Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275.

Biological properties of bone marrow plasma cells influence their recovery in aspirate specimens: impact on classification of plasma cell disorders and potential bias to evaluation of treatment response.

Methods to estimate bone marrow plasma cells (BMPC) basically include histopathology, cytomorphology, and flow cytometry. The present study compares the outcomes of these methods with special focus on the impact of BMPC-specific characteristics on their recovery by either method. Laboratory reports of diagnostic samples from 238 consecutive patients with suspected or known plasma cell disease were retrospectively analyzed. The median (IQR) proportion of BMPC was 30.0% (15.0-70.0%) by histological review (hBMPC), 7.0% (2.0-16.0%) by smear review (sBMPC), and 3.0% (0.8-10.0%) by flow cytometry (fBMPC). The disparity of results between core biopsy and aspirate smear was enhanced in case of poor quality of the smear, increased BM fiber content, higher grade cell atypia, expression of CD56 (all P < 0.0001), the number of cytogenetic aberrations (P = 0.0002), and abnormalities of the MYC gene (P = 0.0002). Conversely, expression of CD19 and a non-clonal plasma cell phenotype were associated with a lower difference between hBMPC and sBMPC (both P < 0.0001). The disparity between the percentages of sBMPC and fBMPC was associated with the quality of the smear (P = 0.0007) and expression of CD56 (P < 0.0001). Our results suggest that the recovery of BMPC in aspirate specimens not only is a matter of sampling quality but also depends on biological cell properties. Aspiration failure due to malignant type features of BMPC may lead to misclassification of plasma cell disorders and represent a bias for the detection of minimal residual disease after therapy.

Transformed mucosa-associated lymphoid tissue lymphomas: A single institution retrospective study including polymerase chain reaction-based clonality analysis.

Given the lack of consistent data regarding the clinico-pathological features and clonal lymphomagenesis of patients with mucosa-associated lymphoid tissue (MALT) lymphoma and histological transformation (HT), we have systematically analysed 379 patients (32% gastric, 68% extra-gastric; median follow-up 52 months) diagnosed with HT at the Medical University Vienna 1999-2017, and reassessed tissues of identified patients by polymerase chain reaction (PCR)-based clonality analysis. HT was documented in 12/379 patients (3·2%) and occurred at a median time of 22 months (range; 6-202 months) after diagnosis of MALT lymphoma. By PCR-based clonality analysis, we detected a clear-cut clonal relationship of MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) in 8 of 11 analysed cases proving that the large majority of DLBCL following MALT lymphoma are clonally-related and constitute a real transformation. Interestingly, HT occurred within the first 2·5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally-unrelated (most likely secondary) lymphoma (82-202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1·5-33 months after HT, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.

Extravasation of Pt-based chemotherapeutics - bioimaging of their distribution in resectates using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS).

Platinum-based drugs (cisplatin, carboplatin and oxaliplatin) are widely used in cancer treatment. They are administered intravenously, thus accidental extravasations of infusions can occur. This may cause severe complications for the patient as the toxic platinum compounds likely persist in subcutaneous tissue. At high concentrations, platinum toxicity in combination with local thrombosis may result in tissue necrosis, eventually requiring surgical intervention. To describe tissue distribution at the anatomic level, we quantified drug extravasation in cryosections of various tissues (muscle, nerve tissue, connective tissue, fat tissue) by means of quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and compared the resulting data with bulk analysis of microwave-assisted digestion of tissue samples followed by ICP-MS analysis. Samples of three patients receiving systemic chemotherapy either via peripheral venous access or central access via port-a-cath® were analyzed. Pt was enriched up to 50-times in connective tissue when compared with muscle tissue or drain samples collected over five days. The large areas of subcutaneous fat tissue showed areactive necrosis and average Pt concentrations (determined upon sample digestion) ranged from 0.2 µg g(-1) (therapy with 25 mg m(-2) cisplatin, four weeks after peripheral extravasation) to 10 µg g(-1) (therapy with 50 mg m(-2) oxaliplatin: four weeks after port-a-cath® extravasation). A peripheral nerve subjected to bioimaging by LA-ICP-MS showed a 5-times lower Pt concentration (0.2 µg g(-1)) than the surrounding connective tissue (1.0 µg g(-1)). This is in accordance with the patient showing no signs of neurotoxicity during recovery from extravasation side-effects. Thus, bioimaging of cutaneous nerve tissue may contribute to understand the risk of peripheral neurotoxic events.

Outcome of chemotherapy extravasation in a large patient series using a standardised management protocol.

PURPOSE: In a longitudinal observation, extravasation of antitumoural compounds and the efficacy of its structured interdisciplinary management were assessed in a routine setting. METHODS: One hundred sixty-nine patients with extravasation of cytotoxics were managed according to a prospective approach documenting the extravasated compound, localisation, duration until full symptom resolution and sequelae. Surgery was implemented in the case of failure of conservative measures. RESULTS: In 155 (91.7 %) out of 169 patients, conservative management was successful (surgical intervention, 14 patients). Extravasations of anthracyclines (N = 44), platinum compounds (N = 41), vinca alkaloids (N = 20) and taxanes (N = 19) were often associated with erythema, oedema and pain. The median period until full resolution of symptoms differed among the administered cytotoxics (anthracyclines, 55 days; taxanes and vinca alkaloids, 27 days; platinum compounds, 14 days) with statistical significance between the vesicants. Histologically, surgically resected specimens showed extensive necrotic areas with inflammatory infiltrates at the periphery of the removed lesions. CONCLUSIONS: In a routine setting, the standardised management of cytotoxic extravasations by an interdisciplinary task force resulted in a satisfactory outcome. When surgical intervention was indicated, complete remission of the lesions within a median of 14 days reduced the delay in the administration of further chemotherapy to a minimum. The proposed approach is therefore considered as suitable to manage extravasations in cancer chemotherapy in a large number of subjects and to ensure patient adherence to cytotoxic treatment.

Improved molecular classification of serrated lesions of the colon by immunohistochemical detection of BRAF V600E.

BRAF V600E mutation in serrated lesions of the colon has been implicated as an important mutation and as a specific marker for the serrated carcinogenic pathway. Recent findings point to microvesicular hyperplastic polyps that have similar histologic and molecular features to sessile serrated adenomas/polyps, as potential colorectal carcinoma precursors. The aim of this study was to evaluate BRAF V600E mutation status by immunohistochemistry in serrated lesions of the colon with regard to histomorphology. We investigated 194 serrated lesions of the colon, comprising 42 sessile serrated adenomas/polyps, 16 traditional serrated adenomas, 136 hyperplastic polyps and 20 tubular/tubulovillous adenomas (conventional adenomas) with the novel BRAF V600E mutation-specific antibody VE1. In addition, BRAF exon 15 and KRAS exon 2 status was investigated by capillary sequencing in selected cases. All sessile serrated adenomas/polyps (42/42, 100%), 15/16 (94%) traditional serrated adenomas and 84/136 (62%) hyperplastic polyps were VE1+. None of the VE1- serrated lesions showed BRAF V600E mutation. Forty out of 42 (95%) sessile serrated adenomas/polyps displayed areas with microvesicular hyperplastic polyp-like features. In microvesicular hyperplastic polyps, VE1 positivity was significantly associated with nuclear atypia (P=0.003); however, nuclear atypia was also present in VE1- cases. Immunostaining with VE1 allows not only the detection of BRAF V600E mutation but also the correlation with histomorphology on a cellular level in serrated lesions. VE1 enables a subclassification of microvesicular hyperplastic polyps according to the mutation status. This improved classification of serrated lesions including immunohistochemical evaluation of BRAF V600E mutation may be the key to identify lesions with higher potential to progression into sessile serrated adenoma/polyp, and further to BRAF V600E-mutated colorectal cancer.

Evaluation of the intraoperative specimens of the thoracic and abdominal aorta.

BACKGROUND: Little is known about the histological patterns of acute and chronic aortic pathology with regard to medial degeneration, atherosclerosis and aortitis as well as their distribution in different age groups. The aim of the study was to evaluate histopathological findings of intraoperatively gained aortic specimens with regard to the incidence of medial degeneration, atherosclerosis and aortitis. METHODS: Intraoperatively gained aortic specimens were evaluated in 151 patients including 83 (55%) aortic aneurysms (65 thoracic, 18 abdominal) and 68 (45%) acute type A aortic dissections. Histological stainings used were hematoxylin and eosin, Van Gieson as well as alcian blue. Patients were stratified according to above and below 65 years of age. High grade medial degeneration represented pooling of mucoid material in the whole aortic wall. High grade atherosclerosis represented severe intimal fibrosis, massive accumulation of macrophages and foam cells or massive calcification of the aortic wall. RESULTS: Medial degeneration was diagnosed in 106 (70%) patients including 55 (52%) aortic aneurysms and 51 (48%) acute type A aortic dissections. High grade medial degeneration was found in 50% of patients with thoracic aortic aneurysms < 65 years of age vs. 44% in patients ≥ 65 years of age (p = 0.64) and in 36% of patients with thoracic aortic dissections < 65 years of age vs. 14% in patients ≥ 65 years of age (p = 0.07). Atherosclerosis was diagnosed in 71 (47%) patients including 46 (65%) aortic aneurysms and 25 (35%) aortic dissections. High grade atherosclerosis was found in 23% of patients with thoracic aneurysms < 65 years of age vs. 36% in patients ≥ 65 years of age (p = 0.24) and in 13% of patients with aortic dissections < 65 years of age vs. 52% in patients ≥ 65 years of age (p < 0.001). Aortitis was rare (n = 2). CONCLUSIONS: Medial degeneration was the most frequent diagnosis in this series of aortic specimens. Medial degeneration was equally common in patients above and below 65 years of age. However in cases with acute type A aortic dissections, high grade atherosclerosis was the leading histopathological diagnosis in patients older than 65 years. Acute type A aortic dissections seem to have different underlying pathologies in different age groups.

Aortitis requiring aortic repair associated with glaucoma, thyroiditis, glaucoma, and neuropathy: case report.

Aortitis may be due to infectious and non-infectious causes. We observed aortitis, associated with glaucoma, thyroiditis, pericarditis, pleural effusion and neuropathy in a 63-years old woman. Despite antibiotic therapy, inflammatory signs persisted and resolved only after initiation of glucocorticoid therapy. Increasing aortic ectasia necessitated resection of the ascending aorta and implantation of a Vascutek 30 mm prosthesis. Histologically a granulomatous aortitis was diagnosed. Since all other possible causes were excluded, an immunological mechanism of the aortitis is suspected and possible triggering factors are discussed.