Erratum to clinical impact of the lung tissue transcriptome in a teenager with multifocal invasive mucinous adenocarcinoma-a case report.

[This corrects the article DOI: 10.21037/tlcr-20-177.].

Clinical impact of the lung tissue transcriptome in a teenager with multifocal invasive mucinous adenocarcinoma-a case report.

The transcriptional profiling of cancer and normal tissues harboring cancer can be a clinical and discovery tool, especially for the study of rare tumors. Invasive mucinous adenocarcinoma (IMA) is a rare lung cancer histotype, which mostly affects the elderly and commonly has a poor prognosis. We investigated the exceptional case of a teenager, exposed to passive smoke and chemical carcinogens, who developed a multifocal IMA with bilateral involvement. The malignancy was asymptomatic and was diagnosed occasionally during hospitalization for acute abdominal pain due to adnexitis. The young patient underwent video-assisted thoracoscopic surgery and lung samples were analysed by RNA-Sequencing. The transcriptome of patient's normal and neoplastic lung tissues was compared with matched healthy controls and IMA signature cases, using Gene Set Enrichment Analyses, Gene Ontology and Genotype Tissue Expression database. Compared to healthy controls, the patient's lung tissue lacked the expression of lymphocyte and humoral-mediated immune response genes, whereas genes driving the response to stimulus, chemical and organic substances, primarily, CXCL8, ACKR1, RAB7B, HOXC9, HOXD9, KLF5 and NKX2-8 were overexpressed. Genes driving extracellular structure organization, cell adhesion, cell movement, metabolic and apoptotic processes were down-modulated in patient's lung tissue. When compared to IMA signature cases, the patient's IMA revealed a prevalent expression of genes regulating the response to stimulus, myeloid and neutrophil activation and immune system processes, primarily CD1a and CXCL13/BCA1, whereas stemness genes and proto-oncogenes, such as SOX4, HES1, IER3 and SERPINH1 were downmodulated. These transcriptional signature associated with a favorable clinical course, since the patient was healthy five years after initial diagnosis. The transcriptome of the normal tissues bearing tumor provides meaningful information on the gene pathways driving tumor histogenesis, with a prospective impact on early diagnosis. Unlike the tumor histotype-related transcriptional signature, the individual patient's signature enables tailored treatment and accurate prognosis.

Interleukin-30/IL27p28 Shapes Prostate Cancer Stem-like Cell Behavior and Is Critical for Tumor Onset and Metastasization.

Prostate cancer stem-like cells (PCSLC) are believed to be responsible for prostate cancer onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In prostate cancer patients, IL30/IL27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here, we asked whether IL30 may favor prostate cancer progression by conditioning PCSLCs and assessed the value of blocking IL30 to suppress tumor growth. IL30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion, and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization, and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL30 knockdown or knockout in PCSLCs. Collectively, these results mark IL30 as a key driver of PCSLC behavior. Targeting IL30 signaling may be a potential therapeutic strategy against prostate cancer progression and recurrence.Significance: IL30 plays an important role in regulating prostate cancer stem-like cell behavior and metastatic potential, therefore targeting this cytokine could hamper prostate cancer progression or recurrence. Cancer Res; 78(10); 2654-68. ©2018 AACR.

Immune response after video-assisted thoracic surgery in non-small cell lung cancer patients.

The effects of immunomodulation processes in patients undergoing video-assisted thoracic surgery (VATS) lobectomy are still debated; although, the reduced surgical stress of minimally invasive surgery is evident. The immunological repercussions could also influence the evolution of the disease and the prognosis of patients. The article aims to raise some points of reflection by considering available evidences and reiterating, once again, the prognostic utility of a minimally invasive procedure rather than classical approach.

Pulmonary metastasectomy in elderly colorectal cancer patients: a retrospective single center study.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and the lung is one of the most frequent sites for CRC metastasis. The geriatric population is increasing, but clinical decision making is often influenced by the effect of aging. For this reason, the elderly population does not often receive potentially curative cancer treatments as offered to younger ones. From January 2000 to March 2016, 21 elderly patients (older than 75 years) underwent pulmonary resections for colorectal cancer pulmonary metastases. A postoperative morbidity rate of 23.8 % and a 30-day mortality rate of 4.8 % were reported. A cumulative overall survival of 34.19 ± 23.51 months (95 % CI 23.71-50.28) and a disease-free interval of 24.62 ± 23.79 months (95 % CI 6.44-39.56) were observed. By considering only R0 surgically resected patients, the 1-, 3- and 5-year OS were 94.1, 59.5 and 21.2 % with a mean overall survival and disease-free interval of 51.10 ± 7.82 and 42.75 ± 9.35, respectively. Concerning risk factors, an important correlation between the number of pulmonary metastases, surgical radicality and overall survival was reported (p = 0.030 and p = 0.005, respectively). In summary, according to our series, pulmonary metastasectomy in selected elderly CRC oligometastatic patients seems to be safe and effective.

Oligometastatic non-small cell lung cancer (NSCLC): adrenal metastases. Experience in a single institution.

Though the actual incidence of an adrenal oligometastasis is between 1.5 and 3.5 %, secondary adrenal neoplasms occur in less than 10 % patients with non-small cell lung cancer (NSCLC). According to 7° ed. TNM staging system, the presence of an adrenal metastasis (M1b disease) configures stage IV, which is usually associated with poor prognosis. We evaluated if metastasectomy in selected patients with oligometastatic disease improves overall survival. A 15-year retrospective study concerning patients with NSCLC was performed and an oligometastatic disease was found in 1.61 % of the patients. 18 adrenalectomies were performed. Clustering the population according to different therapeutic strategies, a benefit in terms of survival was found in patients who underwent adrenalectomy. A statistical relevance was found, indeed, between adrenalectomy (p < 0.01), metachronous disease (p < 0.01), the presence of a homolateral disease (p < 0.05) and overall survival. Adrenalectomy should be offered in selected patients with oligometastatic disease.

Interleukin-27 re-educates intratumoral myeloid cells and down-regulates stemness genes in non-small cell lung cancer.

Current therapies for Non-Small Cell Lung Cancer (NSCLC) still fail to significantly increase its survival rate. Here we asked whether Interleukin(IL)-27, which has revealed powerful antitumor activity and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients. IL-27's effects were tested on Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) cell lines and xenograft models. IL-27Receptor(R) expression was assessed in lung tissues from 78 NSCLC patients. In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROγ/MIP2ß expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with Nestin, SNAI1/SNAIL, SNAI2/SLUG and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease. Our data suggest that even immunocompromised or advancer NSCLC patients may benefit from IL-27's antitumor properties based on its ability to drive myeloid cells towards antitumor activities, and down-regulate stemness- and EMT-related genes in cancer cells.

CD56(bright)perforin(low) noncytotoxic human NK cells are abundant in both healthy and neoplastic solid tissues and recirculate to secondary lymphoid organs via afferent lymph.

As limited information is available regarding the distribution and trafficking of NK cells among solid organs, we have analyzed a wide array of tissues derived from different human compartments. NK cells were widely distributed in most solid tissues, although their amount varied significantly depending on the tissue/organ analyzed. Interestingly, the distribution appeared to be subset specific, as some tissues were preferentially populated by CD56(bright)perforin(low) NK cells, with others by the CD56(dim)perforin(high) cytotoxic counterpart. Nevertheless, most tissues were highly enriched in CD56(bright)perforin(low) cells, and the distribution of NK subsets appeared in accordance with tissue gene expression of chemotactic factors, for which receptors are differently represented in the two subsets. Remarkably, chemokine expression pattern of tissues was modified after neoplastic transformation. As a result, although the total amount of NK cells infiltrating the tissues did not significantly change upon malignant transformation, the relative proportion of NK subsets infiltrating the tissues was different, with a trend toward a tumor-infiltrating NK population enriched in noncytotoxic cells. Besides solid tissues, CD56(bright)perforin(low) NK cells were also detected in seroma fluids, which represents an accrual of human afferent lymph, indicating that they may leave peripheral solid tissues and recirculate to secondary lymphoid organs via lymphatic vessels. Our results provide a comprehensive mapping of NK cells in human tissues, demonstrating that discrete NK subsets populate and recirculate through most human tissues and that organ-specific chemokine expression patterns might affect their distribution. In this context, chemokine switch upon neoplastic transformation might represent a novel mechanism of tumor immune escape.

Mechanisms of the antitumor activity of human Vγ9Vδ2 T cells in combination with zoledronic acid in a preclinical model of neuroblastoma.

Low expression of surface major histocompatibility complex (MHC) class I molecules and defects in antigen processing machinery make human neuroblastoma (NB) cells appropriate targets for MHC unrestricted immunotherapeutic approaches. Human T-cell receptor (TCR) Vγ9Vδ2 lymphocytes exert MHC-unrestricted antitumor activity and are activated by phosphoantigens, whose expression in cancer cells is increased by aminobisphosphonates. With this background, we have investigated the in vivo anti-NB activity of human Vγ9Vδ2 lymphocytes and zoledronic acid (ZOL). SH-SY-5Y human NB cells were injected in the adrenal gland of immunodeficient mice. After 3 days, mice received ZOL or human Vγ9Vδ2 T cells or both agents by intravenous administration once a week for 4 weeks. A significantly improved overall survival was observed in mice receiving Vγ9Vδ2 T cells in combination with ZOL. Inhibition of tumor cell proliferation, angiogenesis and lymphangiogenesis, and increased tumor cell apoptosis were detected. Vγ9Vδ2 T lymphocytes were attracted to NB-tumor masses of mice receiving ZOL where they actively modified tumor microenvironment by producing interferon-γ (IFN-γ), that in turn induced CXCL10 expression in NB cells. This study shows that human Vγ9Vδ2 T cells and ZOL in combination inhibit NB growth in vivo and may provide the rationale for a phase I clinical trial in patients with high-risk NB.

Androgen deprivation boosts prostatic infiltration of cytotoxic and regulatory T lymphocytes and has no effect on disease-free survival in prostate cancer patients.

PURPOSE: The value of neoadjuvant hormone therapy (NHT) prior to radical prostatectomy as a means of restraining prostate cancer (PCa) and strengthening its immunotherapy is still uncertain. This article asks whether it subverts immunoregulatory pathways governing tumor microenvironments, and has an impact on patient outcome. EXPERIMENTAL DESIGN: We microdissected epithelium and stroma from cancerous and normal prostate specimens from 126 prostatectomized patients, of whom 76 had received NHT, to detect cytokine/chemokine gene expression levels by real-time reverse transcriptase PCR. Confocal microscopy was used to identify cytokine/chemokine cell sources, and immunostainings to characterize lymphocyte subsets whose prognostic effects were assessed by Kaplan-Meier analyses. RESULTS: NHT boosted the expression of IL-7 in the stroma and that of IFNγ-inducible protein-10/CXCL10 in the glandular epithelium of normal prostate tissue, and restored the CD8(+) lymphocyte depletion occurring in PCa, whereas it significantly increased the CD4(+) lymphocyte infiltrate. Lymphocytes, mostly with CD8(+) phenotype, expressed the T-cell intracellular antigen-1, granzyme-B, and perforin, typical of cytotoxic-effector T cells. NHT also induced thymus and activation-regulated chemokine/CCL17 production by monocytes/macrophages in the prostate and draining lymph nodes, and increased the number of their Forkhead box P3 (Foxp3)(+)CD25(+)CD127(-) T regulatory (Treg) cells. The χ(2) test disclosed the lack of association (P = 0.27) between NHT and the high intratumoral CD8(+)/Treg ratio indicative of a good prognosis. CONCLUSIONS: Androgen withdrawal regulates cytokine/chemokine gene expression in normal prostate and lymphoid tissues, and this probably favors both CD8(+) and Treg infiltrates, leaves their intratumoral balance unchanged, and thus has no impact on disease-free survival.

[Current treatment of chylothorax: a report of ten cases]. / Il trattamento attuale del chilotorace: a proposito di diecl casi di personale osservazione.

Chylothorax is an uncommon disease resulting from many factors, all of which cause damage to the thoracic duct or its main collectors. The incidence of this disease has increased over the years due to increasing heart and thoracic surgery, in these cases ranging from 0.2% to 0.5%. Its aetiology also includes thoracic traumatic injury, lymphatic neoplasms and inflammatory disease. Over the period considered we observed more than 9000 thoracic patients, ten of whom presented chylothorax, due to a variety of causes. Diagnostic instrumental procedures and clinical investigations enabled us to develop a personalised therapeutic strategy for each case, related to the particular causes responsible for the condition. Most of the patients observed were treated successfully with a non-invasive approach. In two cases surgery (duct ligature and lymphangioma debulking) was performed with positive results. The postoperative course was uneventful with an average hospital stay of 13 days (range: 7-24 days).

[The role of surgery in the treatment of malignant pleural mesothelioma]. / Il ruolo della chirurgia nel trattamento del mesotelioma pleurico maligno.

The role of surgery in the treatment of diffuse pleural malignant mesothelioma is controversial. The procedures proposed to date are extrapleural pneumonectomy, pleurectomy, and thoracoscopy. External radiation or intraoperative implantation of radioisotopes, chemotherapy and intrapleural treatment with various different agents are also considered as adjuvant therapy. Patient selection, postoperative morbidity and mortality and survival rates are discussed. Our personal series of 72 diffuse pleural malignant mesotheliomas is described: 29 had a palliative operation while 43 underwent radical surgery consisting in 24 extrapleural pneumonectomies and 19 pleurectomies.

[Small bowel metastases from lung cancer]. / Le metastasi del piccolo intestino da neoplasie pleuro-polmonari.

Lung cancer is usually diagnosed at an advanced stage and metastases are present in 50% of patients. Small bowel metastases from lung cancer are rare, being more frequent in patients with melanoma, uterine, ovarian, kidney or gastrointestinal cancer, or osteosarcoma. From November 1998 to August 2003, 740 cases of lung cancer (641 non-small-cell lung cancer and 99 neuroendocrine tumours) were diagnosed. We also observed 64 patients with malignant pleural mesothelioma and performed 23 pleuropneumonectomies. Over the same period we admitted 4 patients (one recurrent) with small bowel metastases, three from lung cancer and one from malignant mesothelioma. The clinical symptoms were bowel occlusion and intestinal bleeding. Radiological techniques such as small bowel enema and CT enteroclysis were used with positive results. In one patient with intestinal bleeding capsular endoscopy revealed a bleeding metastasis. All patients were operated on. Neither mortality nor morbidity were observed. All patients were discharged after a median stay of 10 days. One patient is still alive and disease-free 39 months after the first intestinal surgery for metastases. Intestinal metastases from lung cancer are rare and the diagnosis is often late. In some cases the clinical manifestations of the metastases are observed before those of the primitive tumour. However, in the presence of small bowel occlusion and intestinal bleeding of uncertain origin, clinical history-taking is very important and diagnostic procedures must be performed to exclude a secondary pathology.