Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer.

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.

Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-kappaB-independent, proteasome-mediated mechanism.

BACKGROUND: Cadmium has been classified as a human carcinogen, affecting health through occupational and environmental exposure. Cadmium has a long biological half-life (>25 years), due to the flat kinetics of its excretion. The prostate is one of the organs with highest levels of cadmium accumulation. Importantly, patients with prostate cancer appear to have higher levels of cadmium both in the circulation and in prostatic tissues. RESULTS: In the current report, we demonstrate for the first time that cadmium down-regulates expression of the X-linked inhibitor of apoptosis protein (XIAP) in prostate cancer cells. Cadmium-mediated XIAP depletion occurs at the post-transcriptional level via an NF-kappaB-independent, proteasome-mediated mechanism and coincides with an increased sensitivity of prostate cancer cells to TNF-alpha-mediated apoptosis. Prolonged treatment with cadmium results in selection of prostate cancer cells with apoptosis-resistant phenotype. Development of apoptosis-resistance coincides with restoration of XIAP expression in cadmium-selected PC-3 cells. CONCLUSIONS: Selection of cadmium-resistant cells could represent an adaptive survival mechanism that may contribute to progression of prostatic malignancies.

Pathologic concordance of sporadic synchronous bilateral renal masses.

OBJECTIVES: To review the collective experience evaluating pathologic concordance rates of sporadic bilateral synchronous renal tumors reported in the Surveillance, Epidemiology, and End Results (SEER) database and the published English literature and treated at Fox Chase Cancer Center; specifically, to analyze concordance rates of malignant versus benign disease, histologic type, tumor stage, and nuclear grade. METHODS: We reviewed the SEER database, the published English language literature, and our own institutional tumor registry to identify all cases of sporadic, synchronous localized (cT1-3N0M0) bilateral renal masses. Malignant and benign concordance rates were defined as agreement of any benign or malignant tumor type bilaterally. Histologic concordance was defined as bilateral histologic agreement. Tumors with mixed histologies were discordant unless all patterns were identical bilaterally. Nuclear grades were concordant if bilateral tumors were either "high" grade or "low" grade. RESULTS: The malignant concordance rate in the SEER data was 99% (273 of 274), and benign concordance was 0 (0 of 1). In the published literature and Fox Chase Cancer Center series, malignant concordance rates ranged from 84% to 95%, whereas benign concordance ranged from 39% to 67%. The SEER data revealed a histologic concordance rate of 93% (256 of 274), and nuclear grade concordance was 85% (88 of 103). CONCLUSIONS: These data demonstrate that in cases of bilateral sporadic localized synchronous renal masses, a diagnosis of ipsilateral renal cell carcinoma is associated with contralateral renal cell carcinoma in the vast majority of patients, whereas ipsilateral benign pathology is associated with contralateral benign disease at a substantially lower rate. Histologic concordance is similarly high, meaning most cases of clear cell or papillary tumors ipsilaterally are concordant in the contralateral kidney. Concordance rates of nuclear grade were slightly lower. These data are important when counseling and managing patients with bilateral synchronous sporadic renal tumors.

Delayed intervention of sporadic renal masses undergoing active surveillance.

BACKGROUND: Prompt surgical management remains the standard of care for renal cell carcinoma (RCC). Occasionally, it is necessary to postpone or delay surgical treatment. The authors of this report assessed whether delayed intervention following a period of active surveillance altered minimally invasive or nephron-sparing treatment plans, increased the risk of stage progression, and/or decreased recurrence-free survival rates. METHODS: The authors searched their institutional kidney cancer database to identify small (< or =4 cm in greatest dimension on presentation), enhancing renal masses for which treatment initially was delayed or refused. Clinical, radiographic, and pathologic records were reviewed to determine linear tumor growth kinetics, alterations in treatment plan, stage migration, and cancer-specific outcomes related to delayed intervention. RESULTS: Eighty-seven sporadic, localized, enhancing renal masses were identified in 82 patients who had management postponed for a median of 14 months (mean, 21 months; range, 6-97 months). Median tumor diameter was 2.0 cm on presentation. Treatment in 60 of 87 tumors (69%) was delayed for > or =12 months, and treatment was delayed for > or =24 months in 29 of 87 tumors (33%). Overall, 66 of 87 tumors (76%) underwent nephron-sparing approaches. In addition, 52 of 87 tumors (60%) were treated in a minimally invasive fashion. Pathology confirmed RCC in 73 of 87 treated tumors (84%). Fourteen of 54 tumors (26%) that were treated by surgical extirpation were high-risk tumors, and 3 of 54 tumors (6%) were upstaged on pathologic review. CONCLUSIONS: The majority of small, sporadic, clinically localized renal tumors demonstrated slow interval growth. The management of these lesions may be delayed cautiously without limiting or complicating the available treatment options or incurring a high risk of disease progression.

The relationship between inflammation and venous thrombosis. A systematic review of clinical studies.

During the past decade, the role of inflammation in the pathophysiology of arterial thrombosis has been elucidated. However, comparatively little is known about the relationship between inflammation and venous thrombosis. The aim of this study was to perform a systematic review of clinical studies that have examined the association between inflammation and venous thrombosis, specifically: (1) the value of inflammatory markers in predicting the future development of venous thrombosis; (2) test characteristics of markers of inflammation in the diagnosis of acute venous thrombosis; and (3) effect of venous thrombosis on blood levels of inflammatory markers. Using keywords venous thrombosis, venous thromboembolism, inflammation, acute phase markers, C-reactive protein (CRP), interleukin (IL)-6, IL-8, and monocyte chemotactic protein (MCP)-1, PubMed and Medline computerized databases were searched for English language articles published after 1980. Search results were restricted to clinical studies in humans that used study designs that were appropriate to address the above objectives. Results show that plasma CRP levels do not appear to predict risk of future venous thrombosis (two studies; N = 41,308). Four studies (N=562) have examined the utility of plasma CRP in the diagnosis of venous thrombosis; pooled positive and negative predictive values were 53% (95% CI:47%,59%) and 85% (95% CI: 81%, 89%), respectively. A two- to six-fold increase in the risk of deep vein thrombosis (DVT) is associated with elevations in plasma levels of CRP, IL-6, IL-8, MCP-1 or TNF-alpha (three studies). We can conclude that the nature of the relationship between inflammation and clinical venous thrombosis is not yet established. CRP does not appear to be useful in predicting future venous thrombosis or in the diagnosis of acute venous thrombosis. While several markers of inflammation are elevated in acute venous thrombosis, further research is needed to determine the precise relationship between these markers and venous thrombosis. The identification and elucidation of inflammatory markers relevant to venous thrombosis could provide targets for future therapy.

Palatal perforation associated with intranasal prescription narcotic abuse.

BACKGROUND: Palatal perforation resulting from insufflation of cocaine has been well documented. In comparison, reports of destructive orofacial lesions resulting from intranasal abuse of prescription narcotics are rare. We present the clinical and histologic findings in a case of palatal perforation arising in a patient abusing a prescription opioid drug. The patient denied any history of cocaine use but admitted to habitually crushing and snorting a hydrocodone/acetaminophen preparation. Study design The patient presented to our clinic seeking resolution of speech difficulties associated with an oroantral fistula. Surgical repair of the defect had been attempted unsuccessfully in the past. In addition to blood and chemistry panels, endoscopic examination was conducted, with removal of several biopsy specimens for histologic evaluation and flow cytometry. Biopsy specimens included both lesional and perilesional tissue from within the oral and nasopharyngeal cavities. Culture and cytology for fungal organisms were also performed. RESULTS: Histopathologic examination revealed normal mucosa with diffuse and focal inflammatory changes and no evidence of malignancy. Polarizable foreign material was noted in the specimens. The absence of lymphoid neoplasia was confirmed by flow cytometric analysis. The toxicology panel was positive for the presence of opiates in the blood. Culture and cytology were positive for candidal organisms. A palatal obturator was fabricated for the patient, producing significant improvement in the quality of speech. CONCLUSIONS: This may represent a case of palatal perforation resulting from abuse of a drug other than cocaine. The potential for drugs other than cocaine to produce destructive orofacial lesions should be considered.

Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation.

Dapper was isolated in a screen for proteins interacting with Dishevelled, a key factor in Wnt signaling. Dapper and Dishevelled colocalize intracellularly and form a complex with Axin, GSK-3, CKI, and beta-catenin. Overexpression of Dapper increases Axin and GSK-3 in this complex, resulting in decreased soluble beta-catenin and decreased activation of beta-catenin-responsive genes. Dapper also inhibits activation by Dishevelled of c-Jun N-terminal kinase (JNK), a component of beta-catenin-independent Frizzled signaling. Inhibition of Dapper activates both beta-catenin-responsive genes and an AP1-responsive promoter, demonstrating that Dapper is a general Dishevelled antagonist. Depletion of maternal Dapper RNA from Xenopus embryos results in loss of notochord and head structures, demonstrating that Dapper is required for normal vertebrate development.