Fluorescence lifetime of injected indocyanine green as a universal marker of solid tumours in patients.

The surgical resection of solid tumours can be enhanced by fluorescence-guided imaging. However, variable tumour uptake and incomplete clearance of fluorescent dyes reduces the accuracy of distinguishing tumour from normal tissue via conventional fluorescence intensity-based imaging. Here we show that, after systemic injection of the near-infrared dye indocyanine green in patients with various types of solid tumour, the fluorescence lifetime (FLT) of tumour tissue is longer than the FLT of non-cancerous tissue. This tumour-specific shift in FLT can be used to distinguish tumours from normal tissue with an accuracy of over 97% across tumour types, and can be visualized at the cellular level using microscopy and in larger specimens through wide-field imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth and the amount of dye taken up by tumours, FLT is a photophysical property that is largely independent of these factors. FLT imaging with indocyanine green may improve the accuracy of cancer surgeries.

First Clinical Results of Fluorescence Lifetime-enhanced Tumor Imaging Using Receptor-targeted Fluorescent Probes.

PURPOSE: Fluorescence molecular imaging, using cancer-targeted near infrared (NIR) fluorescent probes, offers the promise of accurate tumor delineation during surgeries and the detection of cancer specific molecular expression in vivo. However, nonspecific probe accumulation in normal tissue results in poor tumor fluorescence contrast, precluding widespread clinical adoption of novel imaging agents. Here we present the first clinical evidence that fluorescence lifetime (FLT) imaging can provide tumor specificity at the cellular level in patients systemically injected with panitumumab-IRDye800CW, an EGFR-targeted NIR fluorescent probe. EXPERIMENTAL DESIGN: We performed wide-field and microscopic FLT imaging of resection specimens from patients injected with panitumumab-IRDye800CW under an FDA directed clinical trial. RESULTS: We show that the FLT within EGFR-overexpressing cancer cells is significantly longer than the FLT of normal tissue, providing high sensitivity (>98%) and specificity (>98%) for tumor versus normal tissue classification, despite the presence of significant nonspecific probe accumulation. We further show microscopic evidence that the mean tissue FLT is spatially correlated (r > 0.85) with tumor-specific EGFR expression in tissue and is consistent across multiple patients. These tumor cell-specific FLT changes can be detected through thick biological tissue, allowing highly specific tumor detection and noninvasive monitoring of tumor EFGR expression in vivo. CONCLUSIONS: Our data indicate that FLT imaging is a promising approach for enhancing tumor contrast using an antibody-targeted NIR probe with a proven safety profile in humans, suggesting a strong potential for clinical applications in image guided surgery, cancer diagnostics, and staging.

Distinctive pseudopalisaded histiocytic hyperplasia characterizes the transition of exudative to proliferative phase of diffuse alveolar damage in patients dying of COVID-19.

Severe COVID-19 results in a glucocorticoid responsive form of acute respiratory distress (ARDS)/diffuse alveolar damage (DAD). Herein we compare the immunopathology of lung tissue procured at autopsy in patients dying of SARS-CoV-2 with those dying of DAD prior to the COVID-19 pandemic. Autopsy gross and microscopic features stratified by duration of illness in twelve patients who tested positive for SARS-CoV-2 viral RNA, as well as seven patients dying of DAD prior to the COVID-19 pandemic were evaluated with multiplex (5-plex: CD4, CD8, CD68, CD20, AE1/AE3) and SARS-CoV immunohistochemistry to characterize the immunopathologic stages of DAD. We observed a distinctive pseudopalisaded histiocytic hyperplasia interposed between the exudative and proliferative phase of COVID-19 associated DAD, which was most pronounced at the fourth week from symptom onset. Pulmonary macrothrombi were seen predominantly in cases with pseudopalisaded histiocytic hyperplasia and/or proliferative phase DAD. Neither pseudopalisaded histiocytic hyperplasia nor pulmonary macrothrombi was seen in non-COVID-19 DAD cases, whereas microthrombi were common in DAD regardless of etiology. The inflammatory pattern of pseudopalisaded histiocytic hyperplasia may represent the distinctive immunopathology associated with the dexamethasone responsive form of DAD seen in severe COVID-19.

SARS-CoV-2 Infection-Associated Hemophagocytic Lymphohistiocytosis.

OBJECTIVES: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH. METHODS: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores. RESULTS: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96. CONCLUSIONS: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.

Solitary intramuscular myofibroma in an adult: Case report and MR imaging findings.

Myofibroma is a benign, soft tissue neoplasm that predominantly affects infants and young children. Most occur in the skin or subcutaneous tissues, with a predilection for the head and neck regions. We describe the magnetic resonance (MR) imaging and histophathologic findings of a rare case of intramuscular myofibroma of the right deltoid in a healthy 30-year-old male. MR imaging revealed a well-circumscribed intramuscular mass, with isointense signal on T1-weighted images, hyperintense signal on T2-weighed images, and a "target-sign" with peripheral rim enhancement after gadolinium administration. The lesion was surgically excised with no complications, and the histopathologic analysis revealed the typical morphologic and histochemical markers of a myofibroma. We conclude that, although rare, myofibroma can be considered in the differential diagnosis of adults with lesions the above signal characteristics.

The case of the eyelid silicone granulomas.

Foreign body granulomas can develop even several years after autologous fat or filler injection. In some instances the foreign body granulomas have been found at sites other than the original injection site. We present a case of a 48-year-old male with reported "hyaluronic acid fillers" injected into his upper and lower eyelids several years prior. He subsequently developed periorbital swelling with negative allergic and rheumatologic workup. The patient ultimately underwent a blepharoplasty for improvement of the swelling. Histopathology suggested silicone granulomas of the upper and lower eyelid. This case illustrates the importance of keeping foreign body granulomas on the differential for all patients with a history of facial dermal filler injections. Although hyaluronic acid is the most common dermal filler, providers should suspect the use of other dermal fillers including those not FDA approved particularly when common conservative treatment methods are not sufficient.

Acute promyelocytic leukaemia presenting as necrotising fasciitis of the perineum (Fournier gangrene).

We present a case of an unusual presentation of acute promyelocytic leukaemia (APML), which presented with Fournier gangrene (FG). A 38-year-old man presented with malaise, groin swelling, anal bleeding, fever and was found to have FG. Initial workup revealed pancytopaenia, borderline low fibrinogen, prolonged international normalized ratio (INR), which raised the suspicion for leukaemia. The peripheral blood differential revealed leucopaenia with absolute neutropaenia and a 5% abnormal promyelocytes but no blasts, suspicious for APML. Bone marrow biopsy was performed and fluorescence in situ hydridization (FISH), karyotype and PCR confirmed a t(15;17) translocation, establishing a diagnosis of APML. After 1 month of therapy for intermediate risk APML with All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), repeat chromosomal analysis and repeat bone marrow biopsy revealed no evidence of residual APML. After the consolidation phase was started with ATRA and ATO regimen, the wound healed after 2 months and the patient achieved complete remission.