Serum Depletion of Complement Component 5a Is Associated With Increased Inflammation and Poor Clinical Outcomes in Patients With Perianal Fistulas.

BACKGROUND: Persistent disease is a significant issue in the management of perianal fistulas, with up to 50% of patients requiring additional treatment after surgery. OBJECTIVE: This study aimed to identify a novel prognostic modality in hopes of risk-stratifying patients for persistent disease following corrective surgery. DESIGN: This was a retrospective study based on prospectively collected data using a combination of histopathology, high-throughput proteomic arrays, and ELISA-based methods. SETTINGS: This study used data obtained from patients who underwent corrective surgery for perianal fistulas at the University of Illinois Hospital between June 2019 and July 2020. PATIENTS: A cohort of 22 consecutive patients who had corrective surgery for perianal fistulas were included in this study. The patients were divided into 2 groups: those with resolving fistulas (N = 13) and those with persisting fistulas (N = 9). MAIN OUTCOME MEASURES: Nonresolving fistulas were determined by disease representation within 2 months of corrective surgery. RESULTS: Serum samples from patients with persistent perianal fistulas displayed a consistent decrease in the expression of complement pathway component C5a compared with either healthy controls or patients with resolving forms of disease. This was paralleled by an increase in the fistula expression of C5a and an associated increase in tissue infiltrating leukocytes and interleukin-1ß expression. LIMITATIONS: This study was limited by its retrospective design, relatively small sample size, and single-center data analysis. CONCLUSIONS: These results suggest that C5a is modestly depleted in patients with nonresolving forms of disease and traffics to the site of tissue damage and inflammation. Accordingly, serum C5a warrants continued investigation as a prognostic biomarker and predictor of recurrence in patients presenting with perianal fistulas. See Video Abstract at http://links.lww.com/DCR/B982 . LA DEPLECIN SRICA DEL COMPONENTE A DEL COMPLEMENTO SE ASOCIA CON UN AUMENTO DE LA INFLAMACIN Y MALOS RESULTADOS CLNICOS EN PACIENTES CON FSTULAS PERIANALES: ANTECEDENTES:La persistencia de la enfermedad es un problema significativo en el manejo de las fístulas perianales, presente hasta en el 50 % de los pacientes después de la cirugía y que requieren tratamiento adicional.OBJETIVO:DISEÑO:Se trata de un estudio retrospectivo basado en datos recolectados prospectivamente usando una combinación de histopatología, arreglos proteómicos de alto rendimiento y métodos basados en ELISA.ENTORNO CLÍNICO:Este estudio utilizó datos de pacientes que se sometieron a cirugía correctiva por fístulas perianales en el Hospital de la Universidad de Illinois entre junio de 2019 y julio de 2020.PACIENTES:Se incluyó en este estudio una cohorte de 22 pacientes consecutivos que se sometieron a cirugía correctiva de fístulas perianales. Los pacientes se dividieron en 2 grupos: aquellos con fístulas en resolución (N = 13) y aquellos con fístulas persistentes (N = 9).PRINCIPALES MEDIDAS DE VALORACIÓN:Las fístulas que no se resuelven fueron determinadas por la reaparición de la enfermedad dentro de los 2 meses posteriores a la cirugía correctiva.RESULTADOS:Las muestras de suero de pacientes con fístulas perianales persistentes mostraron una disminución constante en la expresión del componente C5a de la vía del complemento en comparación con controles sanos o pacientes con formas de resolución de la enfermedad. Esto fue paralelo a un aumento en la expresión de C5a en la fístula y un aumento asociado en los leucocitos que se infiltran en el tejido y la expresión de IL-1ß.LIMITACIONES:El estudio estuvo limitado por su diseño retrospectivo, tamaño de muestra relativamente pequeño y análisis de datos de un solo centro.CONCLUSIONES:Estos resultados sugieren que C5a se reduce moderadamente en pacientes con formas de enfermedad que no se resuelven y se desplaza al sitio del daño tisular e inflamación. En consecuencia, el C5a sérico justifica una investigación continua como biomarcador pronóstico y predictor de recurrencia en pacientes que presentan fístulas perianales. Consulte Video Resumen en http://links.lww.com/DCR/B982 . (Traducción- Dr. Ingrid Melo ).

Leukocyte subtyping predicts for treatment failure and poor survival in anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma (SCC) generally carries a favorable prognosis, as most tumors are highly sensitive to standard of care chemoradiation. However, outcomes are poor for the 20-30% of patients who are refractory to this approach, and many will require additional invasive procedures with no guarantee of disease resolution. METHODS: To identify the patients who are unlikely to respond to the current standard of care chemoradiation protocol, we explored a variety of objective clinical findings as a potential predictor of treatment failure and/or mortality in a single center retrospective study of 42 patients with anal SCC. RESULTS: Patients with an increase in total peripheral white blood cells (WBC) and/or neutrophils (ANC) had comparatively poor clinical outcomes, with increased rates of death and treatment failure, respectively. Using pre-treatment biopsies from 27 patients, tumors with an inflamed, neutrophil dominant stroma also had poor therapeutic responses, as well as reduced overall and disease-specific survival. Following chemoradiation, we observed uniform reductions in nearly all peripheral blood leukocyte subtypes, and no association between peripheral white blood cells and/or neutrophils and clinical outcomes. Additionally, post-treatment biopsies were available from 13 patients. In post-treatment specimens, patients with an inflamed tumor stroma now demonstrated improved overall and disease-specific survival, particularly those with robust T-cell infiltration. CONCLUSIONS: Combined, these results suggest that routinely performed leukocyte subtyping may have utility in risk stratifying patients for treatment failure in anal SCC. Specifically, pre-treatment patients with a high WBC, ANC, and/or a neutrophil-dense tumor stroma may be less likely to achieve complete response using the standard of care chemoradiation regimen, and may benefit from the addition of a subsequent line of therapy.

Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Case report: Rapid onset, ischemic-type gastritis after initiating oral iron supplementation.

Oral iron supplements are commonly administered to patients with chronic iron deficiency anemia. This approach is generally well-tolerated, causing only mild adverse effects. Rarely, oral iron supplementation can cause more severe symptoms, one of the most concerning being acute gastritis. This predominantly affects elderly patients and is extremely uncommon in young, otherwise healthy people. Here, we report the case of a 43-year-old woman who presented with upper gastrointestinal (GI) symptoms and iron deficiency anemia and was started on oral iron supplementation following the resolution of her acute symptoms. She soon re-presented with a severe, Helicobacter pylori-negative gastritis with iron deposition on histology. These new onset symptoms resolved rapidly with cessation of iron supplements, consistent with iron pill gastritis. In addition to the limited body of literature describing iron pill gastritis, this case serves as a reminder that any patient receiving oral iron supplementation is at a potential risk for gastritis, particularly in the setting of an ongoing GI pathology. Hence, it is important to provide continued follow-up for patients receiving iron supplementation regardless of age or comorbidity, particularly in the weeks following the start of the treatment.

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer.

Transforming Growth Factor ß (TGFß) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFß inhibitors in select immunotherapy regimens shows early promise. Though the TGFß target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFß modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFß. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.

Progress for Immunotherapy in Inflammatory Breast Cancer and Emerging Barriers to Therapeutic Efficacy.

Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer that carries a particularly poor prognosis. Despite the efficacy of immunotherapy in other difficult to treat forms of breast cancer, progress for immunotherapy in IBC has been difficult. Though immunotherapy has been under clinical investigation in IBC since the 1970s, few approaches have shown significant therapeutic efficacy, and no immunotherapy regimens are currently used in the treatment of IBC. Here, we provide a comprehensive summary of what is known about the immune composition of IBC tumors, clinical and basic science evidence describing the role for immune checkpoints such as PD-L1 in IBC pathobiology, as well as past and present attempts to advance ICIs in the treatment of IBC.

TGFß Signaling in the Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor ß (TGFß) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFß is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFß signaling can have potent tumor-suppressive effects in epithelial cells, TGFß signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFß signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFß pathway, as well as past and present attempts to advance TGFß inhibitors in the treatment of PDAC patients.

Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor.

PURPOSE: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production. EXPERIMENTAL DESIGN: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Hypoxia enhanced HIF-1alpha expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition. CONCLUSIONS: The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.

Chemotherapy-associated neutropenic enterocolitis of the transverse colon post right hemicolectomy.

Neutropenic enterocolitis (NE) is a life-threatening infection of the immunocompromised. NE ubiquitously affects the cecum, often with involvement of the ascending colon and ileum. Classically, NE is associated with high mortality leading to the frequent use of aggressive treatment strategies including surgery. Although conservative approaches are often successful, there are currently no standardized treatment guidelines for NE and it is unclear when such strategies should be implemented. Here, we describe a patient with suspected chemotherapy-associated NE despite having previously undergone a right hemicolectomy. As computed tomography imaging failed to provide a conclusive diagnosis, we performed a gentle endoscopic evaluation that affirmed a diagnosis of NE of the transverse colon, and suggested the patient would benefit from conservative treatment. This case demonstrates that endoscopy can be a safe and useful tool in the diagnosis of NE, and is an important reminder that NE can affect any part of the gastrointestinal tract.

An endovascular canine middle cerebral artery occlusion model for the study of leptomeningeal collateral recruitment.

OBJECTIVES: This work aimed to refine a large animal in minimally invasive reversible middle cerebral artery (MCA) occlusion (MCAO) model to account for leptomeningeal collateral formation. MATERIALS AND METHODS: An angiographically based methodology allowed for transient MCA and carotid terminus occlusion in 12 mongrel dogs and assessment of pial collateral recruitment. Outcome measures included 1- and 24-hour magnetic resonance imaging-based infarct volume calculation, a behavioral scale and histopathologic sections. RESULTS: MCAO succeeded in 8 of 12 dogs (67% efficiency). One-hour postreperfusion infarct volume predicted 24-hour postreperfusion infarct volume (r = 0.997, P < 0.0001). Pial collateral recruitment varied with time and reproducibly assessed predicted infarct volume on 1-hour postreperfusion mean diffusivity maps (P < 0.0001; r = 0.946) and 24-hour fluid-attenuated inversion recovery FLAIR magnetic resonance imaging (P = 0.0033; r = 0.961). The canine stroke scale score correlated with infarct volumes and pial collateral score. CONCLUSION: This canine MCAO model produces defined cerebral infarct lesions whose volumes correlate with leptomeningeal collateral formation and canine behavior.

Improvement in the reproducibility of region of interest using an auditory feedback loop: a pilot assessment using dynamic contrast-enhanced (DCE) breast MR images.

PURPOSE: To augment traditional visual data perception of complex multiparametric imaging data sets by adding auditory feedback to improve the delineation of regions of interest (ROIs) in tumor assessment in dynamic contrast-enhanced (DCE) MRI. MATERIALS AND METHODS: In addition to conventional display methodologies, we have created an application window which interfaces with audio output using dynamically loadable sound modules, providing goodness of fit (GF) information through auditory feedback. We have assessed effectiveness of conveying sound information with three independent readers on eight DCE-MR breast image data sets. The assessment was based on either conventional visual only mode or combined visual plus auditory mode. For statistical comparison between two sensory approaches, interobserver repeatability was measured with three different criteria. RESULTS: Adding auditory feedback improves repeatability significantly (P < 0.01), and the enhanced sensory approach had higher repeatability than visual only mode in visually complex breast tumor cases. However, in easy and moderate cases, visual only mode was more reproducible than the combined mode with very high significance (P < 0.001). CONCLUSION: Adding auditory information to visual based image analysis for identifying tumor ROIs provides higher interobserver repeatability for analyzing complex multidimensional/multiparametric medical image data sets with visually difficult lesions to delineate.

Multispectral co-occurrence with three random variables in dynamic contrast enhanced magnetic resonance imaging of breast cancer.

Presented is a new computer-aided multispectral image processing method which is used in three spatial dimensions and one spectral dimension where the dynamic, contrast enhanced magnetic resonance parameter maps derived from voxel-wise model-fitting represent the spectral dimension. The method is based on co-occurrence analysis using a 3-D window of observation which introduces an automated identification of suspicious lesions. The co-occurrence analysis defines 21 different statistical features, a subset of which were input to a neural network classifier where the assessments of the voxel-wise majority of a group of radiologist readings were used as the gold standard. The voxel-wise true positive fraction (TPF) and false positive fraction (FPF) results of the computer classifier were statistically indistinguishable from the TPF and FPF results of the readers using a one sample paired t-test. In order to observe the generality of the method, two different groups of studies were used with widely different image acquisition specifications.