An Unexpected Diagnosis Uncovered by Quantitative Molecular Findings: A Case Report.

A 74-year-old male presented with rectal pain; workup uncovered an anal mass, and a diagnosis of melanoma was rendered via histologic examination and immunohistochemical (IHC) studies. Droplet digital PCR (ddPCR)-based BRAF testing was performed and revealed the presence of BRAF V600E, which is a common targetable genetic alteration in melanoma. Interestingly, the ratio of mutant to wild-type copy number was low (0.3%), whereas tumor cell percentage on tissue slides was 90%. With additional workup, BRAF V600E IHC confirmed a very small subset of BRAF V600E-positive cells, and a next-generation sequencing (NGS) panel revealed a pathogenic KIT variant, p.L576P, with an allele frequency of 63%. It was initially hypothesized that the main driver of the melanoma was the KIT alteration, whereas a small subclone (not detected by NGS, which has a 5% limit of detection) was driven by the BRAF V600E detected by ddPCR. To determine whether there were morphologic differences between the 2 clones, a careful review of the histology was performed and revealed distinct morphology of the BRAF V600E-positive cells, including pale cytoplasm, nuclear grooves, and infiltrating eosinophils. Additional IHC workup of the BRAF V600E-positive cells showed coexpression of CD1a, Langerin, and S100, diagnostic of Langerhans cell histiocytosis (LCH). This diagnosis was unexpected and would have been missed without highly sensitive molecular testing; yet it is of clinical importance for the patient. This case raises interesting biology questions regarding the relationship between melanoma and LCH; moreover, it highlights the importance of integrating quantitative information in molecular data interpretation.

Epithelioid osteoblastoma with secondary aneurysmal bone cyst and FOS gene rearrangement.

Epithelioid osteoblastoma, sometimes equated with aggressive osteoblastoma, is a variant of osteoblastoma that typically demonstrates more worrisome imaging and pathological features compared to conventional osteoblastoma. These more aggressive features can overlap with those seen in osteosarcoma, creating a diagnostic challenge for radiologists and pathologists. Recent identification of FOS and FOSB gene rearrangements in osteoid osteoma and osteoblastoma has allowed for greater diagnostic confidence following biopsy, but careful radiological-pathological correlation remains a key component for guiding appropriate management. Although the imaging features of conventional osteoblastoma have been previously described, there are limited examples in the literature of the imaging appearance of epithelioid osteoblastoma, and none with secondary aneurysmal bone cyst. In this case report, we detail the clinical, imaging, and histological characteristics of a proximal femoral epithelioid osteoblastoma which was pathologically confirmed by FOS and FOSB genetic testing. The initial imaging impression favored a malignancy, but when the biopsy results were correlated in a multidisciplinary fashion with the imaging, epithelioid osteoblastoma became the leading diagnosis which was subsequently genetically confirmed. This case emphasizes the value of multidisciplinary radiology-pathology correlation in routine practice.

NTRK-rearranged spindle cell neoplasm of the lower extremity: radiologic-pathologic correlation.

Neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm is a recently characterized soft tissue tumor and has been classified as provisional by the World Health Organization. Detection of the genetic rearrangement is important because these tumors are amenable to targeted tyrosine kinase inhibitor therapy, which can play a key role in patients with unresectable or advanced disease. Although the spectrum of histopathology associated with this entity is broad, one notable feature is the infiltrative growth pattern, which is most reminiscent of lipofibromatosis-like neural tumor. Description of their diverse histologic attributes has aided recognition, but so far little attention has been paid to correlating the gross appearance and imaging features of these lesions. In this report, we describe the clinical, imaging, histopathological, and genetic features of a soft tissue NTRK-rearranged spindle cell neoplasm. Inclusion of this more recently identified entity into the imaging differential of tumors with intratumoral relatively hypovascular nodules and infiltrative margins is important because testing for NTRK rearrangement is not routinely performed.

Computational simulation of 1 H NMR profiles of complex biofluid analyte mixtures at differential operating frequencies: Applications to low-field benchtop spectra.

Estimations of accurate and reliable NMR chemical shift values, coupling patterns and constants within a reasonable timeframe remain significantly challenging, and the unavailability of reliable software strategies for the prediction of low-field (e.g., 60 MHz) spectra from those acquired at higher operating frequencies hampers their direct comparison. Hence, this study explored the applications of accessible software options for predicting these parameters in the 1 H NMR profiles of analytes as a function of magnetic field strength; this was performed for individual analytes and also for complex biofluid matrices featured in metabolomics investigations. For this purpose, results from the very first successful experimental acquisition and simulation of the 1 H NMR profiles of intact human salivary supernatant samples on a 60 MHz benchtop spectrometer were evaluated. Using salivary metabolite concentrations determined at 400 MHz, it was demonstrated that simulation of the low-field spectra of five biomolecules with the most prominent 1 H resonances detectable allowed multiple component fits to be applied to experimental spectra. Hence, these salivary 1 H NMR profiles could be successfully predicted throughout the 45-600 MHz operating frequency range. With the exception of propionate resonance multiplets, which revealed more complex coupling patterns at low field and required more astute computational and fitting options, valuable quantitative metabolomics data on salivary acetate, formate, methanol and glycine could be attained from low-field spectrometres. These studies are both timely and pertinent in view of the recent advancement of low-field benchtop NMR facilities for diagnostically significant biomarker tracking in biofluids. Experiments performed with added ammonium chloride to facilitate the release of salivary metabolites from biopolymer binding sites provided evidence that a small but nevertheless significant proportion of propionate, but not lactate, was bound to such sites, an observation of much relevance to biomolecule quantification in salivary metabolomics investigations.

"Inflammatory Leiomyosarcoma" and "Histiocyte-rich Rhabdomyoblastic Tumor": a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as "Inflammatory Rhabdomyoblastic Tumor".

Inflammatory leiomyosarcoma (ILMS), defined as "a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization", is a very rare soft tissue tumor with a generally favorable prognosis. The morphologic features of "histiocyte-rich rhabdomyoblastic tumor" (HRRMT) are similar to those of ILMS, although this lesion shows by definition a skeletal muscle phenotype. Recent gene expression profiling and immunohistochemical studies have also suggested that ILMS and HRRMT may be related. We studied the clinicopathologic, immunohistochemical and genetic features of four cases previously classified as ILMS and nine classified as HRRMT. Tumors from both groups tended to occur in the deep soft tissues of the extremities of young to middle-aged males and exhibited indolent behavior. Morphologically, all were well-circumscribed, often encapsulated, and showed a striking histiocyte-rich inflammatory infiltrate admixed with variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology, eosinophilic cytoplasm, and prominent nucleoli, but few, if any, mitotic figures. Immunohistochemically, the tumor cells expressed desmin, alpha-smooth muscle actin, and the rhabdomyoblastic markers PAX7, MyoD1, and myogenin. H-caldesmon expression was absent in all cases, using the specific h-CD antibody. Karyotypic study (1 HRRMT) and genome-wide copy number analysis (7 HRRMT, OncoScan SNP assay), revealed near-haploidization in four cases, with subsequent genome doubling in one, an identical phenotype to that seen in ILMS. We propose reclassification of ILMS and HRRMT as "inflammatory rhabdomyoblastic tumor", a name which accurately describes the salient morphologic and immunohistochemical features of this distinctive tumor, as well as its intermediate (rarely metastasizing) clinical behavior.

NMR spectral analysis of strongly second-order 6-, 8-, 9- and 10- spin-systems (1 H─19 F, 19 F─19 F, and 13 C─19 F) in perfluorotoluyl- and tetrafluoro-pyridyl-aromatics using the lineshape method ANATOLIA.

A simple to use nuclear magnetic resonance analysis method has been tested on complex 1 H, 19 F, and 13 C multiplets. This open-source line-shape analysis method analysis of total lineshape (ANATOLIA)1 provides some significant advantages over traditional assign-iterate methods of NMR spectral analysis by avoiding false minima and progressing optimisation to the global minimum. The target molecules are 1-perfluorotol-4-yl-2-perfluorotol-4-yl-oxymethyl-1H-benzimidazole (molecule-I) and 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-yl-thio-1H-benzimidazole (molecule-II) which were produced as part of a family of fluorinated drug scaffolds prepared for anticancer and antiparasitic screening. Spectra display significant second-order effects with 1 H Δδ = 3.68 and 4.67 Hz for the aromatic hydrogen "triplets", with 19 F 4 JAA' , 4 JBB' , 4 JXX' , and 4 JYY' coupling constants range from +4.8 to -14.0 Hz and for 13 C-isotopomers 19 F Δδ of up to 111.56 Hz. A spin-system of six coupling nuclei (Ha Hb Hc Hd FY FY' ) was analysed in 12 s, a spin-system of nine coupling fluorine nuclei (AA'BB'CCC-YY') was analysed within 2 min, and 10 coupling nuclei (XX'YY'ZZZ-BB'-Hd ) was optimised in 6 min using a laptop computer. ANATOLIA was also robust enough to be able to yield accurate spectral values from inaccurate input values. In both compounds, a fluorine-fluorine coupling constant was identified between the two fluoro-aromatic rings (FBB' and FYY' ) of +4.05 and +4.67 Hz and attributed to a through-space interaction. Ab initio structure optimisations and coupling constant calculations provided useful input data for spectral analysis. A modern 19 F nuclear magnetic resonance spectrum of perfluorotoluene (octafluorotoluene) and analysis from 1975 was used as a test data set to assess ANATOLIA.

Static and Dynamic Lung Volumes in Swimmers and Their Ventilatory Response to Maximal Exercise.

PURPOSE: While the static and dynamic lung volumes of active swimmers is often greater than the predicted volume of similarly active non-swimmers, little is known if their ventilatory response to exercise is also different. METHODS: Three groups of anthropometrically matched male adults were recruited, daily active swimmers (n = 15), daily active in fields sport (Rugby and Football) (n = 15), and recreationally active (n = 15). Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximal voluntary ventilation (MVV) was measured before and after exercise to volitional exhaustion. RESULTS: Swimmers had significantly larger FVC (6.2 ± 0.6 l, 109 ± 9% pred) than the other groups (5.6 ± 0.5 l, 106 ± 13% pred, 5.5 ± 0.8, 99% pred, the sportsmen and recreational groups, respectively). FEV1 and MVV were not different. While at peak exercise, all groups reached their ventilatory reserve (around 20%), the swimmers had a greater minute ventilation rate than the recreational group (146 ± 19 vs 120 ± 87 l/min), delivering this volume by breathing deeper and slower. CONCLUSIONS: The swimmers utilised their larger static volumes (FVC) differently during exercise by meeting their ventilation volume through long and deep breaths.

Epirubicin chemotherapy in women with breast cancer: Alternating arms for intravenous administration to reduce chemical phlebitis.

OBJECTIVE: To establish whether using alternating arms for peripheral intravenous epirubicin administration affects the severity or duration of epirubicin-induced phlebitis. METHODS: An observational study of women with breast cancer (n = 237) in a UK Cancer Centre. Data were analysed after receiving three treatment cycles according to the arm used for epirubicin administration: same, alternating or mixed arm (two consecutive cycles in one arm and one in the alternate arm). Phlebitis severity was graded by clinical staff after each treatment; participants also self-reported symptoms during treatment and for up to 6 months after. RESULTS: The alternating arm group experienced significantly less severe symptoms than the other arm use groups, 6% (4 of 64) compared with 34% (p < 0.001, odds ratio: 0.13 (95% CI: 0.043-0.38) alternating arm compared with same arm group). The alternating arm group reported less pain (p = 0.013), lower overall impact (p = 0.009), lower effect on function (p = 0.032) and shorter duration of symptoms (p = 0.001) than the other arm use groups. CONCLUSION: Using alternating arms for peripheral administration of epirubicin significantly reduces the severity and duration of chemical phlebitis and is recommended to improve patient experience and reduce the need for central venous access devices.

Combined classical spindle cell/pleomorphic lipoma spectrum imaging and clinical data.

OBJECTIVES: Compile the largest study to date on the imaging and clinical features of the classic spindle cell/pleomorphic lipoma spectrum and suggest this diagnosis be included in the differential for benign and malignant macroscopic fat-containing soft tissue masses regardless of the mass location or patient demographics. MATERIALS AND METHODS: An institutional search was performed to identify all available classic-type spindle cell/pleomorphic lipomas with available demographic and imaging data. Images and reports were analyzed by one MSK-trained radiologist and radiographic, anatomic and clinical data were recorded. Additionally, a literature search was performed to identify studies describing the spindle cell lipoma spectrum imaging features and were combined with institutional data. RESULTS: Forty-two institutional cases were identified, 37 of which had MRIs performed among which 21 had images available (T1- and T2-weighted pulse sequences) for review while the remainder had outside reports detailing the mass imaging features. There was a mean age of 57 with 79% of cases occurring in males. Contrary to prior reports, 57% of masses were subcutaneous, and the neck and back region accounted for 26% of cases. When the institutional cases were combined with available data in the literature, there was a new sample size of 91 masses, 74 of which had MRI and/or CT data. Eighty-seven percent of masses were heterogeneous, 51% were composed of less than 75% fat, 65% were in the back, neck or shoulder region, 27% of masses were deep and 91% demonstrated enhancement. Eighty-two percent of patients were males with a mean age of 58 at excision. CONCLUSION: Imaging features, patient demographics and tumor location alone are not enough to differentiate tumors of the spindle cell lipoma spectrum from other macroscopic fat-containing benign and malignant tumors, and these entities should be included in the same imaging differential diagnosis.

Dedifferentiated chondrosarcoma of the larynx: Radiological, gross, microscopic and clinical features.

Laryngeal chondrosarcoma is an uncommon malignancy with a predilection for the cricoid cartilage of adult male patients. Although rare, identification of aggressive chondrosarcoma variants, such as dedifferentiated chondrosarcoma (DDCS) may influence preoperative patient counseling, definitive surgical management, potential implementation of post-operative adjuvant therapy and prognosis. Herein we describe clinical and imaging features of laryngeal DDCS, the unique perspective of fresh and formalin fixed macroscopic examination, a spectrum of histopathologic findings, and detail the full course of the patient's disease.

Breathing pattern and breathlessness in idiopathic pulmonary fibrosis: An observational study.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive decline in lung function and increasing dyspnoea. The aim of this study was to investigate the relationship among IPF, pulmonary function, resting tidal breathing patterns and level of breathlessness. METHODS: Thirty-one participants with IPF and 17 matched healthy controls underwent lung function testing, followed by a 2-min period of resting tidal breathing. The IPF cohort was stratified according to disease severity, based on their forced vital capacity and diffusion capacity for carbon monoxide. RESULTS: In comparison to the healthy controls, the IPF cohort showed a higher tidal volume, VT , of 0.22 L (P = 0.026) and a raised minute ventilation in the severest IPF group, while no differences in the timing of inspiration or expiration were observed. In the IPF cohort, the ratio of VT to forced vital capacity was around 15% higher. These changes corresponded with an increase in the self-reported sensation of breathlessness. CONCLUSION: Those with IPF increased their depth of breathing with worsening disease severity, with IPF-induced changes in pulmonary function and breathlessness associated with an altered tidal breathing pattern.

Bullous Kaposiform Hemangioendothelioma Masquerading as Aplasia Cutis Congenita.

We present the case of a male infant with violaceous bullae on the scalp that were initially thought to be bullous aplasia cutis but at 3 months of age were diagnosed as a kaposiform hemangioendothelioma. This diagnosis should be considered when evaluating newborns with bullous plaques on the scalp that do not heal in the first 2-3 weeks of life. Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor that typically presents as a violaceous to purpuric plaque at birth or early infancy. It may be associated with Kasabach-Merritt phenomenon (KMP), a potentially life-threatening consumptive coagulopathy.

The histological variants of liposarcoma: predictive MRI findings with prognostic implications, management, follow-up, and differential diagnosis.

Liposarcoma is the single most common soft tissue sarcoma accounting for up to 35 % of sarcomas. It represents a histologically diverse group of soft tissue tumors that demonstrate a wide range of imaging appearances with varied behavior patterns. Correspondingly, more aggressive histological subtypes often require management that includes a combination of surgery, chemotherapy, and radiation therapy. Distinguishing among liposarcoma subtypes has important therapeutic and prognostic implications. In this manuscript, we review the liposarcoma subtypes and their histologic and MRI findings, prognostic implications, and differential diagnostic considerations.

Benign cutaneous biphasic hybrid tumor of perineurioma and cellular neurothekeoma: A case report expanding the clinical and histopathologic features of a recently described entity.

Benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma (BCPHTPCN) is a recently described entity that presents as a solitary papule in the perioral area. As implied by its name, BCPHTPCN displays microscopic features of both perineurioma and cellular neurothekeoma arranged in a plexiform pattern. We report a case of nonplexiform benign cutaneous biphasic hybrid tumor of perineurioma and cellular neurothekeoma in a 36-year-old woman, who presented with a 4-year history of a firm, flesh-colored left ankle nodule. Histologically, there was a biphasic, well-circumscribed unencapsulated dermal mesenchymal proliferation with no connection to the epidermis, which exhibited mild acanthosis with slightly pigmented basal keratinocytes and overlying parakeratosis. The proliferation consisted of uniform bland spindle cells with bipolar cytoplasmic processes arranged in whorls with interspersed islands of epithelioid cells. Immunohistochemically, the spindle cell component was positive for CD34, EMA, and GLUT-1, consistent with perineurial differentiation, whereas the epithelioid nests were positive for NKI/C3 and MiTF, as expected in neurothekeoma. Stains for S100 protein, SOX10, desmin, claudin, pan-melanoma markers, and NSE were negative. We believe this case expands the histopathologic spectrum of BCPHTPCN showing that it can be grown in a nonplexiform pattern, and we suggest the term benign cutaneous biphasic hybrid tumor of perineurioma and cellular neurothekeoma as a more precise name. It is also, to the best of our knowledge, the first case reported outside the head and neck area.

Tidal breathing in preterm infants receiving and weaning from continuous positive airway pressure.

OBJECTIVE: To compare tidal breathing on different continuous positive airway pressure (CPAP) devices and pressures and to serially measure tidal breathing during weaning off CPAP using electromagnetic inductive plethysmography. STUDY DESIGN: Using electromagnetic inductive plethysmography, tidal breathing was measured in 29 preterm infants receiving CPAP, gestational age 28 ± 2 weeks. Variable-flow nasal CPAP (nCPAP), bubble CPAP (bCPAP) at pressures of 5, 7, and 9 cmH2O, nasal bi-level positive airway pressure (nBiPAP) system at pressures of 5, 7/5, and 9/5 cmH2O, and unsupported breathing were studied. Twenty-one infants had weekly tidal breathing measurements on and off nCPAP. RESULTS: Minute volume (MV/kg) was similar between all devices (0.30-0.33 L/kg/min). On bCPAP, weight corrected tidal volume (VT/kg) was the least, changing little with increasing pressures. On nCPAP and nBiPAP, VT/kg increased with increasing pressure and the respiratory rate (fR) decreased. The delivered pressure varied slightly from the set pressure being most dissimilar on nBiPAP and similar on bCPAP. Compared with unsupported breathing, all devices decreased VT/kg, MV/kg, and phase angle, but did not alter fR. Serial tidal breathing measurements showed decreasing difference for VT/kg over time on and off nCPAP. CONCLUSIONS: At different pressure settings, on all CPAP devices the measured MV/kg was similar either through increasing VT/kg and decreasing fR (nCPAP and nBiPAP) or maintaining both (bCPAP). Serial tidal breathing measurements may aid weaning from CPAP.

Vascular tumors of bone.

Vascular tumors of the bone represent a variety of neoplasms, ranging from benign hemangiomas and epithelioid hemangiomas to intermediate grade hemangioendotheliomas to frankly malignant angiosarcomas. Over the years, there has been considerable debate concerning the aggressivity, nomenclature, and mere existence of various nosologic entities, due to morphologic similarities and uncertainty regarding biologic behavior. Such debate has led to confusion among pathologists and clinicians, thus diminishing the prognostic implications in the diagnosis of these lesions. Here we review the current knowledge concerning the primary vascular neoplasms of the bone and correlate clinicopathologic features with tumor behavior.

Acute esophageal stricture after bone marrow transplant.

Esophageal stricture after bone marrow transplantation (BMT) is exceptionally rare, with only a few cases reported in the literature. We present an interesting case of a 58-year-old male with refractory multiple myeloma who developed dysphagia five days following his second bone marrow transplantation. He was found to have a severe esophageal stricture. The patient was treated with multiple esophageal dilations and triamcinolone injections in the following weeks to months, resulting in an improvement in symptoms. Although the exact underlying mechanism remains unknown, high-dose chemotherapy conditioning with melphalan prior to BMT likely contributed to the stricture. Our case highlights the importance of heightened post-bone marrow transplantation management for rare complications, such as an esophageal stricture.

Molecular GBM versus Histopathological GBM: Radiology-Pathology-Genetic Correlation and the New WHO 2021 Definition of Glioblastoma.

Given the recent advances in molecular pathogenesis of tumors, with better correlation with tumor behavior and prognosis, major changes were made to the new 2021 World Health Organization (WHO) classification of CNS tumors, including updated criteria for diagnosis of glioblastoma (GBM). Diagnosis of GBM now requires absence of isocitrate dehydrogenase and histone 3 mutations (IDH-wild-type and H3-wild-type) as the basic cornerstone, with elimination of the IDH-mutant category. The requirements for diagnosis were conventionally histopathological, based on the presence of pathognomonic features such as microvascular proliferation and necrosis. However, even if these histologic features are absent, many lower-grade (WHO grade 2/3) diffuse astrocytic gliomas behave clinically similar to GBM (grade 4). The 2021 WHO classification introduced new molecular criteria that can be used to upgrade the diagnosis of such histologically lower-grade, IDH-wild-type, astrocytomas to GBM. The 3 molecular criteria include: concurrent gain of whole chromosome 7 and loss of whole chromosome 10 (+7/-10); telomerase reverse transcriptase promoter mutation; and epidermal growth factor receptor amplification. Given these changes, it is now strongly recommended to have molecular analysis of WHO grade 2/3 diffuse astrocytic, IDH-wild-type, gliomas in adult patients, as identification of any of the above mutations allows for upgrading the tumor to WHO grade 4 ("molecular GBM") with important prognostic implications. Despite an early stage, there is active ongoing research on the unique MR imaging features of molecular GBM. This paper highlights the differences between "molecular" and "histopathological" GBM, with the aim of providing a basic understanding about these changes.