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Yu Zhi Zhang



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    MA05 - Update on Clinical Trials and Treatments (ID 123)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA05.01 - Second or Third Line Anti-PD-1 Therapy After Multimodality Therapy Including Total Pleurectomy in Malignant Pleural Mesothelioma (Now Available) (ID 1955)

      13:30 - 15:00  |  Author(s): Yu Zhi Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical resection plays an important role in the management of selected patients with malignant pleural mesothelioma (MPM). Early experience with anti-PD-1 immunotherapy showed promise in MPM, but it is yet uncertain if it can improve outcomes when tumour relapses following surgical resection, radiotherapy and chemotherapy. We reviewed our experience in patients who received Pembrolizumab or Nivolumab following multimodality therapy.

      Method

      Retrospective study including patients with histologically-proven MPM having completed multimodality therapy and received anti-PD-1 immunotherapy as 2nd or 3rd line treatment. Data were retrieved from a prospective mesothelioma database. Histopathology, BAP1, MTAP and PD-L1 (22C3) immunohistochemistry were performed on surgical specimens and reported by a senior pathologist. All patients had chest computed tomography and positron emission tomography (PET-CT) as part of their normal follow-up. Response evaluation was determined using RECIST 1.1 criteria.

      Result

      16 patients received anti-PD-1 immunotherapy between August 2015 and March 2019. All patients had total pleurectomy/decortication, prophylactic radiotherapy (21Gy/3) and systemic chemotherapy based on pemetrexed and platinum. Median age was 68.5 years, with male predominance (13/16). 56% had epithelioid type, 44% had biphasic type. Median time to starting immunotherapy was 20 months (range 11-42) following surgery. Median ECOG performance status was 0. Twelve patients received Pembrolizumab and 4 received Nivolumab. Median number of cycles of anti-PD-1 therapy received was 5 (range 1-33). Disease control rate at 12 weeks was 56.2% and 7 (43.7%) patients had disease progression. Adverse events were observed in 6 patients (one Grade 3). Eight patients were alive by 1st April 2019. Median OS from starting immunotherapy was 13.5 months. Three patients received treatment for 14 months or more. Five patients started further therapy after discontinuing immunotherapy.

      Conclusion

      In our cohort, second or third-line anti-PD-1 immunotherapy showed efficacy with DCR comparable to non-surgical setting. Further studies are warranted to validate our preliminary findings.

      wclc 2019 figure 1anti pd1.jpg

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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.02 - Growth Patterns in Epithelioid Malignant Pleural Mesothelioma: A Clinicopathological Review of 614 Cases Over 15 Years (Now Available) (ID 1595)

      14:00 - 15:30  |  Presenting Author(s): Yu Zhi Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      Nuclear grading system has been validated as a powerful prognostic tool for epithelioid malignant pleural mesothelioma (MPM) whilst growth patterns had demonstrated prognostic value in earlier studies. We aim to externally validate the previous findings and evaluate the utility of a composite architecture-nuclear grade scoring system.

      Method

      We retrospectively reviewed 614 consecutive cases of epithelioid MPM diagnosed at our institution over a 15-year period. Clinicopathological information including predominant growth pattern (Solid, Tubulo-papillary, Trabecular, Micropapillary, Microcystic, Discohesive, Pleomorphic) and 2-tier nuclear grade were retrieved from an institutional mesothelioma database. The tumours were categorised into High Grade (Solid, Micropapillary, Score=1) and Low Grade (All others, Score=0). A composite score (0-2) was generated based on growth pattern and 2-tier nuclear grade (0-1). Survival analysis was performed using Kaplan-Meier method.

      Result

      Pleomorphic epithelioid MPM was associated with the worst median overall survival (5.4 months), followed by micropapillary- (6.2 months), solid- (10.5 months), microcystic- (15.3 months), discohesive- (16.1 months), trabecular- (17.6 months) and tubulo-papillary- (18.6 months) patterns. The composite scoring system further improved stratification of overall survival based on 2-tier nuclear grade (19.8 vs. 13.4 vs. 8.1 months, p<0.001).

      growth patterns (except cribriform_wdpm).jpg

      composite architecture-ng score v2.jpg

      Conclusion

      Epithelioid MPM growth patterns predicted survival in our cohort. Composite architecture-nuclear grade scoring system further improved prognostic stratification.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-63 - Correlation of Mutations in TP53, CDKN2A and PIK3CA with VISTA Expression in Pleomorphic Lung Carcinoma (ID 2248)

      09:45 - 18:00  |  Author(s): Yu Zhi Zhang

      • Abstract

      Background

      Pleomorphic Lung Carcinoma (PC) is a rare subtype of NSCLC poorly responsive to systemic therapy. VISTA is an immune checkpoint that negatively regulates T-cells and offers an alternative therapeutic approach to immune checkpoint manipulation. It has increased expression in the tumour microenvironment. We aimed to identify the genomic associations of PC with VISTA immunohistochemistry (IHC) expression and establish its correlation with PD-L1 IHC expression.

      Method

      Histopathological assessment and diagnosis was confirmed for 42 cases of resected PCs from the Royal Brompton Hospital histopathology diagnostic archive. DNA was isolated and a targeted capture panel for next generation sequencing performed. Samples were stained with H&E to confirm diagnosis, VISTA (D1L2G) and PD-L1 (28-8) and scored as the proportion of positively stained cells. Normal lung acted as control.

      Result

      VISTA was increased in tumour infiltrating immune cells compared to background lung and tumour (median: 33% (0-85) vs. 0% (0-15); vs. 0% (0-11); P<0.001). VISTA was upregulated on infiltrating immune cells of cases with variants in TP53 (n=25, median 52.5% vs. 24% P=0.008) and CDKN2A (n=4, median 57.5% vs. 30%; P=0.068) but was reduced in cases with PIK3CA mutations (n=4; median 7% vs. 35%; P=0.029). There was no association of VISTA with PD-L1 expression (spearman rank: -0.19; P=0.22).

      Figure 1: Percent of VISTA staining of immune cells according to tumour mutation

      figure1a.png

      Conclusion

      VISTA is raised in infiltrating immune cells of tumours with TP53 and CDKN2A mutations. This may suggest dampening of the immune reaction to tumours defective in cell cycle control. Conversely, tumours with PIK3CA mutations had reduced VISTA expression by infiltrating immune cells. VISTA and PD-L1 exhibited no association in their levels of expression and therefore offers a therapeutic opportunity.

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    P1.06 - Mesothelioma (ID 169)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.06-08 - WDPM-Like but Not Cribriform as Secondary Growth Patterns Modify Survival in Epithelioid Malignant Pleural Mesothelioma (ID 1609)

      09:45 - 18:00  |  Presenting Author(s): Yu Zhi Zhang

      • Abstract
      • Slides

      Background

      The presence of well differentiated papillary mesothelioma (WDPM)- like and cribriform growth patterns in otherwise unequivocally invasive, tubulo-papillary-predominant epithelioid malignant pleural mesothelioma (MPM) is recognised in clinical practice, but their prognostic impact is largely uncertain. We hypothesise they modify prognosis as secondary patterns.

      Method

      We retrospectively reviewed the tubulo-papillary-predominant, invasive epithelioid MPM (n=269) as a subset of 614 consecutive epithelioid MPM diagnosed at our institution over a 15-year period. The diagnostic criteria for WDPM-like and cribriform patterns were inferred from those of canonical WDPM and lung adenocarcinoma. Survival analysis was performed using Kaplan-Meier method.

      Result

      We identified 10 cases of tubulo-papillary-predominant epithelioid exhibiting WDPM-like pattern, and one case being predominantly WDPM-like (Estimated incidence 4.1%). They are associated with significantly prolonged median overall survival (78.7 months vs. 18.0 months, p=0.001). On the other hand cribriform neither as predominant (n=9, 3.3%, p=0.672) or secondary growth patterns (n=46, 17.1%, p=0.952) achieved statistical significance in univariate setting compared with tubulo-papillary epithelioid MPM without such pattern.

      wdpm-like.jpg

      cribriform pattern (predominant and secondary).jpg

      Conclusion

      We propose tubulo-papillary-predominant epithelioid MPM with WDPM-like features as a rare and favourable prognostic group. Further molecular analysis is planned. Cribriform pattern does not appear to be prognostically relevant. We recommend external validation of our findings for both growth patterns.

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-05 - Multimodality Therapy Using Total Pleurectomy in Malignant Pleural Mesothelioma: Long-Term Outcomes in 150 Consecutive Cases (Now Available) (ID 1441)

      10:15 - 18:15  |  Author(s): Yu Zhi Zhang

      • Abstract
      • Slides

      Background

      We wished to evaluate the long-term outcomes of patients receiving multimodality therapy including total pleurectomy/decortication, radiotherapy and systemic chemotherapy for malignant pleural mesothelioma.

      Method

      Retrospective analysis of patients treated between September 2004 and April 2019 by a specialised thoracic multidisciplinary team. Treatment involved total pleurectomy and decortication of lung, prophylactic radiotherapy (21 Gy in 3 fractions) and systemic chemotherapy based on pemetrexed and platinum. PET-CT was used routinely to diagnose disease recurrence or progression. Second or third-line therapies were administered when appropriate. Survival and prognostic factors were analysed by the Kaplan-Meier method and Cox regression analysis.

      Result

      150 patients had multimodality therapy over a 15-year period. Median age at operation was 62 years (range 32-82) and the male/female ratio was 122/28. Thirty-one patients (20.6%) had received chemotherapy before surgery. Thirty-three patients (22%) had extended resections. Sixty-two patients suffered a postoperative complication and 90-day mortality was nil. Eleven patients (7.3%) had reoperation within 30 days. Histological types were epithelioid in 105 patients and non-epithelioid in 45. Pathological stages were: I:86, II: 9, III: 54, and IV:1 (8th TNM classification). All patients but one received prophylactic radiotherapy. Six patients (4%) did not received systemic chemotherapy. Sixty-five patients (43.3%) received second-line or further systemic therapies. Five patients received stereotactic radiotherapy and three patients had late reoperation for focal tumour recurrence. Median survival was 30.5 months overall (95% CI 25.4-35.6), 34 months for epithelioid type (95% CI 25.8-42.2) and 18.3 months for non-epithelioid type (95% CI 14.2-22.4). Histological type and macroscopic complete resection were predictive of extended survival in our analysis.

      Conclusion

      Total Pleurectomy /Decortication is a safe and well-tolerated procedure associated with no mortality and acceptable morbidity. Most patients can receive prophylactic radiotherapy and systemic chemotherapy in due time. Many can receive second-line or further therapy on progression, resulting in prolonged survival.

      figure survival based on histological type.jpg

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