Use of gemcitabine, oxaliplatin, and anti-CD20 therapy in children and adolescents with non-Hodgkin lymphoma unfit for intensive therapy.

Multiagent immunochemotherapy affords excellent outcomes in pediatric non-Hodgkin lymphoma (NHL); however, scarce data exist for patients unfit for intensive treatment. Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is well tolerated and efficacious in elderly adults with NHL; however, its use has not been described in pediatrics. In this retrospective, single-center study, six children with mature B-cell NHL and significant comorbidities received anti-CD20 therapy with GemOx (rituximab or obinutuzumab or ofatumumab with gemcitabine and oxaliplatin [R/O-GemOx]). R/O-GemOx was well tolerated and resulted in complete response in two of three patients with newly diagnosed NHL and one of three patients with primary refractory NHL. R/O-GemOx is a viable treatment option for children with NHL who cannot tolerate intensive therapy.

Reduced-Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many pediatric malignant and nonmalignant conditions. Gonadal insufficiency or infertility is present in almost all HSCT survivors who received a myeloablative conditioning (MAC) regimen. Reduced-intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with nonmalignant diagnoses to limit the toxicities associated with HSCT; however, the short-term and long-term gonadal toxicity of RIC regimens in pediatric and young adult survivors remains unknown. In this study, we compared the prevalence of gonadal insufficiency and infertility among pubertal and postpubertal pediatric and young adult survivors of HSCT who received a RIC regimen versus those who received a MAC regimen. Twenty-three females (RIC, n = 8; MAC, n = 15) and 35 males (RIC, n = 19; MAC, n = 16) were included in this single-center, retrospective cross-sectional study. Eligible patients were those with available laboratory results who were ≥1 year post-HSCT, age <40 years, and pubertal or postpubertal as assessed by an endocrinologist. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels were measured in females, and FSH, LH, total testosterone, and inhibin B (InhB) levels were measured in males. Twenty-one males (RIC, n = 11; MAC, n = 10) underwent semen analysis through a separate consent. Parametric and nonparametric analyses were undertaken to compare the RIC and MAC groups. Female patients who received RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (P = .02) and low estradiol (P = .01) or elevated LH (P = .09). Most females in the RIC (75%) and MAC (93%) groups had low AMH levels, indicating low or absent ovarian reserve, with no significant difference between the groups (P = .53). In males, there were no significant differences between the 2 groups in the prevalence of abnormal FSH, LH, testosterone, or InhB levels. Ten of 11 RIC males (91%) and 10 of 10 MAC males (100%) had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range, 1.3 to 12.2 years). RIC may pose less risk than MAC for primary ovarian insufficiency among female survivors of HSCT; however, both female and male recipients of either RIC or MAC regimens are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling about the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.

Vertebral osteomyelitis due to Salmonella Poona in a healthy adolescent female.

We present a case of vertebral osteomyelitis in a previously healthy, adolescent Caucasian female athlete. After months of lower back pain, spinal imaging demonstrated phlegmon and suspected osteomyelitis of the L4 vertebral body. A bone biopsy was obtained, and microbiologic cultures yielded pure growth of Salmonella enterica subsp. enterica serovar Poona (S. Poona), a member of the nontyphoid Salmonella group associated with food-borne gastroenteritis in the United States. This case represents the first reported association of S. Poona with osteomyelitis and is interesting in that the infection developed in a patient without traditional risk factors for invasive Salmonella disease (i.e. sickle cell disease). This case highlights the importance of keeping a broad differential diagnosis for lower back pain and emphasizes the value of obtaining specimens for microbiologic culture to aid in diagnosing non-traditional and potentially emerging bacterial pathogens.

Mutations predictive of hyperactive Ras signaling correlate with inferior survival across high-risk pediatric acute leukemia.

BACKGROUND: Cancer remains the number one cause of disease-related mortality in children, and despite advances in the molecular understanding of leukemia and targeted therapies, refractory leukemia remains a leading cause of death. It therefore is essential to further define features, e.g., FLT3 alterations and KMT2A rearrangements, associated with inferior survival early to augment or alter therapeutic strategies to improve outcomes. METHODS: To gain insights into the genetic drivers predictive of aggressive clinical behavior among pediatric leukemia patients, we performed comprehensive integrative clinical sequencing (ICS), including paired tumor/normal DNA sequencing and RNA-seq, for pediatric patients who presented at our institution over a period of five years with acute lymphoblastic or myelogenous leukemia (ALL and AML; n=43) and high-risk clinical features (high white blood cell count, extramedullary disease, or refractory and/or relapsed disease). RESULTS: We found that RAS- and Ras-pathway aberrations, including N-RAS, NF1 and PTPN11, are frequent somatic mutations and, importantly, associated with decreased event free and overall survival (OS) (P=0.04, median event free survival 22.8 vs. 5.6 months; P=0.04, median OS 124 vs. 22.5 months). CONCLUSIONS: We thus propose that hyperactive Ras signaling confers inferior survival in high-risk pediatric acute leukemia and that Ras pathways should be molecularly characterized to inform clinical decision making and to identify patients for experimental clinical trials and RAS-targeted therapy.

Refractory and metastatic infantile fibrosarcoma harboring LMNA-NTRK1 fusion shows complete and durable response to crizotinib.

Infantile fibrosarcoma (IFS) is a rare soft-tissue sarcoma, which classically presents as an aggressive and rapidly enlarging tumor over the distal extremities of children in their first year of life. The presence of ETV6 and NTRK3 gene rearrangement is characteristic of IFS, which can be detected on routine fluorescence in situ hybridization (FISH) testing. Patients with IFS typically respond well to surgical resection and chemotherapy and have an overall survival of ∼90%. In this report, we outline the use of integrative clinical sequencing (ICS) including RNA-seq in a patient with refractory, metastatic IFS to reveal an unusual fusion (LMNA-NTRK1), not detected by routine FISH testing, which was treated with oral crizotinib and resulted in a complete and durable long-term response. This study highlights the utility of ICS in identifying cryptic gene fusions, especially in refractory malignancies, and demonstrates how such information can be used to select targeted therapies in patients with actionable molecular alterations.

Pharmacokinetics of oxaliplatin (NSC 266046) alone and in combination with paclitaxel in cancer patients.

UNLABELLED: Oxaliplatin (OPT), a third-generation platinating agent, is currently being evaluated in a phase II clinical trial in head and neck cancer patients and in a phase I clinical trial in combination with paclitaxel (TXL). PURPOSE: The aim of this study was to investigate the pharmacokinetics and biological correlates of OPT alone as well as the potential pharmacokinetic interaction between OPT and TXL. METHODS: In the phase II study, OPT was given alone as a 2-h i.v. infusion at 60 mg/m(2) weekly for 4 weeks with the cycle repeated after a 2-week rest. In the concurrent phase I combination trial OPT was also given as a 2-h i.v. infusion, but followed by a 1-h i.v. infusion of TXL, weekly for 4 weeks with the cycle repeated after a 2-week rest. The clinical pharmacokinetics of OPT alone and in combination with TXL were investigated in the first cycle of each treatment protocol. The platinum levels in plasma, plasma ultrafiltrate (PUF) and urine were measured by a fully validated inductively coupled plasma mass spectrometry (ICPMS) method. RESULTS: In the ten patients receiving OPT alone, the concentration-time profiles of total platinum exhibited a biexponential decline both in plasma and in PUF. The peak levels of platinum were 2.72+/-0.41 microg/ml in plasma and 1.36+/-0.42 microg/ml in PUF at the end of the OPT infusion, and the platinum levels were still detectable at >10 ng/ml 94 h after the OPT infusion. The mean terminal t(1/2) values of total platinum in plasma and in PUF were 58.9 h and 22.8 h, respectively. The AUC of ultrafilterable platinum represented about 10% of that of the total plasma platinum. The platinum levels in the DNA fraction of peripheral white blood cells (WBC) correlated with the platinum levels in PUF ( r=0.77, P<0.01). In the phase I combination study, the dose level of OPT was escalated from 35 mg/m(2) to 60 mg/m(2). The concentration-time profiles of platinum in the combination trial also showed biexponential decay in plasma and in PUF as exhibited by OPT alone. However, the terminal elimination rate constant (beta) of total plasma platinum increased at all dose levels of OPT when combined with TXL at 45 mg/m(2) ( P<0.05). A concomitant increase in clearance (CL) of total plasma platinum was observed at the OPT dose level of 45 mg/m(2) in combination with TXL at 45 mg/m(2). No statistically significant difference in the 24-h urinary elimination of total platinum was detected between the combination groups and the single-agent group. The AUC values of total platinum in PUF were proportional to OPT doses ranging from 35 to 60 mg/m(2), whether OPT was given alone or in combination with TXL. CONCLUSIONS: OPT clearance may be enhanced by TXL when the two agents are used in combination in patients. The Pt-DNA adduct level in peripheral WBC was found to be a good indicator for oxaliplatin exposure in patients, and should be further exploited for potential tumor drug exposure.

Electromechanical impedance sensor for in vivo monitoring the body reaction to implants.

A novel sensor for in situ monitoring of the body reaction to implants has been developed. A piezoelectric wafer active sensor was adapted for biomedical applications (bio-PWAS). A number of bio-PWAS sensors have been implanted in rats and left in place up to 64 days. The bio-PWAS were able to oscillate in several resonance modes, radial-wise (in-plane) and thickness-wise (out-of-plane). The electromechanical impedance was measured over a wide frequency band, covering several radial vibration modes and the first thickness mode. The recorded data was processed with impedance spectroscopy methods. Preliminary results indicate a correlation between the electromechanical impedance spectrum of the bio-PWAS and the state of implantation. Quantitative studies have shown that the first radial mode amplitude seems to correlate with the short-time inflammatory and immune response, while the thickness mode amplitude seems to correlate with both the short-term inflammatory response and long-term encapsulation and fibrosis response. Since radial vibrations generate shear waves in the surrounding tissue, while thickness vibrations generate pressure waves, it seems that the shear and pressure wave interactions have specificity in detecting the different stages of the body's reaction response to implants. These observations were supported by histological examinations of the tissue surrounding the bio-PWAS. Though these initial results are encouraging, further experiments need to be conducted and more data needs to be collected in correlation with histological determinations. In-depth impedance spectroscopy studies should be conducted on this extensive data and closely correlated with extensive histological studies.

Friction dependence on alpha-relaxations in a tethered polymer monolayer.

Functionalized low-molecular-weight polyisoputylene is commonly used as a lubricant additive to control low-velocity friction in clutches. The friction of tethered monolayers as a function of temperature and velocity was examined using lateral force microscopy. The friction force was found to obey time-temperature superposition, which indicates that the friction originates from a single relaxation mode. The scaling factors are identical to those obtained from neutron spin echo experiments of alpha-relaxations, linking the friction directly to segmental motion.