A Family With A20 Haploinsufficiency Presenting With Novel Clinical Manifestations and Challenges for Treatment.

BACKGROUND: Tumor necrosis factor α-induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation. METHODS: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings. RESULTS: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis. CONCLUSIONS: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.

Proposal for a new staging system for osteoradionecrosis of the mandible.

A new staging system for osteoradionecrosis of the mandible has been retrospectively applied to a group of 31 patients. In this system clinicoradiographic signs and symptoms are incorporated in a simplified manner. For imaging purposes the use of plain radiographs such as periapical films and panoramic radiographs is recommended, mainly because of their readily availability. The presented staging system seems well reproducible, facilitating the comparison of study groups dealing with the various issues of osteoradionecrosis of the mandible. It is yet to be evaluated whether the presently proposed staging system is useful for management purposes.

Cancer-associated fibroblasts and epithelial-mesenchymal transition in metastatic oral tongue squamous cell carcinoma.

We examined cancer-associated fibroblasts (CAFs) and a panel of immunohistochemical markers of epithelial-mesenchymal transition (EMT) in 19 pair-matched oral tongue squamous cell carcinoma (SCC) and metastatic tumors to regional lymph nodes (RLNs). alpha-Smooth muscle actin (alpha-SMA) was studied to identify CAFs. EMT was studied with syndecan-1, Cadherin-11, fibroblast-specific protein (FSP)-1, secreted protein acidic and rich in cysteine (SPARC) and Twist. Triple immunostaining in RLNs was used to highlight the carcinoma cells (E-cadherin and Ki-67) and their relationship to the CAFs (alpha-SMA). We found that metastatic RLNs hosted CAFs similarly as in pair-matched primary tumors. Expression of EMT markers is common in both primary and metastatic tumors. We demonstrate that metastatic carcinoma cells (Ki-67 positive) downregulate E-cadherin expression at the periphery of cancer islands, where they are in direct contact with CAFs. The supporting connective tissue microenvironment also commonly expresses syndecan-1, Cadherin-11, FSP-1, and SPARC. In conclusion, CAFs are common to both primary and metastatic SCC. We hypothesize that CAFs not only promote tumor invasion but also facilitate metastases, either by cometastasizing and/or being recruited to lymph nodes. Evidence of EMT is common within primary tumors and metastatic SCC and may be further modulated by CAFs.

Neonatal thrush of newborns: Oral candidiasis?

Objectives: Neonatal thrush, also called oral candidiasis, is commonly a clinical diagnosis based on white patches on oral mucosal surfaces. Candida albicans is often associated with it. This clinical study aimed to investigate the presence of C. albicans among newborns with or without clinical findings of candidiasis on oral mucosa. Another aim was to investigate how thrush responded to current therapy by acidic liquids such as lingonberry or lemon juice. Material and methods: Swipe samples were collected from 32 healthy, full-term infants younger than 12 months with or without white patches on oral mucosa. Clinical diagnosis of thrush was made by a community nurse based on thick and yellowish white patches. The routine therapy was oral lingonberry or lemon juice or soda water. Disappearing of patches was controlled by a phone call about 2 weeks after the baseline. Both parents and nurses gave background factors by filling a questionnaire. Results: One (3%) infant without clinical signs was diagnosed with Candida parapsilosis, none with C. albicans. Thrush resembling candidiasis was diagnosed clinically in four (12.5%) children. Three out of four parents reported persisting findings after 2 weeks. Only the maternal mastitis and use of antibiotics were significantly associated with thrush (p = .001). C. albicans was not discovered from babies with clinical thrush. Conclusions: Aetiology of the white patches remained unclear. The current way of treating them with acidic liquids is not efficient. Additional studies are needed.

Diagnosis and Treatment of Orofacial Granulomatosis.

Orofacial granulomatosis (OFG) is a chronic inflammatory disorder characterized by lip swelling and gingival alterations. OFG occurs either as a separate clinical entity or associated with a systemic disorder such as Crohn's disease (CD). The purpose of this paper is to report the case of a 13-year old boy who presented with marked granulomatous gingival inflammation and stomach discomfort. Periodontal therapy resulted in only slight reduction in gingival inflammation and enlargement. The diagnosis of OFG, which was evidently associated with inflammation in the bowel, was based on the gingival status and biopsy, self-reported symptoms, and laboratory markers of iron metabolism and fecal calprotectin level. The gingival and bowel inflammation was controlled with, strict adherence to a cinnamon- and benzoate-free diet combined with periodontal prophylaxis. At this point at the age of 17 years, the patient has avoided the use of immune modulatory treatments.

Competing risks analysis of cause-specific mortality in patients with oral squamous cell carcinoma.

BACKGROUND: Survival studies on head and neck cancers are frequently reported with inadequate account for competing causes of death. Realistic descriptions and predictions of postdiagnosis mortality should be based on proper competing risks methodology. METHODS: Prognosis of patients with oral squamous cell carcinoma (OSCC) in terms of mortality from OSCC and from other causes, respectively, was analyzed according to recent methodological recommendations using cumulative incidence functions and models for cause-specific hazards and subdistribution hazards in 306 patients treated in a tertiary care center in Northern Finland. RESULTS: More coherent and informative descriptions and predictions of mortality by cause were obtained with state-of-the-art statistical methods for competing risks than using the prevalent but questionable practice to graph "disease-specific survival." CONCLUSION: From the patients' perspective, proper competing risks analysis offers more relevant prognostic scenarios than naïve analyses of "disease-specific survival"; therefore, it should be used in prognostic studies of head and neck cancers. © 2016 Wiley Periodicals, Head Neck 39: 56-62, 2017.

Head and neck cancer in primary care: presenting symptoms and the effect of delayed diagnosis of cancer cases.

BACKGROUND: Little is known about the diagnosis of head and neck carcinoma in primary care. We sought to estimate the general prevalence of symptoms reported by patients with head and neck carcinomas and to determine the association between detection patterns of head and neck cancer cases in primary care and survival. METHODS: In a cross-sectional survey, we used a questionnaire to estimate the general prevalence of symptoms associated with head and neck cancer from a sample of 5646 primary care visits in 25 randomly selected health centres over 4 weeks throughout Finland. A population-based retrospective cohort study involved the 221 patients resident in one primary health care district (population about 700,000) in whom head and neck carcinoma was diagnosed between Jan. 1, 1986, and Dec. 31, 1996. Data on the initial primary care visit, clinical characteristics and survival were obtained from patient charts. RESULTS: Of 5646 visits to a primary care practitioner, 11% (617) were made because of the same symptoms as those initially reported by patients later found to have head and neck cancer. According to the cohort data, the detection rate of these carcinomas in primary care was 1 per 63,000 visits. At the initial visit of 221 patients later found to have cancer, 56% (123) received referrals, 24% (53) follow-up appointments and 20% (45) neither ("overlooked"). At 3 years, the risk of death was significantly higher among patients whose disease was overlooked (adjusted hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.03-3.45). The excess risk associated with being overlooked, however, was confined to subjects with tongue or glottic tumours (HR 4.25, 95% CI 1.59- 11.4) (number needed to harm 3.0, 95% CI 1.9-6.7). INTERPRETATION: Despite the rarity of patients with head and neck carcinoma in primary care, patients with symptoms of these diseases and especially with symptoms of tongue and glottic carcinomas should be initially referred for further care or followed up.

Cancer-associated fibroblasts, a parameter of the tumor microenvironment, overcomes carcinoma-associated parameters in the prognosis of patients with mobile tongue cancer.

Mobile tongue squamous cell carcinoma (MTSCC) is known for its strong propensity for regional metastasis and poor patient survival despite aggressive treatment, thus calling for new and reliable markers for predicting prognosis and guiding therapeutic management. Towards this end, three classes of markers were investigated: cancer-associated fibroblasts (CAFs; α-SMA positivity) as a representative of the tumor microenvironment, maspin (mammary serine protease inhibitor) as a tumor marker likely to be modulated by factors within the tumor microenvironment, and DNA content and Ki-67 labeling index as inbuilt tumor markers in 128 cases of MTSCC using immunohistochemistry and image cytometry. Of these markers, only CAF density was independently and relatively strongly associated with elevated mortality from MTSCC. The hazard ratio in the CAF-rich type of tumor microenvironment was 4.85 (95% CI 1.41-16.6, versus the CAF-poor) when adjusted by proportional hazards modeling for the center where the patient was managed, gender, tumor stage, presence of neck metastasis and age at diagnosis. CAF density was unrelated to non-MTSSC mortality. Given the strong association between increased CAF density and higher mortality in MTSCC, routine assessment of CAF density for disease course prognosis and inclusion as an integral part of treatment protocols are recommended.

Expression of claudins 1, 4, 5, and 7 and occludin, and relationship with prognosis in squamous cell carcinoma of the tongue.

Claudins and occludin are tight junctional proteins known to play a role in normal tissues and epithelial tumors. We analyzed the distribution patterns of claudins 1, 4, 5, and 7 and occludin in the superficial and invasive front of squamous cell carcinoma of the tongue of 97 patients and their relationship to cause-specific (squamous cell carcinoma of the tongue) patient survival (median follow-up period of 33.5 months; range, 1-234 months). Claudins 1 and 7 were strongly expressed, claudin 4 had moderate expression, whereas claudin 5 was least expressed. Occludin staining was mostly negative or very weak. Western blot analysis of tongue carcinoma (HSC-3) cells showed that all these proteins are also expressed in vitro. In cause-specific survival analysis, strong and low immunoreactivity of claudin 7 tended to be associated with decreased survival compared with medium immunoreactivity. We suggest that analyzing the immunohistologic staining levels of claudin 7 could be used for the prognostic purposes in patients with tongue squamous cell carcinoma.

Differential prognostic impact of comorbidity in head and neck cancer.

BACKGROUND: The aim was to investigate how the effect of comorbid illnesses on survival is modified by other prognostic factors in head and neck cancer. METHODS: A population-based retrospective cohort study involved 221 patients residing in 1 primary health care district (population about 700,000) in whom head and neck carcinoma was diagnosed between January 1, 1986, and December 31, 1996. Data on clinical characteristics and survival were obtained from patient charts. Comorbidity was classified according to Charlson score. RESULTS: At 3 years, the risk of death was significantly higher among the patients with high comorbidity status (score 3 or higher) (adjusted hazard ratio 2.1, 95% confidence interval 1.2-3.7). The excess risk associated with comorbidity, however, was confined to the subjects aged under 65 years and those with tongue or laryngeal tumors or stage I-II cancer. CONCLUSION: To assess the prognostic significance of comorbidity for an individual patient with head and neck cancer, age, tumor site, and cancer stage must be considered.

Incidence and survival of squamous cell carcinoma of the tongue in Scandinavia, with special reference to young adults.

In several countries, increased incidence of squamous cell carcinoma (SCC) of the tongue in young adults has been suspected during the last decades. Some reports indicate a lower survival rate for young patients compared to older patients. In other reports, there has not been any considerable difference in survival when comparing young adults to older patients, whereas some authors have shown better survival for young adults. This disease is rare in young adults, and early reports were based on comparable small numbers and selected patients. Our aim was first to perform a population-based study to determine if an increased incidence in SCC of the tongue could be verified in a larger population comprising the Scandinavian countries Denmark, Finland, Sweden and Norway. A second aim was to determine survival rates for young adults compared to older patients. The material was based on the annual cancer incidence and survival reports from the Scandinavian cancer registries. The study period was 1960-1994. During that period, 5,024 SCCs of the tongue were reported. Of these, 276 (5.5%) were young adults (20-39 years). The incidence increased at all ages except for women 65-79 years old. The increase was most pronounced in young adults: 0.06-0.32 for men and 0.03-0.19 for women, counted by 100,000 person-years. Relative survival was significantly better for young adults compared to older patients.