B-cell infiltration is associated with survival outcomes following programmed cell death protein 1 inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand 1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC. PATIENTS AND METHODS: NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes. RESULTS: High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively). CONCLUSIONS: Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression.

Cancer gene-panel testing identifies two loss-of-function alleles in PALB2 and PTEN.

Synchronous loss-of-function mutations in the cancer predisposing genes, PTEN and PALB2 identified by multigene panel.

Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma.

BACKGROUND: Successful application of programmed death 1 (PD1) checkpoint inhibitors in the clinic may ultimately benefit from appropriate patient selection based upon predictive biomarkers. Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while predictive biomarkers for response to PD1 checkpoint inhibitors are lacking. We sought to assess whether overexpression of PD-L1 in CTCs could be detected at baseline and at different timepoints during treatment in a prospective cohort of head and neck squamous cell carcinoma (HNSCC) patients and used to predict clinical outcome after treatment with curative intent. PATIENTS AND METHODS: We developed a highly sensitive, specific and robust RT-qPCR assay for PD-L1 mRNA expression in EpCAM(+) CTCs. In a prospective cohort of 113 locally advanced HNSCC patients treated with curative intent we evaluated PD-L1 expression in the EpCAM(+) CTC fraction at baseline, after 2 cycles of induction chemotherapy (week 6) and at the end of concurrent chemoradiotherapy (week 15). RESULTS: PD-L1 overexpression was found in 24/94 (25.5%) patients at baseline, 8/34 (23.5%) after induction chemotherapy and 12/54 (22.2%) patients at the end of treatment. Patients with CTCs overexpressing PD-L1 at end of treatment had shorter progression-free survival (P = 0.001) and overall survival (P < 0.001). Multivariate analysis revealed that PD-L1 overexpression at end of treatment was independent prognostic factor for progression-free survival and overall survival. The absence of PD-L1 overexpression at the end of treatment was strongly associated with complete response with an odds ratio = 16.00 (95% CI = 2.76-92.72, P = 0.002). CONCLUSIONS: We demonstrate that detection of CTCs overexpressing PD-L1 is feasible and may provide important prognostic information in HNSCC. Our results suggest that adjuvant PD1 inhibitors deserve evaluation in HNSCC patients in whom PD-L1(+) CTCs are detected at the end of curative treatment.

The promise of immunotherapy in head and neck squamous cell carcinoma.

Squamous cell cancers of the head and neck (HNSCC) comprise a diverse group of malignancies that includes tobacco-related tumors in addition to an increasing number of human papillomavirus-associated cancers. Independently of cause, there is a growing body of evidence supporting that the immune system plays a pivotal role in HNSCC development, as tumor cells evade immunosurveillance by exploiting inhibitory checkpoint pathways that suppress anti-tumor T-cell responses. HNSCC cells have the ability to manipulate the immune system through a variety of different mechanisms, forcing it to promote tumor growth and spread. Over the last decade, discoveries in immunologic research resulted in increased understanding of complex interactions between HNSCC and the host immune system as well as T-cell regulatory mechanisms, promoting the development of a variety of novel immunotherapies. Following the availability of novel immunotherapeutic strategies, the challenge for clinicians is to understand how and in which clinical setting to use these agents in order to provide greater clinical benefit for patients. Combination of immunotherapies with standard treatment approaches also represents an evolving field of research. Herein, we provide a comprehensive review of immune escape mechanisms in HNSCC, as well as current immunotherapy approaches under investigation.

Well-differentiated liposarcomas and dedifferentiated liposarcomas: Systemic treatment options for two sibling neoplasms.

Well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) account for 60 % of all liposarcomas, reflecting the heterogeneity of this type of sarcoma. Genetically, both types of liposarcomas are characterized by the amplification of MDM2 and CDK4 genes, which indicates an important molecular event with diagnostic and therapeutic relevance. In both localized WDLPS and DDLPS of the retroperitoneum and the extremities, between 25 % and 30 % of patients have local or distant recurrence, even when perioperatively treated, with clear margins present. The systemic treatment of WDLPS and DDLPS remains a challenge, with anthracyclines as the gold standard for first-line treatment. Several regimens have been tested with modest results regarding their efficacy. Herein we discuss the systemic treatment options for WDLPS and DDLPS and review their reported clinical efficacy results.

Evaluation of the attributable fraction and burden of HPV-related oropharyngeal cancers in Greece-the ORPHEAS study.

BACKGROUND: Herein, we evaluated the attributable fraction (AF) of human papillomavirus (HPV)-mediated (HPV+) oropharyngeal carcinomas (OPCs) in Greece over a recent calendar period. PATIENTS AND METHODS: ORPHEAS, a retrospective, observational, multicenter, cross-sectional study with prospective recruitment, included adult patients with OPC in 2017-2022, each of them with a high-quality, treatment-naïve tumor specimen. The primary endpoint was the HPV-AF, defined as combined positivity for p16INK4a (p16) overexpression and HPV DNA presence by central laboratory testing, among included patients. Other endpoints evaluated the HPV+/HPV- patient/disease characteristics at OPC diagnosis and the HPV subtypes for HPV+ patients. RESULTS: 144/147 patients with available HPV status by central laboratory testing were analyzed [median age: 60.0 years; males: 111 (77.1%)]. The most common tumor anatomical sites were the tonsils (70/147, 48.6%) and the base of the tongue (51, 35.4%), and most patients were at the American Joint Committee on Cancer eighth edition TNM (tumor-node-metastasis) stages III (25, 22.7%) and IV (43, 39.1%). The HPV-AF was 52.1% (75/144; 95% confidence interval 43.6% to 60.5%). Most HPV+ patients were infected by an HPV type targeted by the 9-valent HPV vaccine (72/75, 96.0%), especially HPV16 (70/75, 93.3%). HPV+ compared with HPV- patients were younger (median age 58.0 versus 64.0 years; P = 0.003); more likely to have tumors in the tonsils (65.0% versus 30.4%; P < 0.001); less likely to have tumors in the base of the tongue (25.3% versus 46.4%; P = 0.008); and less frequently at TNM stage IV (20.4% versus 57.1%; overall P < 0.001). CONCLUSIONS: In Greece, we observed a high HPV-AF (52.1%) in OPC, approximating the AFs reported for some Northern European countries. HPV+ versus HPV- patients were younger, more frequently with tonsillar tumors, and less frequently at TNM stage IV. Since most patients were infected by ≥1 HPV type targeted by the 9-valent vaccine, the HPV+ OPC burden could be mitigated through a routine HPV gender-neutral vaccination program.

Pathologic complete response in patients with localized soft tissue sarcoma treated with neoadjuvant therapy and its correlation with clinical outcomes: A systematic review.

Soft tissue sarcomas (STS), comprising approximately 1% of adult solid malignancies, are primarily treated with surgery, with the choice of perioperative treatment being a challenging and highly individualized decision. Clinical trials assessing neoadjuvant modalities in STS predominantly use clinical outcomes or radiologic response as endpoints, with pathologic complete response (pCR) not being employed as a designated study endpoint. Our systematic review aimed to assess the rates of pCR in clinical trials of different neoadjuvant modalities for STS and its correlation with patient clinical outcomes. 23 phase I, II and III studies were included, from which data regarding rates of pCR with each treatment, as well as correlation of pCR with clinical outcomes were retrieved. In 16 trials that assessed pCR, the percentage of patients who achieved a pCR ranged from 8 to 58%. Most of these trials did not aim to establish an association between pCR and clinical outcomes. However, among those that did investigate this correlation, a positive association was identified between pCR and both 5-year disease-specific survival (DSS) and 5-year overall survival (OS). While pCR serves as a crucial marker guiding treatment decisions in other neoplasms like triple negative breast cancer and urothelial cancer, it is not yet used in a similar setting for STS. Our findings indicate variability in patients achieving pCR across different neoadjuvant treatments for STS and a possible positive correlation with patient outcomes. Consequently, we propose considering pCR as a surrogate endpoint in future prospective trials for STS.

Chemotherapy compliance, tolerance and efficacy in elderly and non-elderly patients with metastatic colorectal cancer: a single institution comparative study.

PURPOSE: To evaluate whether elderly patients with metastatic colorectal cancer (mCRC) receive chemotherapy of suboptimal intensity and duration, mainly due to fears of poor compliance and/or excessive toxicity. METHODS: We carried out a retrospective analysis in a series of 94 mCRC patients. Using the cut-off of 70 years, we compared elderly patients with their younger counterparts in terms of treatment delivery [type, dose intensity (DI), relative dose intensity (RDI), duration], chemotherapy toxicity and efficacy [objective response rate (ORR), overall survival (OS) and progression-free survival (PFS)]. RESULTS: Complete data were available for 72 patients (76.6%) among which 38 (52.8%) were elderly. As compared to the younger, elderly patients were more likely to receive single-agent chemotherapy (13.1 vs 0%, p<0.001). The mean number of chemotherapy cycles was 6.2 for the elderly and 8.3 for the non-elderly patients who received either the FOLFOX or FOLFIRI regimen (p=0.142) and 5.1 vs 5.0 for those who received either the XELOX or XELIRI regimen, respectively (p=0.831). In oxaliplatin-containing regimens, elderly patients received 42.8% of the planned dose, as compared to 78.4% for the younger ones (p=0.012). DI for oxaliplatin was higher in non-elderly than in the elderly (46.66 mg/ m(2)/week vs 32.47 mg/m(2)/week, p=0.008). No difference was observed in the rate of severe (grade III-IV) toxicities. ORR, PFS and OS were similar between the two groups. CONCLUSION: Despite the inferior type and intensity of chemotherapy, elderly patients derived equivalent benefit to their younger counterparts. These data further support the use of optimal chemotherapy in elderly patients with mCRC.

Immune checkpoint inhibitors in sarcomas: a systematic review.

Sarcomas are tumors that originate from mesenchymal cells. The variety of sarcomas' response to chemotherapy and the wide range of prognosis reflect their heterogeneity. In order to improve the rates of response, the research has been orientated toward other forms of therapy, such as targeted therapies and immunotherapy or toward combinations of them. Immune checkpoint inhibitors (ICIs) have been the highlight of immunotherapy in the last decade. Although ICIs are already included in the guidelines of different malignancies, their clinical benefit in sarcomas is still under study. Alveolar soft part sarcomas, undifferentiated pleomorphic sarcomas and other subtypes of sarcoma with high presence of tertiary lymphoid structures tend to respond to ICIs, but further investigation is still needed. Furthermore, the search of predictive biomarkers to determine the type of sarcomas that are sensitive to ICIs is still very challenging. This review will focus on the results of clinical trials, which examine the effect of ICIs and their combination with chemotherapy, targeted therapies and other forms of immunotherapy in sarcomas.

The DNA damage response network in the treatment of head and neck squamous cell carcinoma.

BACKGROUND: We sought to determine whether DNA damage response (DDR)-related aberrations predict therapeutic benefit in cisplatin-treated head and neck squamous cell carcinoma (HNSCC) patients and how DDR pathways are modulated after treatment with olaparib alone or in combination with cisplatin or durvalumab. PATIENTS AND METHODS: Oxidative stress, abasic sites and DDR-related parameters, including endogenous DNA damage, DNA repair mechanisms and apoptosis rates, were evaluated in HNSCC cell lines and peripheral blood mononuclear cells from 46 healthy controls (HC) and 70 HNSCC patients at baseline and following treatment with cisplatin-containing chemoradiation or nivolumab or enrolled in the OPHELIA phase II trial (NCT02882308; olaparib alone, olaparib plus cisplatin, olaparib plus durvalumab). RESULTS: HNSCC patients at diagnosis exhibited deregulated DDR-related parameters and higher levels of oxidative stress and abasic sites compared with HC (all P < 0.05). Accordingly, nucleotide excision repair (NER; ERCC1, ERCC2/XPD, XPA, XPC) and base excision repair (APEX1, XRCC1) genes were downregulated in patients versus HC whereas double-strand breaks repair (MRE11A, RAD50, RAD51, XRCC2) and mismatch repair (MLH1, MSH2, MSH3) genes were overexpressed. Corresponding results were obtained in cell lines (all P < 0.001). Excellent correlations were observed between individual ex vivo and in vivo/therapeutic results, with cisplatin non-responders showing higher levels of endogenous DNA damage, augmented oxidative stress and abasic sites, increased NER capacities and reduced apoptosis than responders (all P < 0.05). Also, longer progression-free survival correlated with lower NER capacity (P = 0.037) and increased apoptosis (P = 0.029). Interestingly, treatment with olaparib-containing regimens results in the accumulation of cytotoxic DNA damage and exerts an extra antitumor effect by elevating oxidative stress (all P < 0.05). Nivolumab induced no significant changes in the DDR parameters examined. CONCLUSIONS: Aberrations in DDR signals are implicated in the response to HNSCC chemotherapy and can be exploited as novel therapeutic targets, sensitive/effective non-invasive biomarkers as well as for the design of novel clinical trials.

Upfront pembrolizumab as an effective treatment start in patients with PD-L1 ≥ 50% non-oncogene addicted non-small cell lung cancer and asymptomatic brain metastases: an exploratory analysis.

INTRODUCTION: The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab. METHODS: Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received. RESULTS: Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients' characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group. CONCLUSIONS: Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population.

Analysis of apoptosis regulatory genes expression in the bone marrow (BM) of adult de novo myelodysplastic syndromes (MDS).

The aim of the present study was to examine caspases, granzyme B and bcl-2 family mRNA expression and the degree of apoptosis in the bone marrow (BM) of 46 Myelodysplastic Syndromes (MDS) and to correlate our findings with clinical parameters. The degree of apoptosis was determined by Annexin V, whereas expression of genes was determined using a multiprobe RNase Protection System. A positive correlation was found between caspases 8, 5, 3, 2, 1 and the level of apoptosis. bfl1 and mcl1 levels were significantly higher in patients with BM blasts >5%. Cases with ratio of bid expression >1 compared to normal pool were associated with IPSS values < or =1.

Liquid biopsy: An emerging prognostic and predictive tool in Head and Neck Squamous Cell Carcinoma (HNSCC). Focus on Circulating Tumor Cells (CTCs).

Molecular diversity and continuing evolution of metastatic tumors are not easily captured by tissue biopsies. Development of non-invasive diagnostic tools, such asanalysis of circulating tumor DNA (ctDNA), Circulating Tumor Cells (CTCs) and exosomes provides the opportunity to assess a blood sample in order to monitor tumor change and extract molecular information from cancers at a given time. "Liquid biopsy", which refers to molecular analysis of tumor's genetic features based on circulating genetic material in the peripheral blood, is already used to monitor disease response and track mechanisms of drug resistance in solid tumors. Head and Neck Squamous Cell Carcinoma (HNSCC) is a malignancy associated with advanced disease at presentation and dismal outcomes; furthermore, there is lack of biomarkers to monitor disease burden. Incorporation of liquid biopsy in the management of HNSCC might help identify patients with occult metastatic disease earlier and in a non-invasive manner. Herein, we aim to review current knowledge regarding CTCs and ctDNA in HNSCC and address open questions in this fast-evolving field of research.

Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG).

BACKGROUND: Platinum-based chemotherapy is the standard front-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, non-platinum combinations of third-generation chemotherapeutic agents are considered an alternative therapeutic option for patients who cannot tolerate the toxic effects of platinum compounds. In this study, the efficacy and toxicity of the combination of irinotecan plus cisplatin (IC) was compared to pemetrexed plus cisplatin (PC) regimen, in platinum-naïve patients with advanced NSCLC, who had been previously treated with the combination of a taxane plus gemcitabine. PATIENTS AND METHODS: A total of 124 patients with locally advanced or metastatic NSCLC were randomly assigned to either irinotecan 110 mg/m2 on day 1 and 100 mg/m2 on day 8 plus cisplatin 80 mg/m2 on day 8 every 3 weeks (IC arm) or pemetrexed 500 mg/m2 plus cisplatin 80 mg/m2 on day 1 every 3 weeks (PC arm). The primary endpoint of the study was the overall response rate (ORR). RESULTS: The ORR and median progression-free survival (PFS) in the IC arm were 18 % and 3.3 months, respectively, while in the PC arm were 19 % and 4.2 months (p = ns). Median overall survival (OS) was significantly higher in patients with PC (6.9 vs. 10.9; p = 0.013). PC regimen had a better toxicity profile compared to IC, with a statistically significant lower incidence of grade 3/4 neutropenia (3 vs. 31 %; p = 0.0001) and diarrhea (1.6 vs. 14.7 %, p = 0.018). CONCLUSIONS: In patients with advanced NSCLC pretreated with docetaxel/gemcitabine, the combination of pemetrexed/cisplatin is associated with increased OS and is better tolerated than the combination of irinotecan/cisplatin and should be considered as a valid therapeutic option for platinum-naive, previously treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT00614965.

Beyond BRCA: new hereditary breast cancer susceptibility genes.

Approximately 5-10% of breast cancer cases might be inheritable, up to 30% of which are due to BRCA1/2 mutations. During the past few years and thanks to technology evolution, we have been witnesses of an intensive search of additional genes with similar characteristics, under the premise that successful gene discovery will provide substantial opportunities for primary and secondary prevention of breast cancer. Consequently, new genes have emerged as breast cancer susceptibility genes, including rare germline mutations in high penetrant genes, such as TP53 and PTEN, and more frequent mutations in moderate penetrant genes, such as CHEK2, ATM and PALB2. This review will summarize current data on new findings in breast cancer susceptibility genes.

Expression of E-cadherin, cellular differentiation and polarity in epithelial salivary neoplasms.

To investigate whether expression of E-cadherin correlates with polarised tissue organisation, grade or tumour type in salivary neoplasms, frozen sections from 30 salivary gland neoplasms were stained immunohistochemically for E-cadherin using the antibody HECD-1 and compared to the staining patterns in five samples of normal salivary gland. Lesions with areas of lack of staining were restained at two higher antibody concentrations. Normal salivary gland stained strongly around the periphery of acinar and ductal cells. Neoplasms mostly stained strongly regardless of neoplasm type. Reproducible loss of expression was found only in epithelial cells showing stromal or plasmacytoid (hyaline) differentiation in pleomorphic adenoma. Low- and high- grade mucoepidermoid carcinomas, adenocarcinoma NOS and carcinoma ex pleomorphic adenoma showed focal loss of expression but this was not related to tissue architecture, differentiation or invasiveness. We conclude that the relationship seen between E-cadherin expression and cell polarity/glandular organisation in breast and colon does not appear to exist for salivary gland neoplasms in which the diversity of architectural patterns precludes detection of any simple relationship. E-cadherin expression seems unlikely to be a useful marker for diagnosis or prognosis in salivary neoplasia in general.

Maxillary angiosarcoma.

A malignant tumor of mesenchymal origin, angiosarcoma, is a rare entity deriving from the endothelium of the blood vessels, that very infrequently is encountered in the jaws. 46 such cases have only been reported.

Aneurysmal bone cyst of the jaws. Review of the literature and report of 2 cases.

Strictly speaking, the aneurysmal bone cyst is not a true cyst. It is a lesion characterized by replacement of bone by fibro-osseous tissue containing blood-filled cavernous spaces. It is usually treated by surgical curettage, and access within the jaws may sometimes be difficult. We reviewed the world literature and found 63 cases of aneurysmal bone cysts involving the face, 22 reported in the maxilla, and 63 in the mandible. One was found in the zygomatic arch. Of the patients reported, 88% were younger than 30 years old; there was an equal sex distribution. Included in this report, are two cases of our own, one involving the maxilla and one the mandible.

Oral histoplasmosis as an indicator of HIV infection.

Histoplasmosis as a serious opportunistic infection in association with AIDS has assumed considerable importance. We have gathered 20 case reports from the literature of oral histoplasmosis in HIV-infected patients. In some cases, oral lesions appear to be the primary or only manifestation of disease. We report one such case of oral histoplasmosis in a bisexual man who was seen with ulcerations on the palate and proved to be infected by HIV.