Neoadjuvant Versus Adjuvant Chemotherapy for Resectable Metastatic Colon Cancer in Non-academic and Academic Programs.

BACKGROUND: Overall survival advantage of chemotherapy before versus after metastasectomy of liver or lung lesion is not clear for colon cancer with synchronous liver or lung metastasis. MATERIALS AND METHODS: Adults 20 years or older with primary colon cancer and single organ metastatic disease either in the liver or lung at diagnosis were identified between 2010 and 2015 through the National Cancer Database (NCDB). Patients were categorized into 2 cohorts: pre-operative/peri-operative chemotherapy (neoadjuvant -[NAC]) or post-operative chemotherapy (adjuvant [AC]). Survivals and factors associated with were compared between the 2 groups. RESULTS: A total of 3038 patients with colon cancer with liver or lung metastases were identified. The percentage of patients receiving NAC had steadily increased from 12.29% to 28.31%, mostly in academic programs. On multivariate analysis, patients who received NAC had an overall survival advantage in the non-academic setting whereas no advantage is seen in the patients treated in the academic settings. The median overall survival for patients receiving NAC and AC was 47.24 months and 38.08 months, respectively. Factors associated with overall survival advantage in NAC patients treated in non-academic programs included age 20-49 years, CEA value of >30, right-sided colon primary, liver metastasis, and clear resection margins. CONCLUSIONS: Metastatic colon cancer with single organ liver or lung lesions benefits from neoadjuvant chemotherapy, especially in -non-academic settings. The overall survival advantage in this setting has not been shown before.

Lenvatinib in Management of Solid Tumors.

Lenvatinib is a type I tyrosine kinase inhibitor exhibiting powerful antiangiogenic activity in cancer therapy. Displaying activity in multiple solid tumors, it has been approved in differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma as single agent or in combination. In addition, lenvatinib has shown promise in several other tumor types including medullary, anaplastic thyroid, adenoid cystic, and endometrial cancer. Exploring synergy between angiogenic and immune checkpoint inhibitors, the lenvatinib/pembrolizumab combination is poised to become the next pair of active drugs in endometrial, lung, and gastrointestinal malignancies. Despite robust activity, the drug can be difficult to tolerate. Optimization of dose and biomarkers for prediction of efficacy and toxicities will be of great help. IMPLICATIONS FOR PRACTICE: Readers will be presented with an update on U.S. Food and Drug Administration approval of lenvatinib and suggestions for off-label use in thyroid cancer and adenoid cystic carcinomas. They will become familiarized with the common side effects, frequency, and predicators of response. In addition, they will learn that different strengths of lenvatinib are prescribed and why. Finally, readers are pointed to the latest efforts to combine lenvatinib and pembrolizumab, as well as to unresolved issues such as long-term side effects/toxicities of this drug.

Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy To Enhance Cytotoxic T Cell Infiltration and Tumor Control.

Carcinoma-associated fibroblasts (CAFs) are found in many types of cancer and play an important role in tumor growth and metastasis. Fibroblast-activation protein (FAP), which is overexpressed on the surface of CAFs, has been proposed as a universal tumor targeting antigen. However, recent studies show that FAP is also expressed on multipotent bone marrow stem cells. A systematic anti-FAP therapy may lead to severe side effects and even death. Hence, there is an urgent need of a therapy that can selectively kill CAFs without causing systemic toxicity. Herein we report a nanoparticle-based photoimmunotherapy (nano-PIT) approach that addresses the need. Specifically, we exploit ferritin, a compact nanoparticle protein cage, as a photosensitizer carrier, and we conjugate to the surface of ferritin a FAP-specific single chain variable fragment (scFv). With photoirradiation, the enabled nano-PIT efficiently eliminates CAFs in tumors but causes little damage to healthy tissues due to the localized nature of the treatment. Interestingly, while not directly killing cancer cells, the nano-PIT caused efficient tumor suppression in tumor-bearing immunocompetent mice. Further investigations found that the nano-PIT led to suppressed C-X-C motif chemokine ligand 12 (CXCL12) secretion and extracellular matrix (ECM) deposition, both of which are regulated by CAFs in untreated tumors and mediate T cell exclusion that prevents physical contact between T cells and cancer cells. By selective killing of CAFs, the nano-PIT reversed the effect, leading to significantly enhanced T cell infiltration, followed by efficient tumor suppression. Our study suggests a new and safe CAF-targeted therapy and a novel strategy to modulate tumor microenvironment (TME) for enhanced immunity against cancer.

YM155 inhibits topoisomerase function.

YM155 (sepantronium bromide) has been evaluated in clinical trials as a survivin suppressant, but despite positive signals from early work, later studies were negative. Clarification of the mechanism of action of YM155 is important for its further development. YM155 affects cells in a cell cycle-specific manner. When cells are in G1, YM155 prevented their progression through the S phase, leaving the cells at G1/S when exposed to YM155. Passage through mitosis from G2 is also defective following YM155 exposure. In this study, YM155 did not behave like a typical DNA intercalator in viscosity, circular dichroism, and absorption spectroscopy studies. In addition, molecular modeling experiments ruled out YM155 DNA interaction to produce DNA intercalation. We show that YM155 inhibited topoisomerase 2α decatenation and topoisomerase 1-mediated cleavage of DNA, suggesting that YM155 inhibits the enzyme function. Consistent with these findings, DNA double-strand break repair was also inhibited by YM155.

Free Lung Cancer Screening Trends Toward a Twofold Increase in Lung Cancer Prevalence in the Underserved Southeastern United States.

OBJECTIVES: The National Lung Screening Trial (NLST) reported that the prevalence of lung cancer in individuals at high risk for the disease is 1%, and that screening these individuals using low-dose helical computed tomography of the chest saves lives. To increase screening accessibility in the underserved southeastern United States, we developed a free lung screening program, modeled after the Lahey Hospital & Medical Center Free Lung Screening Program, for individuals meeting National Comprehensive Cancer Network high-risk criteria. METHODS: This was a chart review of 264 participants screened in the first year of our program. Participants were divided into categories based on the Lung Imaging Reporting and Diagnostic System. Categories three and four were considered positive findings, with demographic and disease criteria collected on these patients. RESULTS: Of 264 participants screened, 28 (10.6%) were Lung Imaging Reporting and Diagnostic System category four, 23 (8.7%) were category three, 78 (29.5%) were category two, and 135 (51.1%) were category one. Eight of the 264 participants (3.0%) had lung cancer, with 75% detected in early stages. CONCLUSIONS: We found a lung cancer prevalence in our high-risk screened population of 3.0% (8 of 264). After adjusting for patients who were symptomatic on clinical evaluation, we report a prevalence of cancer at 2.2% compared with 1.1% in the first year of the National Lung Screening Trial and a prevalence of 1.9% versus 0.6% compared with the National Comprehensive Cancer Network criteria in the first 10 months at Lahey Hospital & Medical Center. This study justifies low-dose helical computed tomography screening in high-risk regions because lung cancer treatment before symptoms appear is more effective, and the prevalence of disease in the detectable preclinical phase is high.

Nanoscintillator-mediated X-ray inducible photodynamic therapy for in vivo cancer treatment.

Photodynamic therapy is a promising treatment method, but its applications are limited by the shallow penetration of visible light. Here, we report a novel X-ray inducible photodynamic therapy (X-PDT) approach that allows PDT to be regulated by X-rays. Upon X-ray irradiation, the integrated nanosystem, comprised of a core of a nanoscintillator and a mesoporous silica coating loaded with photosensitizers, converts X-ray photons to visible photons to activate the photosensitizers and cause efficient tumor shrinkage.

Radiotherapy in Managing Metastatic Hepatocellular Carcinoma With Cardiac Involvement and Pulmonary Tumor Thromboemboli: A Case Report.

Hepatocellular carcinoma (HCC) is the most common liver cancer and presents various degrees of aggressiveness. In this case study, we reported the management of an aggressive HCC patient who was a young immigrant from a hepatitis B endemic country with locally advanced HCC with portal involvement at presentation. Patient was initially managed with Yttrium-90 (Y-90) instillation, then systemic treatment when he had disease progression. Despite multiple lines of systemic treatments, patient continued to progress and developed significant cardiac involvement and pulmonary tumor thromboemboli. His course of treatment was further complicated by hemoptysis, presumably from hemorrhagic tumor thromboemboli. Patient became ineligible for systemic treatment due to the risk of hemoptysis, thus, subsequently managed with a course of palliative radiotherapy. Unfortunately, patient developed hemorrhagic shock, cardiac failure, and septic shock during radiation treatment and expired shortly afterward. In this case report, we discussed multi-modal treatments, including Y-90, systemic treatment, and radiotherapy, in managing complicated and aggressive HCC. We also reported risk factors, prognostic factors, efficacy of Y-90 instillation and the necessity of a personalized treatment approach. In conclusion, there is no consensus on managing patients with metastatic HCC with cardiac and pulmonary involvement currently. Treatment modalities are often highly personalized and require multi-disciplinary discussion.

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Ubiquitin-conjugating enzyme UBE2C: molecular biology, role in tumorigenesis, and potential as a biomarker.

Ubiquitin-conjugating enzyme 2C (UBE2C) participates in cell cycle progression and checkpoint control by targeted degradation of short-lived proteins. As a conjugating enzyme, it directs polyubiquitination to preferred lysine in the substrates. In addition to its well-known role in cyclin B destruction that is essential for exit from mitosis, UBE2C also plays an important role in mitotic spindle checkpoint control. Cells overexpressing UBE2C ignore the mitotic spindle checkpoint signals and lose genomic stability, which is a hallmark of cancer. UBE2C expression is upregulated upon malignant transformation, and amplification of UBE2C is often seen at the chromosome level in cancers in a manner similar to c-Myc, which is directly upstream of UBE2C. UBE2C levels are upregulated in a wide range of solid tumors and hematological malignancies. The level of expression correlates with the aggressiveness of the tumor. High UBE2C expression is predictive of poor survival and perhaps high risk for relapse. UBE2C immunochemistry may be integrated into the diagnosis of thyroid malignancy and gliomas. This minireview summarizes what is known about the function of UBE2C focusing on its role in the regulation of spindle assembly checkpoint, its part in tumorigenesis, and its potential as a tumor marker for various cancers.

Current Strategies for Extensive Stage Small Cell Lung Cancer Beyond First-line Therapy.

Extensive stage small cell lung cancer carries extremely poor prognosis and adding immune checkpoint inhibitor to platinum etoposide combination in first line only improved outcomes modestly. Once disease recurs, treatment response is only transient in nature. Various strategies that are being explored include dual checkpoint blockade, BiTE and CAR-T cell approaches. Immune checkpoint inhibitors are being combined with PARP inhibitors. Other approaches currently being investigated include liposomal irinotecan and combining known active agents for SCLC in relapsed setting such as newly approved lurbinectedin with doxorubicin, paclitaxel, irinotecan or topotecan with ATR inhibitor (Berzosertib). Temozolomide has also been tested in combination with a Parp inhibitor. New antibody or small molecule drug conjugates are being actively investigated, so is a biomarker based approach. Better understanding of small cell lung cancer disease biology via high through-put genomic, proteomic and methylation profiling offer glimpse of hope in our efforts to contain this deadly disease. A table of representative molecular targets under investigation is provided in the end.

Extracorporeal Membrane Oxygenation to Facilitate Chemotherapy-Moving the Goalposts!

Extracorporeal membrane oxygenation (ECMO) is a lifesaving intervention in critically ill patients with cardiorespiratory failure. ECMO in patients with cancer is generally contraindicated not only to conserve precious resources and properly direct use but also due to a multitude of associated physiological derangements in these subsets of patients. ECMO in patients with disseminated cancer is an automatic rule-out except for anecdotal reports. Despite this, select patients with metastatic chemotherapy-sensitive cancer may benefit from ECMO as a bridge to therapy. In this report, we describe the use of veno-arterial-venous ECMO (VAV-ECMO) as a bridge to facilitate chemotherapy in a patient with cardiorespiratory failure secondary to a chemotherapy-sensitive metastatic non-seminomatous germ cell tumor.

Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers.

OBJECTIVES: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. MATERIALS AND METHODS: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). RESULTS: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). CONCLUSIONS: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.

Description of a Lung Cancer Hotspot: Disparities in Lung Cancer Histology, Incidence, and Survival in Kentucky and Appalachian Kentucky.

INTRODUCTION: Kentucky is recognized as the state with the highest lung cancer burden for more than 2 decades, but how lung cancer differs in Kentucky relative to other US populations is not fully understood. PATIENTS AND METHODS: We examined lung cancer reported to the Surveillance, Epidemiology, and End Results (SEER) Program by Kentucky and the other SEER regions for patients diagnosed between 2012 and 2016. Our analyses included histologic types, incidence rates, stage at diagnosis, and survival in Kentucky and Appalachian Kentucky relative to other SEER regions. RESULTS: We found that both squamous cell carcinomas and small-cell lung cancers represent larger proportions of lung cancer diagnoses in Kentucky and Appalachian Kentucky than they do in the SEER registries. Furthermore, age-adjusted cancer incidence rates were higher in Kentucky for every subtype of lung cancer examined. Most notably, for Appalachian women the rate of small-cell carcinomas was 3.5-fold higher, and for Appalachian men the rate of squamous cell carcinoma was 3.1-fold higher, than the SEER rates. In Kentucky, lung cancers were diagnosed at later stages and lung cancer survival was lower for adenocarcinoma and neuroendocrine carcinomas than in SEER registries. Squamous cell carcinomas and small-cell carcinomas were most lethal in Appalachian Kentucky. CONCLUSION: Together, these data highlight the considerable disparities among lung cancer cases in the United States and demonstrate the continuing high burden and poor survival of lung cancer in Kentucky and Appalachian Kentucky. Strategies to identify and rectify causes of these disparities are discussed.

Targeted deletion of Tssk1 and 2 causes male infertility due to haploinsufficiency.

Targeted deletion of Tssk1 and 2 resulted in male chimeras which produced sperm/spermatogenic cells bearing the mutant allele, however this allele was never transmitted to offspring, indicating infertility due to haploinsufficiency. Morphological defects in chimeras included failure to form elongated spermatids, apoptosis of spermatocytes and spermatids, and the appearance of numerous round cells in the epididymal lumen. Characterization of TSSK2 and its interactions with the substrate, TSKS, were further investigated in human and mouse. The presence of both kinase and substrate in the testis was confirmed, while persistence of both proteins in spermatozoa was revealed for the first time. In vivo binding interactions between TSSK2 and TSKS were established through co-immunoprecipitation of TSSK2/TSKS complexes from both human sperm and mouse testis extracts. A role for the human TSKS N-terminus in enzyme binding was defined by deletion mapping. TSKS immunoprecipitated from both mouse testis and human sperm extracts was actively phosphorylated. Ser281 was identified as a phosphorylation site in mouse TSKS. These results confirm both TSSK 2 and TSKS persist in sperm, define the critical role of TSKS' N-terminus in enzyme interaction, identify Ser 281 as a TSKS phosphorylation site and indicate an indispensable role for TSSK 1 and 2 in spermiogenesis.

TSKS concentrates in spermatid centrioles during flagellogenesis.

Centrosomal coiled-coil proteins paired with kinases play critical roles in centrosomal functions within somatic cells, however knowledge regarding gamete centriolar proteins is limited. In this study, the substrate of TSSK1 and 2, TSKS, was localized during spermiogenesis to the centrioles of post-meiotic spermatids, where it reached its greatest concentration during the period of flagellogenesis. This centriolar localization persisted in ejaculated human spermatozoa, while centriolar TSKS diminished in mouse sperm, where centrioles are known to undergo complete degeneration. In addition to the centriolar localization during flagellogenesis, mouse TSKS and the TSSK2 kinase localized in the tail and acrosomal regions of mouse epididymal sperm, while TSSK2 was found in the equatorial segment, neck and the midpiece of human spermatozoa. TSSK2/TSKS is the first kinase/substrate pair localized to the centrioles of spermatids and spermatozoa. Coupled with the infertility due to haploinsufficiency noted in chimeric mice with deletion of Tssk1 and 2 (companion paper) this centriolar kinase/substrate pair is predicted to play an indispensable role during spermiogenesis.

Immunogenicity of a multi-component recombinant human acrosomal protein vaccine in female Macaca fascicularis.

A vaccine formula comprised of five recombinant human intra-acrosomal sperm proteins was inoculated into female monkeys to test whether specific antibodies to each component immunogen could be elicited in sera and whether antibodies elicited by the vaccine affected in vitro fertilization. Acrosomal proteins, ESP, SLLP-1, SAMP 32, SP-10 and SAMP 14, were expressed with his-tags, purified by nickel affinity chromatography and adsorbed to aluminum hydroxide. Five female cynomolgus monkeys were inoculated intramuscularly three times at monthly intervals. All five monkeys developed both IgG and IgA serum responses to each recombinant immunogen on Western blots. Each serum stained the acrosome of human sperm and bound to the cognate native protein on Western blots of human sperm extracts. By ELISA, all monkeys developed IgG to each immunogen, with the highest average absorbance values to ESP, SAMP 32 and SP-10, followed by lower values for SLLP-1 and SAMP 14. IgA was also generated to each component immunogen with the highest average absorbance values to SLLP-1 and SP-10. For antigens that induced an IgA response, the duration of the IgA response was longer than the IgG response to the same antigens. This study supports the concept that a multivalent contraceptive vaccine may be administered to female primates evoking both peripheral (IgG) and mucosal (IgA) responses to each component immunogen following an intramuscular route of inoculation with a mild adjuvant, aluminum hydroxide, approved for human use.

Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death.

The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy.

Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors.

BACKGROUND: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. METHODS: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. RESULTS: Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease. CONCLUSIONS: Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02048709 .

Unusual Contiguous Soft Tissue Spread of Advanced Malignant Mesothelioma Detected by FDG PET/CT.

Malignant pleural mesothelioma (MPM) is a tumor of mesodermal origin that arises from the serosa of the pleura, peritoneum, pericardium or tunica vaginalis. MPM is well known to have a poor prognosis with a median survival time of 12 months. Accurate diagnosis, staging and restaging of MPM are crucial with [18F] flurodeoxy-D-glucose positron emission tomography (FDG PET/CT) playing an increasingly important role. Here we report a case of MPM with unusual contiguous soft tissue spread of the tumor along the dermal and fascial planes characterized by PET/CT. Given that the loco-regional tumor in the thorax was under control on PET/CT, the death of the patient was most likely associated with physiologic or metabolic causes associated with an extra-thoracic tumor.