by
Qiang Wen;
Benjamin Goldenson;
Serena J. Silver;
Monica Schenone;
Vladimir Dancik;
Zan Huang;
Ling-Zhi Wang;
Timothy Lewis;
W. Frank An;
Xiaoyu Li;
Mark-Anthony Bray;
Clarisse Thiollier;
Lauren Diebold;
Laure Gilles;
Martha S. Vokes;
Christopher B. Moore;
Meghan Bliss-Moreau;
Lynn VerPlank;
Nicola J. Tolliday;
William G Woods
The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
BACKGROUND: Hydroxyurea (HU) is underutilized in children with sickle cell disease (SCD) because caregivers frequently decline HU when it is offered. This study explores what impacts this decision. RESULTS: Caregivers of children with clinically severe SCD whose children were offered HU previously were interviewed. We used a qualitative analytical approach to analyze their telephone interview transcripts. Caregivers who chose HU (n = 9) reported their children had severe SCD, sought detailed information about HU, and accepted HU as a preventative therapy. In contrast, caregivers who did not choose HU (n = 10) did not perceive their children as having severe SCD and did not question their child's provider about HU. CONCLUSIONS: This study identifies specific areas that providers should address to when they discuss HU with families so that they can make informed decisions. Our study also uncovered factors that are important to consider when designing future interventions to improve hydroxyurea acceptance and when developing decision-aid tools to assist caregivers of children with SCD who are considering disease modifying therapies.
by
Jonathan Beitler;
Qiang Zhang;
Karen K Fu;
Andy Trotti;
Sharon A Spencer;
Christopher U Jones;
Adam S Garden;
George Shenouda;
Jonathan Harris;
Kian K Ang
Purpose To test whether altered radiation fractionation schemes (hyperfractionation [HFX], accelerated fractionation, continuous [AFX-C], and accelerated fractionation with split [AFX-S]) improved local-regional control (LRC) rates for patients with squamous cell cancers (SCC) of the head and neck when compared with standard fractionation (SFX) of 70 Gy. Methods and Materials Patients with stage III or IV (or stage II base of tongue) SCC (n=1076) were randomized to 4 treatment arms: (1) SFX, 70 Gy/35 daily fractions/7 weeks; (2) HFX, 81.6 Gy/68 twice-daily fractions/7 weeks; (3) AFX-S, 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy; and (4) AFX-C, 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to be compared with SFX. Results With patients censored for LRC at 5 years, only the comparison of HFX with SFX was significantly different: HFX, hazard ratio (HR) 0.79 (95% confidence interval 0.62-1.00), P=.05; AFX-C, 0.82 (95% confidence interval 0.65-1.05), P=.11. With patients censored at 5 years, HFX improved overall survival (HR 0.81, P=.05). Prevalence of any grade 3, 4, or 5 toxicity at 5 years; any feeding tube use after 180 days; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX. When 7-week treatments were compared with 6-week treatments, accelerated fractionation appeared to increase grade 3, 4 or 5 toxicity at 5 years (P=.06). When the worst toxicity per patient was considered by treatment only, the AFX-C arm seemed to trend worse than the SFX arm when grade 0-2 was compared with grade 3-5 toxicity (P=.09). Conclusions At 5 years, only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity.
Background:
The Children's Oncology Group (COG) publishes consensus guidelines with screening recommendations for early identification of treatment-related morbidities among childhood cancer survivors. We sought to estimate the yield of recommended yearly urinalysis screening for genitourinary complications as per Version 3.0 of the COG Long-Term Follow-Up Guidelines and identify possible risk factors for abnormal screening in a survivor population. Procedure: A database of pediatric cancer survivors evaluated between January 2008 and March 2012 at Children's Healthcare of Atlanta was queried for survivors at risk for genitourinary late effects. The frequency of abnormal urinalyses (protein ≥1+ and/or presence of glucose and/or ≥5 red blood cells per high power field) was estimated. Risk factors associated with abnormal screening were identified. Results: Chart review identified 773 survivors (57% male; 67% Caucasian; 60% leukemia/lymphoma survivors; mean age at diagnosis, 5.7 years [range: birth to 17.7 years]; time from diagnosis to initial screening, 7.6 years [range: 2.3 to 21.5 years]) who underwent urinalysis. Abnormal results were found in 78 (5.3%) of 1,484 total urinalyses. Multivariable analysis revealed higher dose ifosfamide (odds ratio [OR] = 6.8, 95% confidence interval [CI] 2.9-16.0) and total body irradiation (TBI, OR = 3.0, 95% CI 1.0-8.4) as significant risk factors for abnormal initial urinalysis screening. Conclusions: Pediatric cancer survivors exposed to higher dose ifosfamide or TBI may be at higher risk of abnormal findings on urinalysis screening. Targeted screening of these higher risk patients should be considered.
by
Rosangela Salerno-Goncalves;
Wilbur H Chen;
Mark Mulligan;
Sharon E Frey;
Jack T Stapleton;
Wendy A Keitel;
Jason Bailey;
Eli Sendra;
Hill Hill;
Robert A Johnson;
Marcelo B Sztein
Objectives: Francisella tularensis, the causative agent of tularaemia, is an exceptionally infectious bacterium, potentially fatal for humans if left untreated and with the potential to be developed as a bioweapon. Both natural infection and live-attenuated vaccine strain (LVS) confer good protection against tularaemia. LVS vaccination is traditionally administered by scarification, and the formation of a cutaneous reaction or take at the vaccination site is recognised as a clinical correlate of protection. Although previous studies have suggested that high antibody titres following vaccination might serve as a useful surrogate marker, the immunological correlates of protection remain unknown. Methods: We investigated the host T-cell-mediated immune (T-CMI) responses elicited following immunisation with LVS vaccine formulated by the DynPort Vaccine Company (DVC-LVS) or the United States Army Medical Research Institute of Infectious Diseases (USAMRIID-LVS). We compared T-CMI responses prompted by these vaccines and correlated them with take size. Results: We found that both LVS vaccines elicited similar T-CMI responses. Interestingly, take size associated with the T cells’ ability to proliferate, secrete IFN-γ and mobilise degranulation, suggesting that these responses play an essential role in tularaemia protection. Conclusions: These results renew the appreciation for vaccination through the scarification as a prime route of inoculation to target pathogens driving specific T-CMI responses and provide further evidence that T-CMI plays a role in protection from tularaemia.
Sickle cell disease (SCD) produces many structural and functional abnormalities in the kidney, including glomerular abnormalities. Albuminuria is the most common manifestation of glomerular damage, with a prevalence between 26 and 68% in adult patients. The pathophysiology of albuminuria in SCD is likely multifactorial, with contributions from hyperfiltration, glomerular hypertension, ischemia-reperfusion injury, oxidative stress, decreased nitric oxide (NO) bioavailability, and endothelial dysfunction. Although its natural history in SCD remains inadequately defined, albuminuria is associated with increased echocardiography-derived tricuspid regurgitant jet velocity, systemic blood pressure, and hypertension, as well as history of stroke, suggesting a shared vasculopathic pathophysiology. While most patients with albuminuria are treated with angiotensin converting enzyme inhibitors/angiotensin receptor blockers, there are no published long-term data on the efficacy of these agents. With the improved patient survival following kidney transplantation, SCD patients with end-stage renal disease should be considered for this treatment modality. Given the high prevalence of albuminuria and its association with multiple SCD-related clinical complications, additional studies are needed to answer several clinically important questions in a bid to adequately elucidate its pathophysiology, natural history, and treatment.
The Insulin-like Growth Factor 1 (IGF-1) signaling pathway activates several downstream signals important to lung cancer development and survival. IGF-1R activation has been linked to cancer risk in epidemiological studies and tumorigenesis in preclinical models. Several inhibitors of the insulin-like growth factor 1 receptor (IGF-1R) have been tested in clinical trials. Despite promising data in early phase studies, most studies of IGF-1R antagonists in combination with chemotherapy or with epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) yielded disappointing results. Biomarker studies of clinical trials have identified IGF-1 levels as a potential marker of sensitivity to IGF-1R inhibition. Further study will need to focus on selection of NSCLC patients most likely to benefit from the addition of IGF-1R antagonists to standard therapy and the development of rational strategies for combination therapy in NSCLC.
High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. IMPLICATIONS FOR PRACTICE: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
BACKGROUND: Pelvic inflammatory disease (PID) is a common gynecologic disorder. One known complication of PID is tubo-ovarian abscess (TOA) formation. The predominant theory on TOA formation postulates that an ascending infection from the cervix through the uterus to the fallopian tubes and ovaries results in abscess formation. Other theories include seeding via a hematogenous infection, diverticular disease, and appendicitis. CASE: A 39-year-old female patient with abdominal pain was referred to our institution and was found to have a pelvic mass. After a thorough evaluation, surgical exploration revealed the presence of TOA. No evidence of gastrointestinal disease was present. The patient's history was significant for an uncomplicated total abdominal hysterectomy for benign disease of the uterus four years prior. Abscess cultures grew Streptococcus intermedius. CONCLUSION: This case reports the rare occurrence of TOA in a patient who had undergone an abdominal hysterectomy four years prior to presentation. If the patient reports a surgical history of prior hysterectomy, TOA is often stricken from consideration. Although unlikely, adnexal abscess formation should be considered in the differential diagnosis of a patient with abdominal pain and a pelvic mass, even with a remote history of hysterectomy.