Pediatric lung transplantation for COVID-19: Unique clinical and psychosocial barriers.

BACKGROUND: SARS-CoV-2 infection in the age group of 0-17 years contributes to approximately 22% of all laboratory-confirmed SARS-CoV-2 infections. Fortunately, this age group has a lower death rate (0.5 per 100 000) that accounts for only 4% of the total deaths due to COVID-19. Despite the low mortality rate in the pediatric population, children of minority groups represented 78% of the deaths highlighting the existing disparities in access to health care. METHODS: With the emergence of the more contagious COVID-19 variants and the relatively slow pace of vaccination among the pediatric population, it is possible to see more cases of significant lung injury and potential for transplantation for the younger age group. RESULTS: To our knowledge, our patient is the youngest to have undergone lung transplantation for SARS-CoV-2. CONCLUSION: The case presented unique challenges, particularly in relation to timing for listing and psychosocial support for parents who were his decision makers.

Performance of Mid-Treatment Breast Ultrasound and Axillary Ultrasound in Predicting Response to Neoadjuvant Chemotherapy by Breast Cancer Subtype.

BACKGROUND: The primary objective was to determine whether mid-treatment ultrasound measurements of index breast tumors and index axillary nodes of different cancer subtypes associate with residual cancer burden (RCB). METHODS: Patients with invasive breast cancer who underwent neoadjuvant chemotherapy and had pre-treatment and mid-treatment breast and axillary ultrasound were included in this single-institution, retrospective cohort study. Linear regression analysis assessed associations between RCB with (a) change in index breast tumor size, (b) change in index node size, and (c) absolute number of abnormal nodes at mid-treatment. Multivariate linear regression was used to calculate best-fit models for RCB. RESULTS: One hundred fifty-nine patients (68 triple negative breast cancer [TNBC], 45 hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-, and 46 HR-/HER2+) were included. Median age at diagnosis was 50 years, range 30-76. Median tumor size was 3.4 cm, range 0.9-10.4. Pathological complete response/RCB-I rates were 36.8% (25/68) for TNBC patients, 24.4% (11/45) for HR+/HER2- patients, and 71.7% (33/46) for HR-/HER2+ patients. Linear regression analyses demonstrated associations between percent change in tumor ultrasound measurements at mid-treatment with RCB index score in TNBC and HR+/HER2- (p < .05) but not in HR-/HER2+ (p > .05) tumors and an association between axillary ultrasound assessment of number of abnormal nodes at mid-treatment with RCB index score across all subtypes (p < .05). CONCLUSION: Performance characteristics of breast ultrasound associated with RCB vary by cancer subtype, whereas the performance characteristics of axillary ultrasound associated with RCB are consistent across cancer subtype. Breast and axillary ultrasound may be valuable in monitoring response to neoadjuvant therapy. The Oncologist 2017;22:394-401 IMPLICATIONS FOR PRACTICE: The differential performance characteristics of breast ultrasound by molecular subtype and the consistent performance characteristics of axillary ultrasound across molecular subtypes can have clinical utility in monitoring response to neoadjuvant therapy.

Benign glandular downgrowth in gastric neuroendocrine neoplasms: a potential mimic of composite tumour.

AIMS: We have observed glandular downgrowth in some gastric neuroendocrine tumours (NETs), in which nonneoplastic appearing gastric glands are admixed with submucosal neuroendocrine nests, that could potentially be confused with composite tumours. METHODS AND RESULTS: We reviewed 68 gastric NETs with at least submucosal invasion, and evaluated associations between glandular downgrowth, clinical parameters (age, gender, NET setting) and tumour characteristics (size, depth of invasion, grade). Controls included 45 duodenal NETs. Glandular downgrowth was present in 28 (41%) gastric NETs but only 2 (4.4%) duodenal NETs (P < 0.0001). It was not related to age, gender, hypergastrinemia (downgrowth present in 43% of NETs arising in autoimmune gastritis, 41% of Zollinger-Ellison syndrome, 36% of sporadic NETs), tumour size, depth of invasion, or grade. Glandular downgrowth was confined to the submucosa even though 12 (18%) gastric NETs invaded muscularis propria. Submucosal gastric glands (pyloric type in 79%, intestinal in 50%, fundic in 29%) showed metaplastic changes similar to overlying mucosa, were usually mitotically inactive (64% of cases lacked mitotic figures), were geographically restricted to the NET, and never metastasized. CONCLUSIONS: Our findings support the frequent occurrence and nonneoplastic nature of glandular downgrowth in gastric NETs, which should not be mistaken for composite tumours.

A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma.

PURPOSE: We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551). PATIENTS AND METHODS: The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses. RESULTS: Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells. CONCLUSIONS: These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.

Inhibition of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance to Programmed Cell Death 1 Blockade in Malignant Mesothelioma.

BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with programmed cell death 1 (PD-1) blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM. METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 nonresponders). We used The Cancer Genome Atlas MPM cohort (n = 73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model. RESULTS: Immunogenomic analysis by applying our anti-PD-1 resistance signature to The Cancer Genome Atlas cohort revealed that deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by cyclin dependent kinase 4/6 (CDK4/6) inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a-/- AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth compared with anti-PD-1 or CDK4/6 inhibitor alone. CONCLUSIONS: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.

Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment.

SIGNIFICANCE: Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy. See related commentary by Lee et al., p. 2515.

Prognostic Role of Programmed Cell Death 1 Ligand 1 in Resectable Pleural Mesothelioma.

BACKGROUND: The prognostic role of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) is incompletely understood. Our objectives were to evaluate the evidence for tumor PD-L1 as a prognostic biomarker in MPM through meta-analysis and to determine whether tumor PD-L1 expression is associated with survival in MPM patients undergoing macroscopic complete resection. METHODS: Meta-analysis was performed to determine the association of PD-L1 with overall survival in MPM (n = 1655) from 14 studies containing overall survival and tumor PD-L1 expression. Univariable and multivariable analyses tested the relationship of tumor PD-L1 with overall survival and recurrence-free survival in an institutional cohort of MPM patients treated by macroscopic complete resection (n = 75). To validate the association of PD-L1 with overall survival, we utilized two independent MPM cohorts (n = 284). RESULTS: Meta-analysis demonstrated that high tumor PD-L1 expression was associated with poor overall survival. Among 75 patients undergoing macroscopic complete resection, 49 tumors (65%) expressed PD-L1 (1% or more), and high PD-L1 (50% or greater) was more commonly expressed on nonepithelial (29%) compared with epithelial tumors (14%). High tumor PD-L1 expression was independently associated with poor overall survival (P < .001, hazard ratio 5.67) and recurrence-free survival (P = .003, hazard ratio 3.28). The association of PD-L1 overexpression with unfavorable survival was more significant in epithelial MPMs than nonepithelial MPMs. These findings were validated in RNA sequencing analyses in two independent cohorts. Exploratory transcriptome analysis revealed that MPM tumors with PD-L1 overexpression displayed coexpression of other immune regulatory molecules, programmed cell death 1 ligand 2 and T-cell immunoglobulin mucin receptor 3. CONCLUSIONS: Tumor PD-L1 expression is a prognostic biomarker in patients undergoing surgical resection for MPM and may be useful in perioperative decision making.

Therapeutic Synergy in Esophageal Cancer and Mesothelioma Is Predicted by Dynamic BH3 Profiling.

Approximately 20,000 patients per year are diagnosed with esophageal adenocarcinoma (EAC) and malignant pleural mesothelioma (MPM); fewer than 20% survive 5 years. Effective therapeutic strategies are limited although patients receive a combination of chemotherapeutics. These tumors harbor thousands of mutations that contribute to tumor development. Downstream of oncogenic driving mutations, altered tumor mitochondria promote resistance to apoptosis. Dynamic Bcl-2 homology-3 profiling (DBP) is a functional assay of live cells that identifies the mitochondrial proteins responsible for resistance to apoptosis. We hypothesized that DBP will predict which protein to target to overcome resistance thereby enhancing combinatorial therapy.DBP predicted that targeting either Mcl-1 or Bcl-xL increases the efficacy of the chemotherapeutic agent, cisplatin, whereas targeting Bcl-2 does not. We performed these assays by treating EAC and MPM cells with a combination of Bcl-2 homology-3 (BH3) mimetics and cisplatin. Following treatments, we performed efficacy assessments including apoptosis assays, IC50 calculations, and generation of a combinatorial index. DBP confirmed that targeting mitochondria with BH3 mimetics alters the threshold of apoptosis. These apoptotic effects were abolished when the mitochondrial pathway was disrupted. We validated our findings by developing knockdown models of antiapoptotic proteins Mcl-1, Bcl-xL, and the mitochondrial effector proteins Bax/Bak. Knockdown of Mcl-1 or Bcl-xL recapitulated the results of BH3 mimetics. In addition, we report an approach for BH3 profiling directly from patient tumor samples. We demonstrate that the DBP assay on living tumor cells measures the dynamic changes of resistance mechanisms, assesses response to combinatorial therapy, and provides results in a clinically feasible time frame.

The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics.

Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conduct whole-exome sequencing and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations are shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrate similar subclonal architecture. On the other hand, transcriptomic profiling reveals shared pathways between the same histologic subtypes from different patients, which is supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data derived from mixed histologic subtypes in the setting of identical genetic background and exposure history support that the histologic fate of lung cancer cells is associated with transcriptomic features rather than the genomic profiles in most tumors.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype.

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.

Findings in 12-core transrectal ultrasound-guided prostate needle biopsy that predict more advanced cancer at prostatectomy: analysis of 388 biopsy-prostatectomy pairs.

We analyzed 5 features on 12-core transrectal ultrasound-guided prostate needle biopsy (TRUS) to predict the extent of cancer at radical prostatectomy (RP). In 388 TRUS-RP pairs, number of positive cores (NPC), percentage of each core involved (%PC), perineural invasion (PNI), Gleason score (GS), distribution of positive cores (DPC), and preoperative prostate-specific antigen (PSA) were correlated with extraprostatic extension (EPE), seminal vesicle invasion (SVI), positive surgical margin (R1), positive lymph nodes (N1), and tumor volume. All features predicted EPE and SVI. NPC, GS, %PC, and PNI strongly predicted R1 status. RP tumor volume was directly proportional to the NPC and %PC. PSA alone and with selected biopsy findings correlated with tumor volume, stage, SVI, and N1 (P < .0001). Contiguous DPC was a significant risk for EPE and SVI (P < .0001) compared with isolated positive cores. Findings at 12-core TRUS along with preoperative PSA reliably predict advanced local disease and have practical value as guides to effective planning for surgical resections.

Tender growth on toe.

A 50-year-old Caucasian man came to the dermatology clinic with a tender growth on his great toe. He first noticed it a year earlier after sustaining trauma to the area. The growth had been getting bigger and had intermittently bled. It had also oozed, so his primary care physician treated it as an infection with topical antibiotics, followed by several courses of oral antibiotics. Despite therapy, the lesion continued to grow and the patient was referred to us. The patient had a 3.4-cm-by-1.8-cm exophytic erythematous nodule on the left lateral great toe. What is your diagnosis? How would you manage this condition?