High dose total marrow irradiation (TMI) does not increase long-term toxicity of myeloablative fludarabine/busulfan (FluBu4) conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT).

OBJECTIVES: Based on a previous phase 1 study, total marrow irradiation (TMI) at 9Gy was added to a myeloablative FluBu4 conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies. Here, we report on the long-term toxicity of TMI combined with FluBu4 and compare it to patients who received only FluBu4. METHODS: We retrospectively analyzed 38 consecutive patients conditioned with FluBu4/TMI (n = 15) or FluBu4 (n = 23, control group) who had at least 1 year follow-up post-transplant. The rate of long-term adverse events that have been previously associated with total body irradiation (TBI) was analyzed in the two groups. RESULTS: The baseline characteristics did not differ between the two groups. The control group had a longer median follow-up (71.2 mo) than the TMI group (38.5 mo) (p = .004). The most common adverse events were xerostomia, dental complications, cataracts, or osteopenia and did not differ between the two groups. Cognitive dysfunction or noninfectious pneumonitis, often detected after high dose TBI, were also not different in the two groups (p = .12 and p = .7, respectively). There was no grade 4 adverse event. CONCLUSION: Our results suggest that a conditioning regimen with TMI 9Gy and FluBu4 does not increase long-term adverse events after allogeneic HSCT.

Molecular features and race-associated outcomes of SPOP-mutant metastatic castration-resistant prostate cancer.

BACKGROUND: Inactivating alterations in SPOP frequently occur in prostate cancer and promote increased dependency on androgen receptor (AR)-mediated oncogenic signaling. The presence of SPOP mutation (SPOP-mutant [SPOP-mut]) may therefore impact therapeutic outcomes with AR-directed therapies and docetaxel in metastatic castration-resistant (mCRPC). METHODS: This was a retrospective study of mCRPC patients treated at an urban academic hospital (n = 103). Patients underwent tumor DNA sequencing to determine SPOP mutational status (SPOP-mut). Outcomes measured were overall survival (OS) from diagnosis and treatment with second-generation AR signaling inhibitor (ARSI) or docetaxel and time to PSA progression (prostate-specific antigen-progression-free survival [PSA-PFS]) compared by SPOP status using Kaplan-Meier curves and log-rank test. The univariable and multivariable Cox proportional hazard model evaluated the association of SPOP mutation and outcomes adjusted for clinicopathologic features. RESULTS: SPOP-mut was associated with longer PSA-PFS in mCRPC (median 1.79 vs. 0.84 years; p = 0.06) and multivariate analysis (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.17-0.84; p = 0.02). SPOP-mut demonstrated a higher median PSA decline compared to SPOP wild-type (median decline 100% vs. 92%, p = 0.02). SPOP-mut was not associated with OS from the start of ARSI or docetaxel (median OS not reached vs. 2.0 years) or PSA-PFS on docetaxel (median PSA-PFS 0.4 vs. 0.5 years) in mCRPC. The majority of SPOP mutations were identified in African American (AA) patients (69.2%) compared to Caucasian patients (30.8%). Race-associated multivariate analysis revealed no significant differences in OS from the start of ARSI or the start of docetaxel and no differences in ARSI or docetaxel PSA-PFS between AA and Caucasian patients. Molecular profiling demonstrated that AA patients had a higher frequency of SPOP mutations and greater heterogeneity of SPOP variants within the coding sequence. Analysis of concurrent genomic alterations revealed that SPOP mutations co-occur with APC mutations (p = 0.001) and alterations in the Wnt pathway (p = 0.017). CONCLUSIONS: Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race-associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker-directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients.

Cetuximab and anemia prevention in head and neck cancer patients undergoing radiotherapy.

BACKGROUND: Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia. METHODS: We queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared. RESULTS: A total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068). CONCLUSIONS: In contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia.

Real-world effectiveness of the pegfilgrastim on-body injector in preventing severe neutropenia.

INTRODUCTION: Granulocyte colony-stimulating factors are used in medical oncology for the prevention of neutropenia. On-body injectors (OBI) have an advantage over the traditional injection (TI) method of not requiring a second visit to the clinic, but these devices are subject to failure. The objective of this study was to assess the efficacy of OBIs in the real-world. METHODS: Women with breast cancer diagnosed between June 2015 and June 2016 treated with cytotoxic chemotherapy and a granulocyte colony-stimulating factor were retrospectively identified from the medical records of Henry Ford Hospital. The primary outcome was the incidence of severe neutropenia (SN), defined as an absolute neutrophil count (ANC) ≤500. Secondary outcomes included incidence of neutropenia (ANC ≤ 1500), neutropenic fever, and mortality. A secondary analysis of the data was performed to identify predictors of SN. RESULTS: A total of 837 cycles of chemotherapy were analyzed. The OBI was used in 395 cycles and the TI in 442. The OBI group had patients that were older, had higher baseline ANC, and were more often white. The incidences of SN, neutropenic fever and neutropenia were not different between groups. Patients with a lower baseline ANC and white ethnicity were at a higher risk for SN. AC (doxorubicin and cyclophosphamide) was the most commonly used chemotherapy regimen (38% of total cycles). CONCLUSIONS: There was no difference in the efficacy of the OBI and TI methods for preventing SN, neutropenic fever and neutropenia.

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches.

Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAFV600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas.

A Case of Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by a pathologic immune dysregulation resulting in extreme inflammation. Clinical manifestations are varied but can include severe multiorgan failure and death. HLH has been associated with malignancies, autoimmune diseases, and infections, such as histoplasmosis. Histoplasmosis commonly has subclinical manifestations but can also present in its disseminated form. We present the case of an immunocompromised patient with worsening liver function caused by hepatic histoplasmosis that later triggered HLH with severe multiorgan dysfunction.

Class III ß-tubulin expression as a predictor of docetaxel-resistance in metastatic castration-resistant prostate cancer.

About half of the patients treated with docetaxel in the setting of metastatic castration-resistant prostate cancer (CRPC) are non-responders. Therefore, a marker of response would be beneficial for clinical decision-making. We evaluated class III ß-tubulin (ßIII-tubulin) expression as a predictor of resistance in this setting, which previously has been correlated with lack of response to taxanes in other cancers. Patients with CRPC were included if they were treated with at least 3 cycles of docetaxel between 1990 and 2011. ßIII-tubulin expression was assessed by immunostaining, which was performed in tissue samples obtained either via biopsy or prostatectomy at the time of diagnosis. Rates of prostate-specific antigen (PSA) response and overall survival (OS) following docetaxel treatment were compared between patients with high (2+ or 3+ staining) vs. low (0 or 1+ staining) ßIII-tubulin expression. Of 73 patients, 26 (35%) had a high expression of ßIII-tubulin. A PSA decline of 10% or greater occurred in 65% of patients with a high ßIII-tubulin expression vs. 89% with a low ßIII-tubulin expression (p = 0.0267). The median OS for patients with a high ßIII-tubulin expression was 17.4 (95% CI 8.7-21.0) months vs. 19.8 (95% CI 16.6-23.6) months for patients with a low expression (p = 0.039). Our results show that a high ßIII-tubulin expression is a negative prognostic factor in metastatic CRPC patients treated with docetaxel.

Lung Lavage and Surfactant Replacement During Ex Vivo Lung Perfusion for Treatment of Gastric Acid Aspiration-Induced Donor Lung Injury.

BACKGROUND: Ex vivo lung perfusion (EVLP) provides opportunities to treat injured donor lungs before transplantation. We investigated whether lung lavage, to eliminate inflammatory inhibitory components, followed by exogenous surfactant replacement, could aid lung recovery and improve post-transplant lung function after gastric aspiration injury. METHODS: Gastric acid aspiration was induced in donor pigs, which were ventilated for 6 hours to develop lung injury. After retrieval and 10 hours of cold preservation, EVLP was performed for 6 hours. The lungs were randomly divided into 4 groups (n = 5, each): (1) no treatment (control), (2) lung lavage, (3) surfactant administration, and (4) lung lavage, followed by surfactant administration. After another 2-hour period of cold preservation, the left lung was transplanted and reperfused for 4 hours. RESULTS: Physiologic lung function significantly improved after surfactant administration during EVLP. The EVLP perfusate from the lavage + surfactant group showed significantly lower levels of interleukin (IL)-1ß, IL-6, IL-8, and secretory phospholipase A2. Total phosphatidylcholine was increased, and minimum surface tension was recovered to normal levels (≤5 mN/m) in the bronchioalveolar fluid after surfactant administration. Lysophosphatidylcholine in bronchioalveolar fluid was significantly lower in the lavage + surfactant group than in the surfactant group. Post-transplant lung function was significantly better in the lavage + surfactant group compared with all other groups. CONCLUSIONS: Lung lavage, followed by surfactant replacement during EVLP, reduced inflammatory mediators and prevented hydrolysis of phosphatidylcholine, which contributed to the superior post-transplant function in donor lungs with aspiration injury.

Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation.

BACKGROUND: Ex vivo lung perfusion (EVLP) presents a unique therapeutic opportunity to administer mesenchymal stromal cells (MSCs) to lung grafts before transplantation. We sought to determine the optimal route and dose of viable human umbilical cord-derived MSCs to be delivered into ex vivo-perfused damaged swine lungs, and to measure their effect on concentration of growth factors and inflammatory mediators. METHODS: Pig lungs were conventionally retrieved, cold preserved for 18 hours, and perfused normothermically ex vivo for 12 hours. Physiologic data were recorded. No cells were administered to a control group of animals (n = 5). To examine the routes of administration, lungs were administered 50 × 106 MSCs endobronchially (n = 3) or via the pulmonary artery (n = 3). To determine the doses, a dose-escalation study was performed wherein lungs were administered 50 × 106 (n = 3), 150 × 106 (n = 5) and 300 × 106 (n = 3) MSCs via the pulmonary artery. Concentrations of human growth factors and pig cytokines were measured in lung biopsies and perfusate. RESULTS: Intravascular administration of 50 × 106 MSCs was associated with significant and sustained retention of MSCs in lung parenchyma, whereas intrabronchial administration was not. Intravascular administration of 150 × 106 MSCs was the optimal tolerated dose and was associated with increased concentrations of human vascular endothelial growth factor (VEGF) in lung biopsies and decreased concentrations of pig interleukin-8 (IL-8) in the perfusate during 12 hours of EVLP. CONCLUSIONS: Intravascular delivery of 150 × 106 MSCs showed preferred outcome compared with intrabronchial delivery to damaged lungs perfused ex vivo. The method was well tolerated and associated with an increased concentration of human VEGF in the lung tissue and a decreased concentration of pig IL-8 in the perfusate.

Parotid gland tumors: a retrospective study of 154 patients / Tumores de glândula parótida: estudo retrospectivo de 154 pacientes

INTRODUCTION: Benign tumors of the parotid gland comprise the majority of salivary gland tumors. OBJECTIVE: To review the clinical characteristics of parotid gland tumors submitted to surgical treatment by the same surgeon. METHODS: Retrospective study with 154 patients who had parotid gland tumors. Clinical and histological data, type of surgery, and complications were assessed and described. RESULTS: The main manifestation was a mass with a median evolution of 12 months for benign tumors and five months for malignant tumors. Ultrasonography was the most frequent complementary exam. Pleomorphic adenoma was the most common of the benign tumors, and mucoepidermoid carcinoma was the most frequent malignant tumor. Superficial parotidectomy with preservation of the facial nerve was the most common surgical procedure and reversible paresis of branches of the facial nerve was the most common complication. CONCLUSIONS: Pleomorphic adenoma is the most common parotid gland tumor and superficial parotidectomy with preservation of the facial nerve is the most common and appropriate treatment for most low-morbidity tumors. .

INTRODUÇÃO: Os tumores de parótida são frequentemente de natureza benigna e correspondem à maioria dos tumores de glândulas salivares. OBJETIVO: Revisar as características clínicas de neoplasias de parótidas submetidas a tratamento cirúrgico pelo mesmo cirurgião. MÉTODO: Estudo retrospectivo, onde foram avaliados 154 pacientes com neoplasia de parótida. Dados clínicos, histológicos, tipo de cirurgia e complicações foram compilados e descritos. RESULTADOS: A principal manifestação foi a de uma massa tumoral com uma mediana de tempo de evolução de 12 meses para os tumores benignos e 5 meses para os tumores malignos. A ecografia foi o exame complementar mais indicado. Dentre os tumores benignos, o adenoma pleomórfico foi o mais comum e o carcinoma mucoepidermóide o mais frequente dentre os malignos. A parotidectomia superficial com preservação do nervo facial foi a cirurgia mais indicada e a paresia reversível de ramos do nervo facial, a complicação mais prevalente. Conclusões: O adenoma pleomórfico é o tumor mais comum da glândula parótida e a parotidectomia superficial com preservação do nervo facial é o tratamento mais adequado para a maioria dos tumores de baixa morbidade. .

Parotid gland tumors: a retrospective study of 154 patients.

INTRODUCTION: Benign tumors of the parotid gland comprise the majority of salivary gland tumors. OBJECTIVE: To review the clinical characteristics of parotid gland tumors submitted to surgical treatment by the same surgeon. METHODS: Retrospective study with 154 patients who had parotid gland tumors. Clinical and histological data, type of surgery, and complications were assessed and described. RESULTS: The main manifestation was a mass with a median evolution of 12 months for benign tumors and five months for malignant tumors. Ultrasonography was the most frequent complementary exam. Pleomorphic adenoma was the most common of the benign tumors, and mucoepidermoid carcinoma was the most frequent malignant tumor. Superficial parotidectomy with preservation of the facial nerve was the most common surgical procedure and reversible paresis of branches of the facial nerve was the most common complication. CONCLUSIONS: Pleomorphic adenoma is the most common parotid gland tumor and superficial parotidectomy with preservation of the facial nerve is the most common and appropriate treatment for most low-morbidity tumors.