Development and validation of a novel TNM staging N-classification of oral cavity squamous cell carcinoma.

BACKGROUND: For oral cavity squamous cell carcinoma (OSCC), extent of extranodal extension (ENE) (minor, ≤2 mm; major, >2 mm) is differentially prognostic, whereas limitations exist with the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N-classification (TNM-8-N). METHODS: Resected OSCC patients at four centers were included and extent of ENE was recorded. Thresholds for optimal overall survival (OS) discrimination of lymph node (LN) features were established. After dividing into training and validation sets, two new N-classifications were created using 1) recursive partitioning analysis (RPA), and 2) adjusted hazard ratios (aHRs) and were ranked against TNM-8-N and two published proposals. RESULTS: A total of 1460 patients were included (pN0: 696; pN+: 764). Of the pN+ cases, 135 (18%) had bilateral/contralateral LNs; 126 (17%) and 244 (32%) had minor and major ENE, and two (0.3%) had LN(s) >6 cm without ENE (N3a). LN number (1 and >1 vs. 0: aHRs, 1.92 [95% confidence interval (CI), 1.44-2.55] and 3.21 [95% CI, 2.44-4.22]), size (>3 vs. ≤3 cm: aHR, 1.88 [95% CI, 1.44-2.45]), and ENE extent (major vs. minor: aHR, 1.40 [95% CI, 1.05-1.87]) were associated with OS, whereas presence of contralateral LNs was not (aHR, 1.05 [95% CI, 0.81-1.36]). The aHR proposal provided optimal performance with these changes to TNM-8-N: 1) stratification of ENE extent, 2) elimination of N2c and 6-cm threshold, and 3) stratification of N2b by 3 cm threshold. CONCLUSION: A new N-classification improved staging performance compared to TNM-8-N, by stratifying by ENE extent, eliminating the old N2c category and the 6 cm threshold, and by stratifying multiple nodes by size.

Prognostic impact of autoimmune disease in oral cavity squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: Recent literature has highlighted the role of the host in the prognosis of oral squamous cell carcinoma (OSCC). In this study, we retrospectively examined the impact of autoimmune (AI) disorders as an aspect of the host status on survival outcomes in OSCC patients. METHODS: From a departmental database of OSCC patients (n = 1369), 123 patients with an AI disorder were identified. AI and no-AI groups were compared for survival outcomes. RESULTS: There were no significant differences in survival between groups for overall survival, disease-specific survival, local, regional, and distant recurrence-free probabilities. However, survival and recurrence-free probabilities were poorer in the AI group versus the no AI group. CONCLUSION: Patients with AI disease trended towards worse outcomes. This suggests immune dysregulation in these patients may impact oncologic outcomes.

Paragangliomas of the head and neck.

Paragangliomas are rare neuroendocrine tumors that can be found from the skull base to the pelvis. Head and neck paragangliomas have been historically treated with surgery. However, surgical resection adds risk of injury to vascular structures and cranial nerves that can lead to morbidity such as hoarseness, dysarthria, dysphagia, or aspiration. Recently, improved understanding of the behavior of these tumors and increasing experience in non-surgical treatments, such as observation and radiation therapy, have changed the paradigms of management of this entity. Multiple series now show a trend toward a more conservative management, with a higher percentage of patients being observed or treated with radiotherapy. Several factors should be taken into consideration when deciding the most appropriate treatment for head and neck paragangliomas, starting by differentiating carotid body tumors from non-carotid body tumors. In general, surgical resection is normally recommended for carotid body tumors as the complications from treatment are usually minimal. In contrast, for non-carotid body tumors, surgery is often associated with significant functional impairment due to cranial nerve paralysis. As such, non-surgical treatment is now usually recommended for this subset of head and neck paragangliomas. In young patients with no comorbidities and a small to medium carotid body tumors, surgery should be considered. Moreover, surgery should be offered for secreting tumors, malignant tumors, tumors with rapid growth or increase in symptomatology, and when radiotherapy cannot be performed. Conversely, conservative management with active surveillance or radiotherapy can be offered in the remaining cases in order to avoid unnecessary morbidity while still providing acceptable tumor control.

Surgical management of vascular tumors and malformations of the head and neck in adults.

Vascular tumors and malformations present a diagnostic and therapeutic challenge to many physicians. Because these lesions are rare, few surgeons have enough experience with them other than those practicing in tertiary vascular anomaly treatment centers. Some patients may have been misdiagnosed or mistreated during childhood and present in adult age with either recurrence or with an untreated lesion. Ideally, a multidisciplinary treatment team should be involved to discuss management with the patient including specialists in surgery, interventional radiology, pathology, hematology, genetics, and dermatology. As our understanding of the pathogenesis of these lesions grows, novel therapies are being employed which may decrease the need for surgery. Nevertheless, some lesions need definitive treatment with surgery. Improving understanding of the surgical management of vascular anomalies will improve cosmetic and functional outcomes for patients.

Vasculitis flare after COVID-19: report of two cases in patients with preexistent controlled IgA vasculitis and review of the literature.

COVID-19 has been related to several autoimmune diseases, triggering the appearance of autoantibodies and endothelial dysfunction. Current evidence has drawn attention to vasculitis-like phenomena and leukocytoclastic vasculitis in some COVID-19 patients. Moreover, it has been hypothesized that COVID-19 could induce flares of preexisting autoimmune disorders. Here, we present two patients with previously controlled IgA vasculitis who developed a renal and cutaneous flare of vasculitis after mild COVID-19, one of them with new-onset ANCA vasculitis. These patients were treated with glucocorticoids and immunosuppressants achieving successful response. We also provide a focused literature review and conclude that COVID-19 may be associated with triggering of vasculitis and could induce flares of previous autoimmune diseases.

Depth of invasion versus tumour thickness in early oral tongue squamous cell carcinoma: which measurement is the most practical and predictive of outcome?

AIMS: The 8th edition of the American Joint Committee on Cancer (AJCC) Staging introduced depth of invasion (DOI) into the pT category of oral cavity squamous cell carcinoma. However, we noted multiple practical obstacles in accurately measuring DOI histologically in our daily practice. METHODS AND RESULTS: To compare the prognostic effects of DOI and tumour thickness (TT), a meticulous pathology review was conducted in a retrospective cohort of 293 patients with AJCC 7th edition pT1/T2 oral tongue squamous cell carcinoma. Overall survival (OS) and nodal metastasis rate at initial resection were the primary and secondary outcomes, respectively. We found that TT and DOI were highly correlated with a correlation coefficient of 0.984. The upstage rate was only 6% (18 of 293 patients) when using TT in the pT stage compared with using DOI. More importantly, DOI and TT, as well as pT stage using DOI and pT stage using TT, performed identically in predicting risk of nodal metastasis and OS. CONCLUSIONS: We therefore propose to replace DOI, a complicated measurement with many challenges, with TT in the pT staging system.

Staging of human papilloma virus related cancers of the oropharynx.

For the past two decades an increasing number of oropharyngeal cancers have been found to be associated with the human papilloma virus (HPV). These tumors are a biologically distinct entity with better prognosis and excellent response to therapy. Therefore, a separate staging system has been introduced for HPV-related oropharyngeal tumors in the latest edition of the American Joint Committee on Cancer (AJCC eighth Ed).

Nodal characteristics associated with adverse prognosis in oral cavity cancer are linked to host immune status.

BACKGROUND AND OBJECTIVE: Nodal metastasis is one of the strongest predictors of outcomes in oral cavity squamous cell carcinomas (OSCC). The aim was to analyze the interplay of nodal characteristics in OSCC prognosis. METHODS: In this retrospective cohort study we included OSCC patients treated with primary surgery including neck dissection between 2005 and 2015 (n = 619). Disease-specific survival (DSS) was the primary endpoint. Optimal cutoffs were identified using recursive-partitioning analysis (RPA). A novel characteristic-metastatic focus-to-lymph node size ratio (MLR)-was introduced. We compared the American Joint Committee on Cancer, Eighth Edition (AJCC8) pN categories to a new categorization. RESULTS: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. All nodal characteristics were significant predictors of DSS in univariable analysis. In multivariable analysis, only number of positive nodes and MLR remained significant. An RPA including all nodal covariates confirmed the results. Compared with AJCC8, our RPA categorization had better hazard discrimination (0.681 vs. 0.598), but poorer balance value (0.783 vs. 0.708). CONCLUSION: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. Total number of metastatic lymph nodes is the strongest predictor of outcomes in OSCC. MLR is a more powerful predictor than metastatic lymph node size or metastatic focus size alone.

Efficacy and safety of switching Jak inhibitors in rheumatoid arthritis: an observational study.

OBJECTIVES: Different Jak inhibitors (jakinibs) have shown efficacy in rheumatoid arthritis (RA), but in a significant proportion of patients, an insufficient response leads to therapy withdrawal. We describe the efficacy and safety of a second jakinib in patients stopping the first due to insufficient response or side effects. METHODS: This is an observational retrospective multicentric study of 31 patients with RA sequentially treated with baricitinib or tofacitinib in any order in clinical practice in ten medical centres in Spain. RESULTS: We identified 31 patients, sequentially treated with both jakinibs. An equal proportion had received tofacitinib or baricitinib first. Most patients (87%) had previously received one or several bDMARD, median 4 (2-5). Median survival for the first jakinib was 5 (3-8) months, and the reasons for withdrawal were inefficacy in 61% and adverse effects in 39%. Most patients (23/31, 74%) maintained the response to the second jakinib after a mean follow-up of 19.5 (12-24) months. In all 8 patients who discontinued the second jakinib, the reason was inefficacy. The treatment suspension rate was similar among patients that had discontinued the first jakinib for inefficacy (26%) or for adverse effects (25%). CONCLUSIONS: Therapy of RA with a second jakinib seems a safe and efficacious option after discontinuation of the first, either for inefficacy or for side effects.

Practical protocol of the food allergy committee of the seicap on open oral food challenges to nuts.

Food allergy is rising rapidly among children, and allergy to nuts is one of the most prevalent allergies among them. The category "nuts and seeds" include several plant foods from different botanical families, very different from each other. It is not uncommon to detect co-sensitization to different nuts. However, true co-allergy is less frequent. Up to 80% of patients with positive skin prick tests or specific IgE without true history of reaction who avoid certain nuts, might tolerate them in an Oral Food Challenge (OFC). Although molecular diagnostic techniques help to improve nut allergy diagnosis, OFC still remains the gold standard. For this reason, after reviewing the current bibliography and the recommendations of different allergy societies on standardization of open OFC, the Food Allergy Committee of the Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology (SEICAP) food allergy working group proposed a unified protocol to undertake these OFC, which include preliminary recommendations, unification of total dose, number of doses and interval between doses. Additionally, this group offers an interactive table to facilitate calculation of doses specific to each nut under study.

Pretreatment peripheral blood leukocytes are independent predictors of survival in oral cavity cancer.

BACKGROUND: Inflammation and immune surveillance evasion are cancer hallmarks. Peripheral blood leukocytes (PBLs) represent both. The aim of the current study was to examine PBLs as predictors of outcomes in oral cavity squamous cell carcinoma (OSCC), and to find specific cutoffs with the goal of including PBLs as host factor in patients' preoperative risk assessment. METHODS: Previously established head and neck squamous cell carcinoma (HNSCC) cutoffs were examined in an independent cohort of 1369 OSCC patients. Then optimal OSCC cutoffs were found and validated in the subset of patients with OSCC (n = 119) from the external HNSCC cohort. The PBLs analyzed were neutrophils, monocytes, and lymphocytes individually, the neutrophil-to-lymphocyte ratio (NLR), and a combined index using all PBLs called Systemic Inflammation Response Index (SIRI). RESULTS: All parameters were significant predictors of survival using the previous cutoffs. However, OSCC cutoffs stratified survival outcomes better. Considering neutrophils ≤4.8 × 109 /L as reference, patients with 4.8-9.1 × 109 /L neutrophils had 1.536 times higher risk of death (95% CI, 1.295-1.822), and patients with ≥9.1 × 109 /L had 3.076 times higher risk (95% CI: 2.170-4.360). All PBLs maintained independent prognostic capacity in multivariable analysis. Neutrophils, NLR, and SIRI were significant predictors of survival when validating OSCC cutoffs in the external validation cohort. CONCLUSIONS: Pretreatment peripheral blood neutrophils, NLR, and SIRI are the most robust independent predictors of overall survival among all PBLs in OSCC. The authors report externally validated cutoffs that demonstrate the feasibility of including PBLs as host features in the preoperative prognostication of OSCC.

Does age influence disease-specific survival in patients with squamous cell carcinomas of the head and neck?

BACKGROUND AND OBJECTIVES: The number of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) at an advanced age has increased. The aim of this study is to evaluate the age at which disease-specific survival (DSS) significantly decreases in HNSCC. METHODS: We performed a retrospective study of 5469 patients with HNSCC treated at our center (1985-2016). External validation with 2082 oral squamous cell carcinomas from a collaborative institution from another continent was performed. RESULTS: We observed an orderly decrease in overall survival as age at diagnosis increased. There were no differences in DSS based on age for patients <80 years old (P = .623), while older patients had a significant decrease in DSS. These results were validated in the independent dataset. In a multivariable analysis performed in the test set, compared to patients <80 years old, patients between 80 to 85 had a 1.50 times higher risk of disease-specific death (95% confidence interval [CI]: 1.19-1.89; P = .001), and patients >85 had a 2.19 times higher risk (95% CI: 1.68-2.87; P < .001). CONCLUSIONS: DSS started to significantly decrease in HNSCC at 80 years old. These findings, validated in an independent cohort, indicate that chronological age on its own should not withhold curative treatment in the majority of patients with HNSCC.

Relationship between response to induction chemotherapy and disease control in patients with advanced laryngeal carcinoma included in an organ preservation protocol.

The aim of the study is to analyze the relationship between the degree of response to induction chemotherapy and the disease control in patients with locally advanced laryngeal carcinomas candidates to total laryngectomy. This retrospective study includes 389 patients with T3-T4 laryngeal tumors candidates to total laryngectomy, diagnosed between 1985 and 2013, treated with induction chemotherapy in an organ preservation protocol. Five-year local recurrence-free survival for patients receiving conservative treatment with radiotherapy after a complete response to induction chemotherapy was 75.4%; for patients with partial response greater than 50%, it was 62.0%; and for patients with the absence of response, it was 32.7%. There were significant differences in local recurrence-free survival and laryngeal dysfunction-free survival according to the response to induction chemotherapy (P = 0.0001) at the expense of patients with absence of response to induction chemotherapy. Patients with partial response greater than 50% treated with radiotherapy had a tendency to have worse local recurrence-free survival and laryngeal dysfunction-free survival than patients with complete response, but the differences did not reach statistical significance. Patients with the absence of response after induction chemotherapy had significant differences in disease-specific survival according to the second treatment: for patients treated with surgery it was 70.2%, whereas for patients treated with radiotherapy, it was 28.2% (P = 0.0001). In patients with the absence of response to induction chemotherapy, conservative treatment with radiotherapy implies a significant decrease in survival.

Host-related indexes in head and neck cancer.

PURPOSE OF REVIEW: Peripheral blood host-related indexes have been widely studied in cancer patients. Several authors have shown the prognostic capacity of these indexes in head and neck cancer. Therefore, there has been an increasing interest in this topic recently. RECENT FINDINGS: The main variables analyzed and used to create these host-related indexes are peripheral blood leukocytes - including neutrophils, monocytes and lymphocytes - albumin and hemoglobin levels. Other factors with proven prognostic capacity in some studies are: platelets, C-reactive protein, and BMI. Among all the combined indexes, the neutrophil-to-lymphocyte ratio has been the most accepted and used worldwide. Nonetheless, there are other indexes which group multiple of these factors that have shown better prognostic capacity, and are promising in the near future. SUMMARY: Host-related indexes are ideal biomarkers to be used on our daily-basis. There is enough evidence to start considering them when assessing patients with head and neck cancer.

External validation of the GETTEC algorithm for elective neck dissection in patients candidates for salvage total laryngectomy.

OBJECTIVE: To perform an external validation of the algorithm for elective treatment of the lymph node areas proposed by GETTEC for patients candidates to salvage total laryngectomy after radiotherapy. This algorithm is based on the initial lymph node status, local extension of the recurrence and time to recurrence. MATERIAL AND METHODS: Retrospective study performed in 151 patients treated with salvage total laryngectomy without clinical or radiological evidence of regional involvement at the time of diagnosis of recurrence (rcN0). The percentage of patients with occult lymph node metastases was calculated according to the algorithm proposed by GETTEC. RESULTS: A total of 14.6 % (n = 22) of the patients had occult lymph node metastases. Patients with locally advanced recurrences (rcT4) had a higher risk of occult lymph node metastases. There were no significant differences in the risk of occult lymph node metastases according to initial lymph node status or time to recurrence. When applying the algorithm proposed by GETTEC, there were no significant differences in the percentage of occult lymph node metastases between the group of patients who were candidates for follow-up (14.4 %) and those candidates for elective neck dissection (14.9 %) (P = 0.940). According to our results, patients who were candidates for an elective neck dissection were those with tumors located in the supraglottis or rcT4 glottic tumors. CONCLUSION: Our results do not validate the algorithm proposed by GETTEC for the management of the lymph nodes in rcN0 patients who are candidates for salvage total laryngectomy after radiotherapy.

Prognostic capacity of PIV (pan-immune-inflammation value) in patients with head and neck squamous cell carcinoma.

INTRODUCTION: The pan-immune-inflammation value (PIV), an index that results from the following ratio: (neutrophils × monocytes × platelets)/lymphocytes, has been proposed as a prognostic biomarker in different tumour models. The aim of this study is to analyse the prognostic capacity of PIV in patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Retrospective study of 1187 patients with HNSCC treated at our centre between 2000-2017. PIV value was obtained from an analysis performed within 3 weeks prior to the start of treatment. RESULTS: PIV value was significantly associated with toxic consumption (0.001), tumour location (0.0001), tumour extension (0.0001), and histological grade (0.016). Four categories were defined based on PIV value using a recursive partitioning analysis: category I: PIV < 136.3 (n = 118, 9.9%), category II: PIV 136.3-451.1 (n = 594, 50.0%), category III: PIV 451.1-1,141.2 (n = 357, 30.1%), and category IV: PIV > 1141.2 (n = 118, 9.9%). A significant and ordered decrease in disease-specific survival was observed as the PIV category increased. This decrease in survival was independent of the type of treatment, tumour extension, or location of the primary tumour. The PIV category was and independent prognostic factor of disease-specific survival in a multivariable study. CONCLUSIONS: PIV is a prognostic biomarker in patients with HNSCC.

Results of surgical treatment of lymph node metastases in patients with cutaneous squamous cell carcinoma of the head and neck.

INTRODUCTION: Out of all cutaneous squamous cell carcinomas originating in the head and neck (HNCSCC), 2-4% are associated with parotid or cervical lymph node metastasis. The aim of this study is to analyse the prognostic factors of patients with HNCSCC with lymph node involvement treated surgically. Additionally, we aim to compare the prognostic capacity of the classification of these patients according to the 8th edition of the TNM, and an alternative classification proposed by O'Brien et al. PATIENTS AND METHODS: Retrospective review of 65 patients with HNCSCC with lymph node metastasis treated surgically during the period 2000-2020. RESULTS: During the study period we carried out 13 neck dissections and 52 parotidectomies + neck dissection in patients with lymph node metastases from a HNCSCC. The great majority of patients (89.2%) received post-operative radiotherapy. The 5 year disease-specific survival was 69.9%, and the overall survival it was 42.8%. The classification proposed by O'Brien et al., based on the parotid or cervical location of the lymph node metastases, and the size and number of the metastatic lymph nodes, had a better prognostic capacity than the TNM classification. CONCLUSIONS: The surgical treatment of lymph node metastases in patients with HNCSCC achieved a high disease control. The classification based on the location, size and number of lymph node metastases proposed by O'Brien et al had better prognostic capacity than the TNM classification.

Predictive capacity for local disease control of neogenin-1 (NEO1) transcriptional expression in patients with head and neck squamous cell carcinoma.

PURPOSE: To analyze the predictive capacity for local disease control of the transcriptional expression of neogenin-1 (NEO1) gene in patients with head and neck squamous cell carcinoma (HNSCC). METHODS/PATIENTS: A retrospective study was performed on tumor biopsies from 107 patients with HNSCC treated surgically. The transcriptional expression of NEO1 was determined by RT-PCR. NEO1 transcriptional expression value was categorized according to local disease control by recursive partitioning analysis. RESULTS: Lower NEO1 transcriptional expression was associated with worse local control after surgical treatment. Patients with lower NEO1 expression (n = 25, 23.4%) had a 5-year local recurrence-free survival of 61.8% (95% CI: 42.1-81.5%), while patients with higher NEO1 expression (n = 82, 76.6%) had a 5-year local recurrence-free survival of 85.6% (95% CI: 77.6-93.6%), (P = 0.003). According to the result of multivariable analysis, patients with lower NEO1 expression had a 2.7-fold increased risk of local tumor recurrence (95% CI: 1.0-7.0, P = 0.043) compared to patients with higher NEO1 expression. CONCLUSIONS: HNSCC patients with a lower transcriptional expression of NEO1 have a significantly higher risk of local recurrence after surgical treatment.