Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient-derived orthotopic xenografts, cell lines and tumor entities.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient-derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro-in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic, and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another was a neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm, and, finally, the last was an unclassifiable tumor bearing neurofibromin-2 (NF2) inactivation, a neuroblastoma RAS viral oncogene homolog (NRAS) oncogenic mutation, and a SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression, and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.

Hand surgeons and amyloidosis specialists warning: transthyretin-associated amyloidosis with bifid median nerve as a cause of bilateral carpal tunnel syndrome. A case report and literature review.

INTRODUCTION: Approximately 75% of patients with carpal tunnel syndrome (CTS) are diagnosed as idiopathic. Despite this, the presence of an underlying cause such as an anatomical variant or a systemic disease must always be suspected, especially in cases of bilateral presentation without an obvious cause, recurrence or complications. The anatomical variant known as the bifid median nerve (BMN) is a very rare abnormality that can occasionally lead to CTS. On the other hands, transthyretin-associated amyloidosis (ATTR) is one of the possible causes of bilateral CTS. We report a case where these two very rare pathologies converge as the cause of bilateral CTS and a review of the literature. CASE REPORT: We report a 71-year-old male with prior history of lumbar canal stenosis, bilateral trigger finger, rupture of the supraspinatus muscle tendon and of the long portion of the right biceps brachial. He also had 8-year-old bilateral CTS that recurred after CTS surgery. He was surgically re-intervened and was diagnosed incidentally with BMN and an ultrasound of the other hands also showed BMN. Because of all the prior musculoskeletal history, a biopsy of the transverse carpal ligament was taken showing ATTR deposits that led to the diagnosis of cardiac ATTR wild type. CONCLUSIONS: This case highlights the natural history of the multiple musculoskeletal manifestations related to ATTR and the importance of performing intraoperative biopsies in patients with CTS surgery as this can lead to early diagnosis of cardiac ATTR.

Clonal relationship in multisited mucosa-associated lymphoid tissue lymphomas: a single-centre experience.

Clonal heterogeneity in multisited or recurrent lymphoid neoplasms is a phenomenon that has been increasingly studied in recent years. However, in mucosa-associated lymphoid tissue (MALT) lymphomas it remains largely unexplored. Patients diagnosed at our institution with multisited MALT lymphoma, from January 2009 to October 2018, were studied. Molecular studies were performed for the detection of clonally rearranged immunoglobulin by polymerase chain reaction.In all, 91 patients were included. Of those, 28 had a multisited disease and in 16 clonality studies were done. In eight cases, multifocal involvement was synchronous and in eight metachronous. Patients with non-gastric gastrointestinal tract involvement tended to disseminate within the same tract, without observing other specific dissemination patterns. Four cases (25%) had clonal heterogeneity at the different organs involved. All patients with late relapses (two patients) had different clones. The majority of patients with multisited MALT lymphomas presented with the same clone in the different involved organs, identifying a different clone in those with late relapses. These patients could represent de novo neoplasms, rather than a relapse. This could mean that some individuals might have a genetic predisposition to develop this type of lymphoma and it could also have clinical implications regarding therapeutic decisions.

Long-term outcome comparing histological grades of follicular lymphoma patients treated with immunochemotherapy as first-line therapy: A retrospective analysis from two institutions.

OBJECTIVES: To clarify the impact of histological grades in follicular lymphoma. METHODS: We retrospectively analysed 250 patients diagnosed with FL treated with chemoimmunotherapy: 188 patients were grades 1-2 and 62 grade 3A. RESULTS: In our series, grade 3A FL patients were older, higher proportion of localised disease and lower bone marrow infiltration at diagnosis comparing grades 1-2 FL patients. Estimated six-year progression-free survival and time to progression showed no differences between both groups [grade 3A: 56% (95%CI: 39%-73%) and 51% (95%CI: 41%-61%) vs grades 1-2:55% (95%CI: 46%-63%) and 57% (95%CI: 49%-65%), P = .782 and P = .521, respectively]. Estimated six-year overall survival was lower, 76% (95%CI: 64%-88%) for the grade 3A group than grades 1-2 83% (95%CI: 77%-89%); P = .044. In addition to that, cumulative incidence curves of death not related to lymphoma at 10 years between groups were as follows: [0.26 (95%CI: 0.25-0.27) and 0.05 (95%CI: 0.04-0.06) for G3AFL and G1-2FL, respectively], P = .010. Grade 3A FL showed in PFS curve no relapses after 6 years. These results were absolutely reproduced in 199 patients receiving R-CHOP regimen as induction. CONCLUSIONS: Our results indicate similar long-term outcomes in terms of progression-free survival and time to progression in grades 1-2 and 3A. No relapses were observed in G3AFL group after 6 years.

[2018 Consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary]. / Consenso 2018 de la Sociedad Española de Anatomía Patológica y la Sociedad Española de Oncología Médica sobre el diagnóstico y tratamiento del cáncer de origen desconocido.

Cancer of unknown primary is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, cancer of unknown primary can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological and molecular studies conducted to analyse and determine the origin of cancer of unknown primary. The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.

The velcro mustache: a potential barrier to effective bag-and-mask ventilation in neonates on nasal cpap: two case reports.

Hudson prongs (Hudson RCI, Teleflex Medical, Research Triangle Park, North Carolina) (a device to deliver nasal continuous positive airway pressure) are often secured with a "Velcro mustache" in neonatal intensive care units. We report 2 premature infants who required bag-and-mask ventilation while on Hudson prongs secured with a Velcro mustache. Effective ventilation was achieved only after removing the Velcro mustache.

Reduction in the incidence of chronic lung disease in very low birth weight infants: results of a quality improvement process in a tertiary level neonatal intensive care unit.

OBJECTIVE: Our objective was to reduce the incidence of chronic lung disease by introducing potentially better practices in our delivery room and NICU. METHODS: We compared the incidences of chronic lung disease in infants with birth weights of 501 to 1500 g in 2002 and 2005, after implementation of the changes. Medical records for infants of 501 to 1500 g who were born in 2002 and 2005 were reviewed for maternal characteristics, care of the infant in the delivery room and the NICU (including surfactant usage, duration of ventilation, duration of continuous positive airway pressure therapy, and duration of oxygen treatment), length of stay, and short-term clinical outcomes (eg, pneumothorax, severe intracranial hemorrhage, retinopathy of prematurity, and weight gain). RESULTS: There was a significant reduction in our incidence of chronic lung disease, from 46.5% in 2002 to 20.5% in 2005. The number of infants discharged from the hospital with oxygen therapy also decreased significantly, from 16.4% in 2002 to 4.1% in 2005. The overall relative risk reduction for chronic lung disease in 2005, compared with 2002, was 55.8%. CONCLUSIONS: By using a quality improvement process that included avoidance of intubation, adoption of new pulse oximeter limits, and early use of nasal continuous positive airway pressure therapy, we demonstrated a significant reduction in the incidence of chronic lung disease in infants with birth weights of <1500 g in 2005, in comparison with 2002. These results have persisted to date. There were no significant short-term complications.

Comparison of a restricted transfusion schedule with erythropoietin therapy versus a restricted transfusion schedule alone in very low birth weight premature infants.

OBJECTIVE: Erythropoietin (EPO) is commonly used in very low birth weight neonates to minimize blood transfusions during hospitalization. Data are limited comparing the use of EPO along with a restricted transfusion schedule versus a restricted transfusion schedule alone. We compared the effects of a restricted transfusion schedule with EPO versus a restricted transfusion schedule alone during two consecutive 6-month periods. METHODS: In period I, infants born at <30 weeks gestational age (GA) or <1,500 g birth weight (BW) were treated prophylactically for six weeks with EPO 1,000 U/kg/wk in three divided doses and blood transfusions were given using a restricted transfusion schedule. This was the called the EPO Group. In period II, a restricted transfusion schedule was utilized, but EPO was not administered. This constituted the No EPO Group. No other changes in clinical practice were introduced in either period. RESULTS: There were 30 neonates in the EPO Group and 20 in the No EPO Group. There were no significant differences in sex, race, mean birth weight (1,074 +/- 283 versus 965 +/- 330 g), mean gestational age (28.9 +/- 2.96 versus 27.8 +/- 2.86 wks), 5 minute Apgar score (7.8 +/- 1.2 versus 7.6 +/- 1.1), or mean hematocrit (48.2% +/- 6.05 versus 48.6% +/- 6.31) at admission. There were no significant differences in the total number of transfusions between the two periods. In the EPO Group, 8/30 patients received 27 transfusions. Six transfusions violated guidelines based on hematocrit level. EPO was discontinued in three infants secondary to treatment-related neutropenia. There were two deaths unassociated with EPO treatment. Excluding deaths, 6 patients received 16 transfusions. In the No EPO Group, 8/20 patients received 13 transfusions. Two transfusions violated guidelines based on hematocrit. There were three deaths and one patient transfer. Excluding these four patients, 6 infants received 11 transfusions (P < or = 1.) Among survivors, there were no significant differences in mean total length of stay (49.3 +/- 22.7 versus 53.2 +/- 26.4 d), mean discharge weight (2,144 +/- 405 versus 2,358 +/- 458 g), or average weight gain/d (20.7 +/- 5.44 versus 22.6 +/- 6.81 g), between the two groups respectively, nor were there significant differences when all babies were included in the analysis. There was a significant difference in mean hematocrit at discharge, respectively, (38.3% +/- 6.84 versus 31.4% +/- 6.26; P = 0.003) in survivors. CONCLUSIONS: A restricted transfusion schedule without EPO use was associated with lower mean hematocrit at discharge, but not with an increased frequency of transfusions, nor significant differences in length of stay, discharge weight, or average daily weight gain. A restricted transfusion schedule alone avoided side effects and costs associated with EPO. Indications for transfusion and what constitutes appropriate levels of hemoglobin still require clinical investigation, including long-term clinical outcomes.