bims-mesote 2021-10-24 papers

Issue of 2021‒10‒24
six papers selected by
Laura Mannarino
Humanitas Research

Front Oncol. 2021 ;11 679285

A3 Adenosine and P2X7 Purinergic Receptors as New Targets for an Innovative Pharmacological Therapy of Malignant Pleural Mesothelioma.

Fabrizio Vincenzi, John Charles Rotondo, Silvia Pasquini, Francesco Di Virgilio, Katia Varani, Mauro Tognon.

Human malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor of the serosal cavities whose 5-year survival rate is 15%. At present, there are no effective therapies for MPM. Although recent findings suggest that A3 adenosine (A3AR) and P2X7 (P2X7R) receptors can be employed as antitumoral pharmacological targets in MPM, their potential role in a combined therapy is currently unknown. The A3AR agonist Cl-IB-MECA and the P2X7 receptor antagonist AZ10606120, as a single compound or in combination, were investigated in vitro for their anti-tumor activities. Assays were carried out in MPM cell lines IST-Mes2 and MPP89 and in primary human normal mesothelial cells (HMCs), as control. Single treatment with Cl-IB-MECA reduced cell proliferation and favored a pro-apoptotic effect in both MPP89 and IST-Mes2 cell lines, whereas AZ10606120 inhibited cell proliferation and induced apoptosis in IST-Mes2, only. The combined treatment with Cl-IB-MECA and AZ10606120 reduced cell proliferation and favored apoptosis in MPP89 and IST-Mes2 cell lines, whereas no synergistic effect was detected. These data cumulatively suggest the absence of a synergistic effect in combined targeting of A3 adenosine and P2X7 receptors of MPM cell lines. This study may stimulate further investigations aimed at determining new combinations of antitumor compounds and more effective therapeutic strategies against MPM.

Keywords: A3 adenosine receptor; AZ10606120; Cl-IB-MECA; P2X7 receptor; anticancer therapy; malignant pleural mesothelioma

DOI: https://doi.org/10.3389/fonc.2021.679285

Indian J Pathol Microbiol. 2021 Oct-Dec;64(4):64(4): 834-836

Thigh mass in a patient with malignant pleural mesothelioma: Metastasis at an unusual site.

S Sunitha, Ashini H Shah, Amisha Gami, Priti Trivedi.

Soft tissue tumors are a highly heterogeneous group of lesions with varied clinical presentation. The majority is primary tumors and metastatic tumors are very rare. Malignant pleural mesothelioma presenting as a soft tissue mass at a distant site is even rarer and can cause diagnostic challenges both clinically and pathologically. We report a case of malignant pleural mesothelioma presenting as a soft tissue mass in the left thigh. A 59-year-old man, non-smoker, working in a cement factory since 30 years presented with complains of difficulty in walking since 1½ months. Review of his previous medical records revealed malignant pleural mesothelioma, which was diagnosed 9 months before. He had denied chemotherapy and was on Ayurvedic medication. The lesion involved the adjacent intercostal muscles. Few enlarged lymph nodes were noted in mediastinal and cervical regions. Biopsy of left supraclavicular and right cervical lymph nodes showed metastases. Metastasis from malignant pleural mesothelioma to the thigh was confirmed by immunohistochemistry. The tumor was positive for CK5/6, CK7, Calretinin and vimentin and immunonegative for CEA, Napsin A and TTF 1.

Keywords: Immunohistochemistry; malignant pleural mesothelioma; skeletal muscle; soft tissue metastases

DOI: https://doi.org/10.4103/IJPM.IJPM_463_20

Oncol Lett. 2021 Dec;22(6): 813

Short 57 kb CDKN2A FISH probe effectively detects short homozygous deletion of the 9p21 locus in malignant pleural mesothelioma.

Yuzo Oyama, Makoto Hamasaki, Shinji Matsumoto, Ayuko Sato, Tohru Tsujimura, Kazuki Nabeshima.

Homozygous deletion (homo-d) of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is frequently found in malignant pleural mesothelioma (MPM). Fluorescence in situ hybridization (FISH) is commonly used to detect chromosomal deletion, and sometimes reveals more frequent heterozygous deletion (hetero-d) compared with homo-d. In clinical practice, such CDKN2A FISH results belong to the 'borderline' homo-d rate, which makes it difficult to definitively diagnose MPM. Microdeletion, [<200 kilobase (kb)], can induce a 'pseudo' hetero-d signal in FISH assays with long probes owing to redundant probe reactivity. Thus, the present study hypothesized that shorter FISH probes can effectively detect the small deletion status of the CDKN2A gene and increase homo-d rate in MPM, which has high hetero-d and low homo-d status. The present study aimed to evaluate the effectiveness of a shorter CDKN2A FISH probe in diagnosing MPM. CDKN2A FISH with either a 222 kb long probe (L-probe) or a 57 kb short probe (S-probe) was performed in four MPM cases with high hetero-d and low homo-d patterns. Furthermore, immunohistochemistry for methylthioadenosine phosphorylase (MTAP) and quantitative (q)PCR analyses were performed to confirm the microdeletion of the 9p21 locus. The results demonstrated that all four MPM cases retained MTAP protein expression. CDKN2A FISH with L-probe revealed high hetero-d (cases 1-4; 73.3, 37.1, 59.2 and 64.8%, respectively) and low homo-d (cases 1-4; 12.1, 12.4, 25.4 and 22.2%, respectively). CDKN2A FISH with S-probe revealed high homo-d (cases 1-4; 96.8, 90.0, 87.5 and 82.6%, respectively), with low hetero-d (cases 1-4; 0.0, 1.2, 1.2 and 4.3%, respectively). qPCR analysis demonstrated no allele deletions of the MTAP gene and two-allele deletions of the CDKN2A gene in 3/4 cases. Taken together, these results suggest that the S-probe detects the short homo-d of the 9p21 locus more effectively than the L-probe in MPM. This can assist in solving diagnostic difficulties in cases involving high hetero-d with low homo-d.

Keywords: CDKN2A; MTAP; fluorescence in situ hybridization; malignant mesothelioma; microdeletion; qPCR

DOI: https://doi.org/10.3892/ol.2021.13074

Gen Thorac Cardiovasc Surg. 2021 Oct 21.

Staged removal of artificial patches for thoracic empyema after extrapleural pneumonectomy for diffuse malignant pleural mesothelioma.

Makoto Sonobe, Yuuki Kou, Nobuhisa Yamazaki, Yasuto Sakaguchi, Hirokazu Tanaka.

A 69-year-old man with occupational exposure to asbestos was referred to our hospital with right diffuse malignant pleural mesothelioma. He underwent extrapleural pneumonectomy with reconstruction of the pericardium and diaphragm using elongated polytetrafluoroethylene patches, followed by postoperative chemotherapy and chest wall irradiation. One year later, he was hospitalized because of a right empyema caused by Escherichia coli infection. As chest drainage and systemic antibiotics did not eliminate the abscess around the artificial patches, a Clagett window was created. To avoid mediastinal and liver overshift into the right thoracic cavity, we only performed partial resection of the diaphragm patch and incision of the artificial pericardium. After 19 days of irrigation and dressing change, the artificial patches were completely removed. Two months later, the patient provided a culture-negative sample and had an improved nutritional status; we therefore performed closure of the Clagett window with thoracoplasty. He did not experience recurrence of empyema.

Keywords: Clagett window; Extrapleural pneumonectomy; Malignant pleural mesothelioma; Staged removal of artificial patch; Thoracic empyema

DOI: https://doi.org/10.1007/s11748-021-01723-0

Indian J Pathol Microbiol. 2021 Oct-Dec;64(4):64(4): 655-663

Malignant mesothelioma: A clinicopathological study of 76 cases with emphasis on immunohistochemical evaluation along with review of the literature.

Tarang Patel, Priyanka Aswal.

Introduction: Malignant mesothelioma is an aggressive neoplasm arising from serosal lining and has a poor prognosis. Definite diagnosis requires confirmation through a biopsy; however, it is sometimes difficult on microscopic evaluation alone and requires the use of a wide panel of immunohistochemical markers. So, immunohistochemistry (IHC) is of paramount importance and must be routinely used for a definite diagnosis. Till date, very few studies on morphology and detailed IHC markers of mesothelioma have been reported from India.Aims: To analyze the histomorphological findings of malignant mesothelioma, study the utility and role of the various immunohistochemical markers.
Material and Methods: A total of 76 cases of mesotheliomas diagnosed at a tertiary cancer center in Udaipur were analyzed retrospectively from January 2015 to January 2020. Comprehensive data were analyzed including demographic, clinical, radiological, histopathological features along with a wide panel of IHC markers.
Results: Mesothelioma occurs over a wide age range from 40 to 70 years. It most commonly involved pleura in 68 cases (89.47%) with very few cases from the peritoneum. On computed tomography (CT) scan, nodular pleural or peritoneal thickening was present. On microscopy, the most common histopathological type was epithelioid mesothelioma (58 cases, 74.3%) followed by sarcomatous (9 cases, 12.8%), deciduoid (6 cases, 8.6%), and 3 cases of biphasic (4.3%). On IHC, WT1, mesothelin, and calretinin markers were positive in 85.91%, 80%, and 93.33% cases of mesothelioma, respectively. Other markers were helpful to rule out differential diagnosis in difficult scenarios.
Conclusion: Therefore, the correlation of histopathology with clinico-radiological findings and judicious use of a panel of IHC markers is required for routine evaluation and definite diagnosis. IHC is also useful in situations with similar morphological spectrum in specific locations.

Keywords: Differential diagnosis; IHC markers; epithelioid type; histomorphological evaluation; mesothelioma; pleural involvement

DOI: https://doi.org/10.4103/IJPM.IJPM_617_20

Lancet Oncol. 2021 Oct 14. pii: S1470-2045(21)00471-X. [Epub ahead of print]

Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.

CONFIRM trial investigators

BACKGROUND: No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.METHODS: This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.
FINDINGS: Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.
INTERPRETATION: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.
FUNDING: Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.

DOI: https://doi.org/10.1016/S1470-2045(21)00471-X