Invasive mould sinusitis in patients with haematological malignancies: a 10 year single-centre study.

OBJECTIVES: Invasive mould sinusitis (IMS) is a severe infection in patients with haematological malignancies. Because of a paucity of contemporaneous data about IMS, we sought to evaluate clinical aspects and outcome of IMS in these patients. METHODS: The records of adult haematological malignancy patients with proven or probable IMS over a 10 year period were reviewed retrospectively. RESULTS: We identified 44 patients with IMS. Mucorales were isolated in 13 (35.1%) patients and Fusarium and Aspergillus were isolated in 9 (24.3%) patients each. Patients with IMS owing to Mucorales were more likely to have a history of diabetes mellitus (P = 0.003) and high-dose corticosteroid use (P = 0.03). Thirty-five (80%) patients received antifungal combinations and 36 (82%) underwent surgical debridement. The 12 week IMS-attributable mortality was 36.4% (16 patients). A relapsed and/or refractory haematological malignancy was an independent risk factor for 6 week IMS-attributable (P = 0.038), 12 week all-cause (P = 0.005) and 12 week IMS-attributable (P = 0.0015) mortality. Neutrophil count <100/µL and lymphocyte count <200/µL were associated with increased 12 week IMS-attributable and 6 week all-cause mortality, respectively (P = 0.044 and 0.013). IMS due to Aspergillus was an independent risk factor for both 12 week all-cause (P = 0.011) and IMS-attributable (P = 0.026) mortality. Initial antifungal therapy with a triazole-containing regimen was associated with decreased 6 week all-cause (P = 0.032) and IMS-attributable (P = 0.038) mortality. Surgery was not an independent factor for improved outcome. CONCLUSIONS: Despite combined medical and surgical therapy, IMS had high mortality. Mortality risk factors were relapsed and/or refractory malignancy, cytopenia and Aspergillus infection in this study.

Addressing an unmet need in oncology patients: rehabilitation of upper aerodigestive tract function.

BACKGROUND: Laryngeal dysfunction in the oncology population is common and may detract from quality of life (QoL) due to vocal restriction and aspiration. Therapies to address this complex issue have not been explored to date. We examined the outcomes among oncology patients treated with a minimally invasive office-based surgical approach for the rehabilitation of laryngeal dysfunction. PATIENTS AND METHODS: A retrospective analysis was carried out of oncology patients referred for laryngeal dysfunction. Patients who underwent minimally invasive injection laryngoplasty (IL) were selected. Subjective outcome measures, objective voice analysis parameters, and swallowing studies were annotated. RESULTS: Sixty-one patients underwent IL for the management of laryngeal dysfunction. Lung cancer was the most common cancer diagnosis (39.3%), and 52% of patients had thoracic malignancies. All patients had a self-reported improvement in vocal function with a single injection, and 55 patients (90%) reported lasting effects at 3 months. In patients with pre- and postoperative voice analysis, phonatory function increased from 5.0 to 10.5 s, more than twofold improvement compared with baseline functioning. Seventy-one percent of patients who aspirated before injection no longer required a modified diet. There were no major complications. CONCLUSIONS: Interventions to improve the QoL in oncology patients continue to evolve. We report significant improvements in both subjective and objective measures of laryngeal function after IL for vocal fold dysfunction that are both immediate and sustained. We conclude that IL is a safe and efficacious procedure for the treatment of laryngeal dysfunction in oncology patients, resulting in palliation and improved QoL.

Effect of chronic resistive loading on ventilatory control in a rat model.

Acute resistive loading of the airway has been shown to activate the endogenous opioid system, with subsequent depression of ventilation. The present investigation was designed to assess the effect of chronic airway loading on ventilation and CO2 sensitivity, and to determine whether the endogenous opioid system contributes to long-term modulation of ventilatory control in this setting. A flow-resistive ventilatory load was imposed in 2-mo-old rats by surgical implantation of a circumferential tracheal band that approximately tripled tracheal resistance. Respiration and CO2 sensitivity were serially and noninvasively assessed by barometric plethysmography over a period of 21 wk. Ventilatory output was assessed as minute inspiratory effort, which was defined as the product of plethysmograph signal amplitude, inspiratory time, and respiratory rate (RR). CO2 sensitivity was calculated as the percent change in minute inspiratory effort from room air to CO2 exposure. The effect of naloxone administration on these parameters was also determine. Arterial blood gases demonstrated hypercapnia with maintenance of normoxia in loaded rats; these findings persisted for the duration of the study. Two days after surgery, rats with tracheal obstruction demonstrated a lower RR than controls during room air breathing and during CO2 stimulation. CO2 sensitivity was significantly depressed in obstructed animals at this time. Escape from suppression of RR and CO2 sensitivity was evident by 14 to 21 d after obstruction; however, suppression of these parameters reappeared and was maintained from 56 to 147 d after obstruction. Naloxone augmented minute inspiratory effort during CO2 stimulation at 2 d after obstruction but not thereafter; naloxone had no effect in control rats. These data indicate that chronic airway loading suppresses RR and CO2 sensitivity in a triphasic manner. The early suppression is partially reversible by naloxone; late-appearing suppression is unaffected by naloxone and is presumably mediated by mechanisms that do not involve endogenous opioids.

Comparison of tube and gel red blood cell agglutination techniques in detecting chimeras after major ABO-mismatched allogeneic hematopoietic stem cell transplantation.

We compared the ability of tube and gel red blood cell (RBC) agglutination techniques to follow erythroid engraftment in a patient who received a major ABO-mismatched peripheral blood stem cell transplant and bone marrow transplant. Tube and gel RBC agglutination techniques were used to detect mixed-field reactivity in cell mixtures containing A/O and c+/c- RBCs and the ability of these two technologies to detect RBC chimeras were compared. We detected c+ RBCs in c+/c- RBC populations microscopically at 1% by the tube RBC agglutination technique, but not until 10% by the gel technique. Group A RBCs in A/O RBC populations were detected at 10% by both techniques. In the patient studied, group A RBCs and c+ RBCs were detected on Days 20 and 14, respectively, with the tube RBC agglutination technique, but neither marker was detected until Day 26 with the gel technique. Tube and gel RBC agglutination techniques comparably identified ABO mixed fields. Although the tube RBC agglutination technique showed greater sensitivity than the gel technique in detecting the c antigen, the gel technique was easier to use and allowed more reliable interpretation of mixed fields by the technologist.

KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma.

Although surgery and radiotherapy have been the standard treatment modalities for head and neck squamous cell carcinoma (HNSCC), the integration of cisplatin (CDDP)-based therapy has led to improvements in local and regional control of disease for patients. However, many trials show that only 10-20% of patients benefit from this treatment intensification, which can result in profound treatment-associated morbidity and mortality. Moreover, the marginal survival improvement suggests that CDDP resistance is an innate characteristic of HNSCC. To elucidate the biological mechanisms underpinning CDDP resistance in HNSCC, we utilized an experimental model of CDDP resistance in this disease. We first observed significant enhancements in local tumor growth and metastasis, as well as adverse survival, in CDDP-resistant (CR) tumors compared with sensitive tumors. To elucidate the molecular mechanisms of this phenotype, we undertook a systems biology-based approach utilizing high-throughput PCR arrays, and we identified a significant suppression of KiSS1 mRNA and protein expression in the CR cells, but no significant regions of genomic loss with array comparative genomic hybridization. Genetic suppression of KiSS1 in CDDP-sensitive cell lines rendered them CR, an observation that was mechanistically linked to alterations in glutathione S-transferase-π expression and function. We next confirmed that, in human HNSCC tumors, loss of KiSS1 expression was associated with metastatic human HNSCC tumors compared with non-metastatic tumors. Genetic reconstitution of KiSS1 in CR cells abrogated cellular migration and induced CDDP sensitivity. To confirm these findings in a murine model, either CR or KiSS1-transfected CR cells were studied in an orthotopic model of HNSCC, or survival studies revealed significant improvement in survival of the mice bearing CR-KiSS1 tumors. Mechanistically, alterations in apoptotic pathways and CDDP metabolism contributed to KiSS1-associated chemotherapy sensitization. These studies provided further direct evidence for the role of KiSS1 loss in biologically aggressive HNSCC and suggest potential targets for therapy in CR cancers.

TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a significant public health problem, accounting for over 5% of all cancer-related deaths, and these deaths primarily result from metastatic disease. The molecular processes involved in HNSCC pathogenesis and progression are poorly understood, and here we present experimental evidence for a direct role of the cell surface receptor tyrosine kinase, TrkB, in HNSCC tumor progression. Using immunohistochemical analysis and transcriptional profiling of archival HNSCC tumor specimens, we found that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are expresses in greater than 50% of human HNSCC tumors, but not in normal upper aerodigestive tract (UADT) epithelia. Studies with HNSCC cell lines reveal that in vitro stimulation with BDNF, the ligand for TrkB, upregulates the migration and invasion of HNSCC cells, and both transient and stable suppressions of TrkB result in significant abrogation of constitutive and ligand-mediated migration and invasion. Furthermore, enforced overexpression of TrkB results in altered expression of molecular mediators of epithelial-to-mesenchymal transition (EMT), including downregulation of E-cadherin and upregulation of Twist. Using an in vivo mouse model of HNSCC, we were able to show that downregulation of TrkB suppresses tumor growth. These results directly implicate TrkB in EMT and the invasive behavior of HNSCC, and correlate with the in vivo overexpression of TrkB in human HNSCC. Taken together, these data suggest that the TrkB receptor may be a critical component in the multi-step tumor progression of HNSCC, and may be an attractive target for much needed new therapies for this disease.

Reciprocal negative regulation between S100A7/psoriasin and beta-catenin signaling plays an important role in tumor progression of squamous cell carcinoma of oral cavity.

Overexpression of S100A7 (psoriasin), a small calcium-binding protein, has been associated with the development of psoriasis and carcinomas in different types of epithelia, but its precise functions are still unknown. Using human tissue specimens, cultured cell lines, and a mouse model, we found that S100A7 is highly expressed in preinvasive, well-differentiated and early staged human squamous cell carcinoma of the oral cavity (SCCOC), but little or no expression was found in poorly differentiated, later-staged invasive tumors. Interestingly, our results showed that S100A7 inhibits both SCCOC cell proliferation in vitro and tumor growth/invasion in vivo. Furthermore, we demonstrated that S100A7 is associated with the beta-catenin complex, and inhibits beta-catenin signaling by targeting beta-catenin degradation via a noncanonical mechanism that is independent of GSK3beta-mediated phosphorylation. More importantly, our results also indicated that beta-catenin signaling negatively regulates S100A7 expression. Thus, this reciprocal negative regulation between S100A7 and beta-catenin signaling implies their important roles in tumor development and progression. Despite its high levels of expression in early stage SCCOC tumorigenesis, S100A7 actually inhibits SCCOC tumor growth/invasion as well as tumor progression. Downregulation of S100A7 in later stages of tumorigenesis increases beta-catenin signaling, leading to promotion of tumor growth and tumor progression.

Matrix metalloproteinase 9 promoter activity is induced coincident with invasion during tumor progression.

Matrix metalloproteinase 9 (MMP-9, also known as gelatinase B or 92-kd Type IV collagenase) is overexpressed in many human and murine cancers. We induced carcinomas in mice carrying a transgene that links the MMP-9 promoter to the reporter ss-galactosidase so that activation of the MMP-9 promoter would be indicated by ss-galactosidase. Mammary carcinomas were induced by mating the MMP-9 promoter reporter transgenic mice with mice carrying a transgene for murine mammary tumor virus promoter linked to polyoma middle T antigen, a transgene that leads to rapid development of mammary tumors in female mice. None of the hyperplastic mammary glands and none of the carcinomas in situ expressed ss-galactosidase. However, all invasive tumors had evidence of ss-galactosidase expression. In addition to the breast carcinomas, a malignant teratoma in a female and a papillary adenocarcinoma in the pelvic region of a male arose and were also ss-galactosidase positive. We also induced skin tumors in the mice with the MMP-9 reporter transgene with 7, 12-dimethylbenz[a]anthracene (DMBA) treatment followed by phorbol 12 myristate 13-acetate (TPA). None of the papillomas or in situ carcinomas showed any ss-galactosidase expression, but expression was seen in invasive carcinoma. Although normal skin epithelial cells did not express ss-galactosidase, we did find staining in a few cells at the duct of the sebaceous gland at the base of the hair follicles. The MMP-9 reporter transgene did not lead to expression in the alveolar macrophages, confirming that additional upstream sequences are required for expression in macrophages. These experiments have revealed that MMP-9 promoter activity is induced coincident with invasion during tumor progression. Furthermore, this indicates that the more proximal upstream elements of the promoter are sufficient for MMP-9 transcription during tumor progression.