cause of cancer death in the United States and worldwide. While most patients present with advanced metastatic disease for which a cure is elusive, increased use of spiral CT screening has led to identification of more early-stage patients who can be treated. At the same time, immunotherapy and new targeted therapies have improved survival in advanced disease. These new therapies are now being studied in the neoadjuvant and adjuvant settings to reduce systemic recurrences and improve cure rates. The results of early clinical trials of checkpoint inhibitor immunotherapy alone and combined with chemotherapy, as well as those of neoadjuvant studies of molecular therapies, have been promising. Ongoing large neoadjuvant trials of immunotherapies and molecular therapies alone and in combination with chemotherapy are underway and eagerly awaited. In this article, we review these new developments in neoadjuvant therapy for lung cancer.

Deep Learning on Multi Sensor Data for Counter UAV Applications-A Systematic Review.

Usage of Unmanned Aerial Vehicles (UAVs) is growing rapidly in a wide range of consumer applications, as they prove to be both autonomous and flexible in a variety of environments and tasks. However, this versatility and ease of use also brings a rapid evolution of threats by malicious actors that can use UAVs for criminal activities, converting them to passive or active threats. The need to protect critical infrastructures and important events from such threats has brought advances in counter UAV (c-UAV) applications. Nowadays, c-UAV applications offer systems that comprise a multi-sensory arsenal often including electro-optical, thermal, acoustic, radar and radio frequency sensors, whose information can be fused to increase the confidence of threat's identification. Nevertheless, real-time surveillance is a cumbersome process, but it is absolutely essential to detect promptly the occurrence of adverse events or conditions. To that end, many challenging tasks arise such as object detection, classification, multi-object tracking and multi-sensor information fusion. In recent years, researchers have utilized deep learning based methodologies to tackle these tasks for generic objects and made noteworthy progress, yet applying deep learning for UAV detection and classification is considered a novel concept. Therefore, the need to present a complete overview of deep learning technologies applied to c-UAV related tasks on multi-sensor data has emerged. The aim of this paper is to describe deep learning advances on c-UAV related tasks when applied to data originating from many different sensors as well as multi-sensor information fusion. This survey may help in making recommendations and improvements of c-UAV applications for the future.

Dipstick proteinuria is an independent predictor of high on treatment platelet reactivity in patients on clopidogrel, but not aspirin, admitted for major adverse cardiovascular events.

The effectiveness of aspirin and clopidogrel in patients with chronic kidney disease (CKD) suffering from acute cardiovascular events is unclear. High on treatment platelet reactivity (HTPR) has been associated with worse outcomes. Here, we assessed the association of dipstick proteinuria (DP) and renal function on HTPR and clinical outcomes. Retrospective cohort analysis of 261 consecutive, non-dialysis patients admitted for Major Adverse Cardiovascular Events (MACE) that had VerifyNow P2Y12 and VerifyNow Aspirin assays performed. HTPR was defined as P2Y12 reactivity unit (PRU) > 208 for clopidogrel and aspirin reaction units (ARU) > 550 for aspirin. Renal function was classified based on the estimated glomerular filtration rate (eGFR), and dipstick proteinuria was defined as ≥ 30 mg/dl of albumin detected on a spot analysis. All cause mortality, readmissions, and cardiac catheterizations were reviewed over 520 days. In patients on clopidogrel (n = 106), DP was associated with HTPR, independent of eGFR, diabetes mellitus, smoking or use of proton pump inhibitor (AOR = 4.76, p = 0.03). In patients with acute coronary syndromes, HTPR was associated with more cardiac catheterizations (p = 0.009) and readmissions (p = 0.032), but no differences in in-stent thrombosis or re-stenosis were noted in this cohort. In patients on aspirin (n = 155), no associations were seen between DP and HTPR. However, all cause mortality was significantly higher with HTPR in this group (p = 0.038). In this cohort, DP is an independent predictor of HTPR in patients on clopidogrel, but not aspirin, admitted to the hospital for MACE.

Keeping an Eye Out for Immunotherapy Toxicity: A Case of Unilateral Ptosis Caused by Ipilimumab/Nivolumab Therapy.

Despite ocular adverse events from immune checkpoint inhibitors being uncommon, they are still important complications to be aware of. We present the case of metastatic melanoma on ipilimumab/nivolumab in a patient who developed immunotherapy complications with delayed diagnosis because the only presenting symptom was unilateral ptosis. We reviewed the literature for relevant and important ocular and neurological complications of immune checkpoint inhibitors.

Real-world Trends, Rural-urban Differences, and Socioeconomic Disparities in Utilization of Narrow versus Broad Next-generation Sequencing Panels.

Advances in genetic technology have led to the increasing use of genomic panels in precision oncology practice, with panels ranging from a couple to hundreds of genes. However, the clinical utilization and utility of oncology genomic panels, especially among vulnerable populations, is unclear. We examined the association of panel size with socioeconomic status and clinical trial matching. We retrospectively identified 9,886 eligible adult subjects in the Mayo Clinic Health System who underwent genomic testing between January 1, 2016 and June 30, 2020. Patient data were retrieved from structured and unstructured data sources of institutional collections, including cancer registries, clinical data warehouses, and clinical notes. Socioeconomic surrogates were approximated using the Area Deprivation Index (ADI) corresponding to primary residence addresses. Logistic regression was performed to analyze relationships between ADI or rural/urban status and (i) use of genomic test by panel size; (ii) clinical trial matching status. Compared with patients from the most affluent areas, patients had a lower odds of receiving a panel test (vs. a single-gene test) if from areas of higher socioeconomic deprivation [OR (95% confidence interval (CI): 0.71 (0.61-0.83), P < 0.01] or a rural area [OR (95% CI): 0.85 (0.76-0.96), P < 0.01]. Patients in areas of higher socioeconomic deprivation were less likely to be matched to clinical trials if receiving medium panel tests [(OR) (95% CI): 0.69 (0.49-0.97), P = 0.03]; however, there was no difference among patients receiving large panel tests (P > 0.05) and rural patients were almost 2x greater odds of being matched if receiving a large panel test [(OR) (95% CI): 1.76 (1.21-2.55), P < 0.01]. SIGNIFICANCE: We identified socioeconomic and rurality disparities in the use of genomic tests and trial matching by panel size, which may have implications for equal access to targeted therapies. The lack of association between large panel tests and clinical trial matching by socioeconomic status, suggests a potential health equity impact, while removing barriers in access to large panels for rural patients may improve access to trials. However, further research is needed.

Real-World Treatment Patterns and Outcomes Across Three Lines of Therapy in Patients with ALK+ NSCLC.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy. METHODS: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling. RESULTS: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042). CONCLUSIONS: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs.

Impact of EML4-ALK variants and co-occurring TP53 mutations on duration of first-line ALK tyrosine kinase inhibitor treatment and overall survival in ALK fusion-positive NSCLC: Real-world outcomes from the GuardantINFORM database.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Factors such as variant allele frequencies (VAF), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting. METHODS: Adults with advanced/metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated. RESULTS: 307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n=280), brigatinib (n=15), lorlatinib (n=9), or ceritinib (n=3); 150 patients (49%) had ALK-fusion VAF ≥1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF <1% versus ≥1% had median TTD of 32.2 (95% CI: 20.7-NE) versus 14.7 months (10.4-19.9; HR: 1.57 [95% CI: 1.09-2.26]; P=0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-not estimable [NE]) in patients with versus without TP53mt detected (HR: 1.53 [1.07-2.19]; P=0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR: 1.29 [0.83-2.01]; P=0.2641). Patients with TP53mt and v3 had median TTD of 7.4 months (95% CI: 4.2-31.1). CONCLUSION: High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Introduction: Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. Methods: In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. Results: The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Conclusion: Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Neoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable Stage III melanoma: the Phase II NeoACTIVATE trial.

Both targeted therapies and immunotherapies provide benefit in resected Stage III melanoma. We hypothesized that the combination of targeted and immunotherapy given prior to therapeutic lymph node dissection (TLND) would be tolerable and drive robust pathologic responses. In NeoACTIVATE (NCT03554083), a Phase II trial, patients with clinically evident resectable Stage III melanoma received either 12 weeks of neoadjuvant vemurafenib, cobimetinib, and atezolizumab (BRAF-mutated, Cohort A, n = 15), or cobimetinib and atezolizumab (BRAF-wild-type, Cohort B, n = 15) followed by TLND and 24 weeks of adjuvant atezolizumab. Here, we report outcomes from the neoadjuvant portion of the trial. Based on intent to treat analysis, pathologic response (≤50% viable tumor) and major pathologic response (complete or near-complete, ≤10% viable tumor) were observed in 86.7% and 66.7% of BRAF-mutated and 53.3% and 33.3% of BRAF-wild-type patients, respectively (primary outcome); these exceeded pre-specified benchmarks of 50% and 30% for major pathologic response. Grade 3 and higher toxicities, primarily dermatologic, occurred in 63% during neoadjuvant treatment (secondary outcome). No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + TCM cell expansion associated with favorable pathologic responses (exploratory outcome).

Measurement of aldehyde dehydrogenase 1 expression defines a group with better prognosis in patients with non-small cell lung cancer.

Aldehyde dehydrogenase 1 (ALDH1) has been suggested as a surrogate biomarker for cancer stem cells in breast cancer and other tumors. We quantitatively measured ALDH1 in two large cohorts of patients with non-small cell lung cancer (NSCLC) and investigated its prognostic value. The AQUA method of quantitative immunofluorescence was used to measure ALDH1 in 134 patients with NSCLC from Yale University and 296 patients with NSCLC from Sotiria and Patras University hospitals in Greece, using tissue microarrays. Patients were classified as positive or negative for ALDH1 based on the detection threshold for quantitative immunofluorescence. Patients with squamous cell carcinoma had higher scores than patients with adenocarcinoma. Detectable ALDH1 predicted better prognosis in both cohorts (P = 0.0035 for the Yale cohort; P = 0.0238 for the Sotiria/Patras cohorts). The effect of ALDH1 expression was independent of clinicopathologic factors in the Yale cohort (risk ratio = 3.2, P = 0.0008), but did not reach significance in the Sotiria/Patras cohort (hazard ratio = 1.51, P = 0.08). Among patients with adenocarcinoma, the ALDH1-negative group had shorter survival compared with the ALDH1-positive group in the Yale cohort (P = 0.00001), but not in the Sotiria/Patras cohort (P = 0.45). Unlike breast cancer, in which ALDH1 expression predicts poor outcome, in NSCLC our exploratory and retrospective study indicates that ALDH1 expression is associated with favorable outcome.

Novel agents in the treatment of pancreatic adenocarcinoma.

The development of new agents and treatment strategies against pancreatic adenocarcinoma is vital, given the poor prognosis of the patients with this particular type of cancer. Three novel compounds were tested at different phases of clinical research and the results were presented in the recent ASCO Gastrointestinal Cancers Symposium. FG-3019 inhibits the connective tissue growth factor which is important in the biology of pancreatic cancer and was shown to be relatively safe in a phase I study (Abstract #213). In addition, ASG-5ME, an antibody specific for SLC44A4 that is universally expressed in pancreatic cancer and also carries a conjugate chemotherapy particle was safe at the appropriate dosing in a phase I trial (Abstract #176). Last but not least, tanespimycin, a molecule that inhibits heat shock protein 90 was not effective in the first line treatment of patients with pancreatic cancer in a phase II study (Abstract #245). Further studying of FG-3019 and ASG-5ME will show the potential activity if any of these compounds in patients with pancreatic cancer.

Update on novel therapies for pancreatic neuroendocrine tumors: 2013.

Neuroendocrine tumors of the pancreas (pNETs) are classified on the basis of their differentiation as well as the functional status. Current treatment options for non resectable disease include everolimus, sunitinib, somatostatin analogs and chemotherapy. A number of trials with novel compounds and drug combinations were reported at the recent ASCO Annual Meeting. Pasireotide is a novel somatostatin analog with broader affinity for the somatostatin receptors compared to the traditional octreotide and lantreotide and it appears to be safe in patients with pNETs according to a phase I study (Abstract #e15126). The combination of octreotide with everolimus showed promising response rate and progression free survival in a phase II study (Abstract #4136). In another phase II study, the AKT inhibitor MK-2206 was well tolerated with moderate efficacy (Abstract #e15133). Last but not least, we discuss the updated data from a phase II study that used the combination of temsirolimus with bevacizumab in patients with advanced pNETs (Abstract #4032).

Primary antiphospholipid syndrome and necrotizing pancreatitis: a diagnostic challenge.

The objective of this study was to report an unusual case of primary antiphospholipid syndrome (APS)-associated severe necrotizing pancreatitis. Since the APS was first recognized in the 1980s, a number of manifestations of the disorder have been described. We report primary APS presenting as severe necrotizing pancreatitis. This is the first such case to date that fulfills the revised Sapporo classification criteria. A 38-year-old previously healthy woman presented with new-onset hypertensive emergency and acute kidney injury. She subsequently developed severe epigastric pain attributable to necrotizing pancreatitis and extensive splenic infarcts. Biopsies of both the pancreas and kidney revealed thrombotic microangiopathy. Her lupus anticoagulant was positive on both weeks 1 and 12 of her disease course. A diagnosis of primary APS was made. Despite 6 months of aggressive care, she died of sepsis.

Time to Think about HLA-Based Diagnostics in Lung Cancer?

HLA evolutionary divergence reflects the ability to recognize diverse neoantigens as non-self, and as a biomarker is conceptually distinct from programmed cell death ligand 1 expression and tumor mutation burden. HLA-based assays to predict benefit from immunotherapy in lung cancer require prospective validation. See related article by Jiang et al., p. 4830.