Prognostic Significance of the Microenvironment in Human Papillomavirus Oropharyngeal Carcinoma: A Systematic Review.

OBJECTIVE: The immune microenvironment of HPV-associated (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) (HPV+OPSCCs) differs from that of HPV-independent oropharyngeal cancers (HPV-independent OPSCCs). The literature on the subject is very abundant, demanding an organized synthesis of this wealth of information to evaluate the hypothesis associating the favorable prognosis of HPV+OPSCC patients with a different immune microenvironment. A systematic review of the literature was conducted regarding the microenvironment of HPV+OPSCCs. DATA SOURCE: MEDLINE/PubMed, Embase, and Cochrane Library databases. REVIEW METHODS: A literature search was performed following PRISMA guidelines (Moher D. PLoS Med. 2009). The PEO (Population, Exposure, and Outcome) framework is detailed as follows: P: patients with oropharyngeal squamous cell carcinomas, E: human papillomavirus (HPV), and O: histological and immunological composition of the tumoral microenvironment (TME). No meta-analysis was performed. RESULTS: From 1,202 studies that were screened, 58 studies were included (n = 6,474 patients; n = 3,581 (55%) HPV+OPSCCs and n = 2,861(45%) HPV-independent OPSCCs). The presence of tumor-infiltrating lymphocytes (TIL), CD3+ in 1,733 patients, CD4+ in 520 patients, and CD8+ (cytotoxic T lymphocytes (CTL)) in 3,104 patients, and high levels of PD-L1 expression in 1,222 patients is strongly correlated with an improved clinical outcome in HPV+OPSCCs. CONCLUSION: This systematic review provides the most comprehensive information on the immune microenvironment of HPV+OPSCCs to date. Tumor-infiltrating lymphocytes and PD-L1 expression are associated with a favorable prognosis. B, CD8+ and resident memory cells densities are higher in HPV+OPSCCs. The importance of myeloid lineages is still a matter of debate and research. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1507-1516, 2024.

Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting.

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

Progressive clinical case-based multiple-choice questions: An innovative way to evaluate and rank undergraduate medical students.

INTRODUCTION: In France, at the end of the sixth year of medical studies, students take a national ranking examination including progressive clinical case-based multiple-choice questions (MCQs). We aimed to evaluate the ability of these MCQs for testing higher-order thinking more than knowledge recall, and to identify their characteristics associated with success and discrimination. METHODS: We analysed the 72 progressive clinical cases taken by the students in the years 2016-2019, through an online platform. RESULTS: A total of 72 progressive clinical cases (18 for each of the 4 studied years), corresponding to 1059 questions, were analysed. Most of the clinical cases (n=43, 60%) had 15 questions. Clinical questions represented 89% of all questions, whereas basic sciences questions accounted for 9%. The most frequent medical subspecialties were internal medicine (n=90, 8%) and infectious diseases (n=88, 8%). The most frequent question types concerned therapeutics (26%), exams (19%), diagnosis (14%), and semiology (13%). Level 2 questions ("understand and apply") accounted for 59% of all questions according to the Bloom's taxonomy. The level of Bloom's taxonomy significantly changed over time with a decreasing number of level 1 questions ("remember") (P=0.04). We also analysed the results of the students among 853 questions of training ECNi. Success and discrimination significantly decreased when the number of correct answers increased (P<0.0001 both). The success, discrimination, mean score, and mean number of discrepancies did not differ according to the diagnosis, exam, imaging, semiology, or therapeutic type of questions. CONCLUSION: Progressive clinical case-based MCQs represent an innovative way to evaluate undergraduate students.

Evaluation of robotic surgery for transoral resection of T1-2 squamous cell carcinoma of the tonsillar fossa.

GOAL: To evaluate transoral robotic surgery (TORS) for isolated previously untreated squamous cell carcinoma (SCC) of the tonsillar fossa classified as T1-2. METHOD: Retrospective analysis of two cohorts of isolated untreated T1-2 tonsillar fossa SCC consecutively operated on by a transoral approach, with (R=21) and without (NR=24) robotic assistance, in the period 2006-2014. Three main (survival, local control, and operative morbidity) and three secondary (pathologic data, incidence and duration of tracheotomy and nasogastric intubation, and hospital stay) endpoints were compared between groups. The significance threshold was set at P< .005. RESULTS: Three- and five-year actuarial survival estimates were 80.2% and 74.5% respectively in group R, and 91.5% and 82.5% respectively in group NR (NS: P=.34). Three- and five-year actuarial local control estimates were 90% and 90% respectively in group R, and 95.8% and 91% respectively in group NR (NS: P=.81). There were no significant differences in morbidity, tracheotomy/nasogastric intubation time, or hospital stay. Positive resection margins (R1) were noted in 38.1% and 16.7% in groups R and NR, respectively (NS: P=.05) without significant impact on 5-year actuarial local control (P=0.78). CONCLUSION: Robotic assistance in transoral lateral oropharyngectomy for T1-2 tonsillar fossa SCC did not significantly impact oncologic or functional outcome.

[Multidisciplinary consultation for patients with HPV-related invasive carcinoma or precancerous lesions]. / Consultation multidisciplinaire pour les patients atteints d'une pathologie tumorale (carcinome infiltrant ou lésion précancéreuse) liée à HPV : la consultation multidisciplinaire papillomavirus.

Given the recent increase in the number of human papillomavirus (HPV)-induced cancers in other locations than gynaecological, the number of patients with two cancers at distinct sites, and because of the lack of exhaustive data, we decided to create a multidisciplinary network around an HPV consultation at the Georges-Pompidou European Hospital (HEGP). This network aims to set up the best tools for detecting HPV-associated "multisite" precancerous lesions in order to determine the possible impact of dedicated care for this at-risk population. This monthly consultation was created at the HEGP in June 2014. It is currently organized around five consultations: gynaecological, ENT, urological, digestive and immunological. Every patient who has been diagnosed with HPV-related cancer and whose care is provided at the HEGP is offered this particular follow-up: systematically, once the initial lesion has been treated, the patient is convened annually for a day during which it benefits from the consultations mentioned above. A consultation with a psychologist is systematically proposed. Local samples are taken at each site: a cytological examination, the analysis of known predictive and prognostic virological markers are carried out. This study fits more broadly in a theme of clinical and fundamental research around cancers related to HPV.

Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer.

Background: Various programed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed and used in clinical trials in association with different drugs. In order to harmonize and make PD-L1 testing in non-small-cell lung cancer (NSCLC) widely available, we conducted a multicenter study comparing PD-L1 standardized assays and laboratory-developed tests (LDTs). Methods: IHC with five anti-PD-L1 monoclonal antibodies (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers using Dako Autostainer Link 48 (3 centers), Leica Bond (2 centers) or Ventana BenchMark Ultra (2 centers) platforms. For each matching platform, 22C3, 28-8 and SP263 assays were performed. For nonmatching platforms and other antibodies, LDTs were developed in each center. A total of 35 stainings were performed for each case across different platforms and antibodies. PD-L1 staining was assessed in tumor cells and immune cells by seven trained thoracic pathologists. For statistical analysis, 1%, 50% and 1%, 5%, 10% expression thresholds were used for tumor cells and immune cells, respectively. Results: 28-8, 22C3 and SP263 assays were highly concordant for tumor cells staining across the five Dako or Ventana platforms. Among 27 LDTs developed in 7 centers on Dako, Ventana and Leica platforms, 14 (51.8%) demonstrated similar concordance when compared with reference assays for tumor cell staining. Clone SP263 achieved the highest concordance rate across all platforms. Lower concordance was observed for immune cells staining when using a four categories scale. Conclusion: 28-8, 22C3 and SP263 assays had close analytical performance for tumor cell staining across seven centers. Some LDTs on Dako, Ventana and Leica platforms achieved similar concordance, but caution is warranted for their validation. These LDTs will be further validated in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.

The keys to conservative treatment of early-stage squamous cell carcinoma of the tonsillar region.

To analyze the medical literature devoted to work-up, epidemiology, local control, survival, complications and sequelae after conservative treatment for early-stage squamous cell carcinoma of the tonsillar region. An analysis of the PubMed (1975-2016) database was performed using the following keywords and associations: "tonsil/tonsillar region/oropharynx" AND "squamous cell carcinoma" AND "early-stage (I-II; T1-2N0M0)" AND "radiation therapy/radiotherapy" OR "conservative surgery/oropharyngectomy/transoral surgery/radical tonsillectomy". The search retrieved 10 retrospective series documenting local control and/or survival in series with more than 50 cases and a minimum 2 years' follow-up after conservative treatment; no prospective studies, meta-analyses and/or Cochrane analyses were found. Magnetic resonance imaging is the key radiological exam for local extension assessment. Human papilloma virus infection (HPV) is a risk factor that must be screened for systematically, since it induces tumoral radio-sensitivity and increases the risk of specific synchronous and metachronous second primaries. Whatever conservative treatment used, local control and survival rates higher than 85% were achieved. Implementing intensity-modulated radiation therapy reduced the incidence and severity of radiation-related complications and sequelae. Transoral surgery yielded very low morbidity/mortality rates, enabled association to ipsilateral neck dissection, and allowed radiation therapy to be reserved for the management of metachronous second primaries. Transoral surgery appeared to be the first-line option in the majority of cases. Lifetime follow-up adapted to HPV status is mandatory. The development of HPV vaccination does not mean that campaigns against smoking and alcohol abuse are of diminished importance.

[Cancer immunotherapy: Rational and recent breakthroughs]. / Immunothérapie des cancers : rationnel et avancées récentes.

Cancer immunotherapy has occupied a marginal therapeutic option in cancer despite strong arguments documenting the role of the immune system in controlling the proliferation of cancers. The recent success of immunotherapy results from a change in the past paradigm. From now on, the goal is not only to activate the immune system against tumor, but also to take account of the immunosuppressive tumor microenvironment Among these mechanisms, negative costimulatory molecules (CTLA-4, PD-1, etc.) expressed by T cells in the tumor could explain their lack of effectiveness in inhibiting tumor growth. Blocking these molecules allowed the reactivation of anti-tumor T cells. Clinically, the administration of anti-CTLA-4 antibody (ipilimumab: Yervoy®) was granted marketing authorization for patients with metastatic melanoma. The anti-PD-1 antibodies (nivolumab: Opdivo®, pembrolizumab: Keytruda®) have demonstrated clinical efficacy when compared to the standard therapy in metastatic melanomas, advanced lung cancers and metastatic renal cell carcinoma. In phase I and II clinical trials, other tumors (Hodgkin's disease, head and neck cancers, bladder cancer, gastric cancer, etc.) appear to be responsive to these immunomodulators. These treatments were associated with the occurrence of side effects dominated by autoimmunity predictable by unlocking the breaks exerted by immune system to maintain tolerance against self-antigen. The optimization of therapeutic combination based on these molecules and the search for biomarkers associated with these treatments constitute a challenge for the future for this new therapeutic class of drugs for oncology.

Warthin's tumor of parotid gland: Surgery or follow-up? Diagnostic value of a decisional algorithm with functional MRI.

PURPOSE: Warthin's tumor is the second most frequent benign tumor of the parotid gland, with no risk of malignant evolution. That is why surgery should be avoided if the preoperative diagnosis is certain. The aim of the study was to assess the added value of a decisional algorithm for the preoperative diagnosis of Warthin's tumor. MATERIALS AND METHODS: This retrospective IRB-approved study included 75 patients who underwent standardised MRI with conventional sequences (T1- and T2-weighted images, and T1 post-contrast sequences with fat saturation) and functional sequences: diffusion (b0, b1000) and perfusion MR. Two independent readers reviewed the images using the decisional algorithm. The conclusion of each reader was: the lesion is or is not a Warthin's tumor. The MRI conclusion was compared with histology or with cytology and follow-up. We calculated the Cohen's kappa coefficient between the two observers and the sensitivity and specificity of the algorithm-helped-reading for the diagnosis of Warthin's tumor. RESULTS: Seventy-five patients; histology (n=61) or cytology and follow-up (n=14) results revealed 20 Warthin's tumors and 55 other tumors. Using the algorithm, sensitivity and specificity were 80-96%, and 85-100%, respectively for readers 1 and 2. The Cohen's kappa coefficient between the two observers was 0.79 (P<0.05) for the diagnosis of Warthin's tumor. CONCLUSION: Our decisional algorithm helps the preoperative diagnosis of Warthin's tumor. The specificity of the technique is sufficient to avoid surgery if a parotid gland tumor presents all the MRI characteristics of a Warthin's tumor.

[HPV (Human Papilloma Virus) implication in other cancers than gynaecological]. / Impact de l'HPV (Human Papilloma Virus) dans les carcinomes autres que gynécologiques.

Worldwide, approximately 5 to 10% of the population is infected by a Human Papilloma Virus (HPV). Some of these viruses, with a high oncogenic risk (HPV HR), are responsible for about 5% of cancer. It is now accepted that almost all carcinomas of the cervix and the vulva are due to an HPV HR (HPV16 and 18) infection. However, these viruses are known to be involved in the carcinogenesis of many other cancers (head and neck [SCCHN], penis, anus). For head and neck cancer, HPV infection is considered as a good prognostic factor. The role of HPV HR in anal cancer is also extensively studied in high-risk patient's population. The role of HPV infection in the carcinogenesis of esophageal, bladder, lung, breast or skin cancers is still debated. Given the multiple possible locations of HPV HR infection, the question of optimizing the management of patients with a HPV+ cancer arises in the implementation of a comprehensive clinical and biological monitoring. It is the same in therapeutics with the existence of a preventive vaccination, for example.

Administration of low doses of IL-2 combined to rapamycin promotes allogeneic skin graft survival in mice.

Human CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) prevent allogeneic graft rejection by inhibiting T cell activation, as has been shown in mouse models. Recently, low-dose IL-2 administration was shown to specifically activate Tregs but not pathogenic conventional T cells, leading to resolution of type 1 diabetes in nonobese diabetic mice. We therefore tested the ability of low-dose IL-2 to prevent allogeneic skin graft rejection. We found that while IL-2 alone was inefficient in preventing rejection, combined with rapamycin, IL-2 treatment promoted skin graft survival both in minor disparate and semi-allogeneic skin graft combinations. Tregs are activated by this combined treatment while conventional CD4(+) cell expansion and activation are markedly inhibited. Co-administration of anti-CD25 antibodies dramatically reduces the effect of the IL-2/rapamycin treatment, strongly supporting a central role for Treg activation. Thus, we provide the first preclinical data showing that low-dose IL-2 combined with rapamycin can significantly delay transplant rejection in mice. These findings may form the rational for clinical evaluation of this novel approach for the prevention of transplant rejection.

Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours.

BACKGROUND: Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific targets for optimising and personalising treatments are yet to be identified. DESIGN: Immunohistochemistry for C-KIT, EGFR, HER2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival. High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology. RESULTS: Several therapy leads were identified, including high levels of HER2 and androgen receptors in salivary duct carcinomas, C-KIT in myoepithelial carcinomas and EGFR in mucoepidermoid carcinomas. Recurrent mutations involving downstream elements of the EGFR pathway were found in HRAS, notably in tumours with a myoepithelial component, and in other key oncogenes (KRAS/NRAS/PI3KCA/BRAF/MAP2K). On the other hand, <1% of samples had EGFR or HER2 mutations. CONCLUSION: Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads. Genotyping results suggest activation downstream of EGFR in 18 of the 107 samples that could be associated with low efficacy of EGFR inhibitors. Other molecules, such as PI3K/MEK or mTOR inhibitors, may have anti-tumour activity in this subgroup. The high mutation rate in HRAS highlights a novel key oncogenic event in MSGT.

Isolated laryngeal plasmacytosis.

INTRODUCTION: Laryngeal plasmacytosis (LP) is a rare benign lesion of mature polyclonal plasma cells, which should be differentiated from extramedullary plasmacytoma. CASE REPORT: Isolated laryngeal plasmacytosis was discovered in a 59-year-old woman, free of symptoms other than chronic hoarseness. DISCUSSION: Histological presentation, treatment modalities and prognosis are discussed. CONCLUSION: Laryngeal plasmacytosis is a rare benign lesion that must be considered in case of submucosal polyclonal plasma cell infiltrate.

Late recurrence or secondary location? Towards a better understanding of the physiopathology of inverted papilloma.

INTRODUCTION: Inverted papilloma (IP) is the most frequent benign tumor of the nasal cavities. Recurrence is found in 12 to 14% of cases, mainly at the primary site, although also exceptionally in remote locations. The present paper discusses the physiopathogenesis of IP on the basis of a report of late second occurrence of IP at a remote location and a review of the literature. CASE REPORT: A man, who had undergone surgery in 1997 for ethmoid IP at the age of 56, presented 11 years later with nasal cavity IP at a second (frontal) location, discovered serendipitously during systematic follow-up and managed surgically without complication. DISCUSSION AND CONCLUSION: The physiopathology of nasal cavity IP remains unexplained. No reliable histologic or biological markers predict risk of recurrence or of malignant transformation. The sole treatment is total surgical resection. The risk of local recurrence, often due to incomplete resection, is well known, but that of a secondary location is less so, and regular very long-term follow-up is justified.

Initial staging of squamous cell carcinoma of the oral cavity, larynx and pharynx (excluding nasopharynx). Part I: Locoregional extension assessment: 2012 SFORL guidelines.

OBJECTIVES: To set out good practice guidelines for locoregional extension assessment of squamous cell carcinoma of the head and neck (excluding nasopharynx, nasal cavities and sinuses). MATERIALS AND METHODS: A critical multidisciplinary review of the literature on locoregional extension assessment of squamous cell carcinoma of the head and neck was conducted, applying levels of evidence in line with the French health authority's (HAS) literature analysis guide of January 2000. CONCLUSION: Based on the levels of evidence of the selected articles and on work-group consensus, graded guidelines are set out for clinical, endoscopic and imaging locoregional extension assessment of head and neck cancer.

Initial staging for squamous cell carcinoma of the mouth, larynx and pharynx (except nasopharynx). Part 3: general assessment. 2012 SFORL recommendations.

OBJECTIVES: The French Society of Otorhinolaryngology (SFORL) set up a work group to draw up guidelines for initial staging of head and neck squamous cell carcinoma. Locoregional and remote extension assessment are dealt with in two separate reports. The present part 3 deals with the assessment of frequent associated symptoms and pathologies, requiring early treatment and the collection of data on a certain number of clinical and paraclinical parameters for therapeutic decision-making in the multidisciplinary team meeting. MATERIALS AND METHODS: A multidisciplinary critical analysis of the literature was conducted. General assessment here covers screening, assessment and initial management of the following: usual risk factors (smoking, alcohol, HPV), the most frequent medical comorbidities, nutritional status, social and psychological status, dental status, pain and possible anemia. As oncologic management frequently associates surgery, radiation therapy and chemotherapy, the underlying examinations should be early, as part of initial staging. The levels of evidence for the examinations were estimated so as to grade guidelines, failing which expert consensuses were established. RESULTS: The high rates of pain, malnutrition and anemia call for systematic screening and early management, especially as rapidly effective treatments exist. Assessing comorbidity and social and psychological status enables general health status to be assessed, along with possible contraindications to the usual treatments. Tracheal intubation problems may require intubation under flexible endoscopy or jet-ventilation by inter-cricothyroid catheterization from the diagnostic endoscopy stage. Assessment and adapted dental care should be conducted if radiation therapy is likely or certain. CONCLUSION: Early management of symptoms and comorbidity and anticipation of subsequent treatment are intended to shorten initial staging time and to collate the data needed for therapeutic decision-making. This assessment should be performed at the same time as the locoregional and remote extension assessment, and is obviously to be adapted according to tumoral extension stage and the possible treatment options.

Intraparotid Kimura disease.

INTRODUCTION: Intraparotid locations are extremely rare in Kimura disease, especially in Europe. CASE REPORT: A 31-year-old man presented with intraparotid Kimura disease, managed by parotidectomy. DISCUSSION/CONCLUSION: The case was analyzed in the light of a review of the literature, focusing on the diagnostic and anatomopathologic problems encountered, and the physiopathology and treatment of this pathology. Any parotid mass found in a patient of Far-Eastern origin showing hypereosinophilia should suggest a diagnosis of intraparotid Kimura disease.

Pre-therapeutic histological and cytological assessment in head and neck squamous cell carcinomas. French Society of Otorhinolaryngology Guidelines--2012.

OBJECTIVES: The authors present the French Society of Otorhinolaryngology (SFORL) guidelines for histopathologic assessment of head and neck cancer. MATERIAL AND METHODS: [corrected] A multidisciplinary workgroup set up by the SFORL performed an exhaustive review of the literature according to levels of evidence, following the 2000 guidelines of the French national health approvals and assessment agency (ANAES). RESULTS: Comparison between histologic and clinical data is essential. In case of discrepancy between clinical, radiological and histological findings, reinterpretation or new biopsy may be required (professional consensus). Mere suspicion of carcinoma on fine-needle aspiration lymph-node biopsy only exceptionally warrants aggressive treatment (professional consensus). Exploration for HPV is not recommended as routine practice, being without therapeutic impact (professional consensus). Anti-p16 immunohistochemistry is optional, for epidemiological purposes (professional consensus). Tumor-bank tissue storage must conform strictly to prevailing legislation and good practice rules for sampling and preservation (professional consensus). CONCLUSION: Pathology assessment is mandatory in suspected H&N squamous cell carcinoma. The present guidelines are intended to optimize management.