Dysbiosis linking periodontal disease and oral squamous cell carcinoma-A brief narrative review.

An association between periodontal disease and oral squamous cell carcinoma (OSCC) has been recognized. However, there is no causal relationship between the two. The polymicrobial etiology of periodontal disease is confirmed, and so are the proven etiological factors for OSCC. Inflammation lies at the core of periodontal pathogenesis induced by the putative microbes. OSCC has inflammatory overtures in its pathobiology. Bacterial species involved in periodontal disease have been extensively documented and validated. The microbial profile in OSCC has been explored with no specific conclusions. The scientific reasoning to link a common microbial signature that connects periodontal disease to OSCC has led to many studies but has not provided conclusive evidence. Therefore, it would be beneficial to know the status of any plausible microbiota having a similarity in periodontal disease and OSCC. This brief review attempted to clarify the existence of a dysbiotic "fingerprint" that may link these two diseases. The review examined the literature with a focused objective of identifying periodontal microbial profiles in OSCC that could provide insights into pathogen commonality. The review concluded that there is great diversity in microbial association, but important bacterial species that correlate with periodontal disease and OSCC are forthcoming.

Acantholytic variant of squamous cell carcinoma in the mandible: A rare entity and a brief review.

Acantholytic Squamous Cell Carcinoma (ASCC) is an uncommon histopathologic variant of Squamous Cell Carcinoma which occurs in the sun-exposed skin and rarely in the oral cavity. Although the World Health Organization (WHO) has defined ASCC as a unique entity, its occurrence in the oral cavity has been just about 60 cases in the literature. There have been cases reported in the lips, tongue, gingiva and maxillary alveolus but rarely in the mandible. Definitive diagnosis and treatment of such a rare condition is challenging as there are not much available data in the literature. We report a rare case of Acantholytic Squamous cell carcinoma with pathologic fracture of the mandible which was managed aptly considering its hostile clinical, radiological and histological presentation. The reconstruction was done using a vascularised free fibula graft which helped in achieving a functional and aesthetic rehabilitation for the patient thereby improving his quality of life.

Histological assessment of budding and depth of invasion (BD) model in biopsies of oral squamous cell carcinoma.

OBJECTIVES: Recognizing precise prognosticators from preoperative biopsies that aids in treatment is of immense clinical importance. Thus, the aim of this study was to assess and compare the tumor budding (B), depth of invasion (D) and combined scores (BD) model in the preoperative biopsies and subsequent postoperative specimens of oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: B and D were assessed in the pre- and postoperative specimens of 65 OSCC cases treated in the institution. Relationship between pre- and postoperative assessments was subjected to McNemar's, Chi-square, Fisher's exact, sensitivity and specificity statistics. RESULTS: There was an agreement between the pre- and postoperative B scores in 54 cases with accuracy of 83% (95% confidence interval 71.73%-91.24%). The preoperative scores showed a good sensitivity of 67.86% and a high specificity of 94.59% in predicting the postoperative score of the same. The difference in assessing intensity B as low and high between preoperative and postoperative biopsies was not statistically different. There was an agreement between the pre- and postoperative scores of the BD model in 72%. The difference in BD scoring as low intermediate and high between preoperative and postoperative biopsies were significantly different statistically. Postoperative BD scoring showed a significant association with stage and lymph node metastasis. CONCLUSIONS: The findings validate the prognostic value of BD model in the postoperative specimens. Its value in preoperative biopsies is questionable. A judicious representative biopsy may increase the accuracy and reliability in the assessment of preoperative B and precision in BD model evaluation.

Architectural changes in the regional lymph nodes of oral squamous cell carcinoma.

BACKGROUND: The lymph nodes (LNs) in oral squamous cell carcinoma (OSCC) are enlarged as a result of reactive lymphadenopathy, metastasis or both. In response to tumor-associated antigens, diverse cell populations of LNs react in different ways, giving rise to a multitude of morphological patterns (MPs). The prognostic value of MPs has been contested. Hence, the aim of the study was to evaluate morphological alterations in the LNs related to LN metastasis (LNM), tumor size, grade and stage and the prognostic value for OSCC. MATERIALS AND METHODS: LN sections of 40 OSCCs were evaluated. Six MPs were observed: germinal center predominance (GCP), lymphocyte predominance (LP), sinus histiocytosis (SH), vascular transformation of sinuses (VTS), lymphocyte depleted (LD) and granulomatous reaction (GR). The data were subjected to Chi-square test. RESULTS: Four-hundred and eighteen nodes were evaluated, of which 24 were metastatic and 394 nonmetastatic. The predominant MP of LN reactivity was of VTS (116 nodes) followed by GCP (105); LP (90), LD (52), SH (43) and GR (12). A significant association was noted between LN status and the MPs. Risk of LNM with LP was less (13%) when compared with GCP (79%). A statistically significant relation was noted between the predominant MP and metastatic and nonmetastatic cases and with the tumor stage. CONCLUSION: GCP pattern prevails in metastatic and advanced-stage tumors. LP or VTS/SH is prominent in early-stage tumors and nonmetastatic cases. MPs indicate the immune status and aid in foreseeing susceptibility to LNM, thus serving as a surrogate marker.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in chronic periodontitis before and after nonsurgical therapy.

BACKGROUND: Various biomarkers have been evaluated for understanding the systemic inflammatory response (SIR) to periodontitis. Hematological markers have been reported to be useful biomarkers in a variety of diseases, including periodontal diseases. The role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in periodontitis and their possible role in the SIR are not extensively documented. Therefore, this study assessed NLR and PLR in chronic periodontitis (CP) patients before and after periodontal treatment, which to the best of knowledge has not been reported in the literature. MATERIALS AND METHODS: Sixty participants were grouped as systemically and periodontally healthy (H) (n = 30) and with CP (n = 30). Plaque index, gingival index, probing pocket depth, clinical attachment loss, leukocyte counts, platelet (PLT) counts, NLR, and PLR were estimated at baseline and also after treatment in the CP group. NLR was calculated as total neutrophil count/absolute lymphocyte count, and PLR was calculated as total PLT count/absolute lymphocyte count. The data were statistically analyzed. RESULTS: Periodontal parameters differed significantly between groups H and CP at baseline and posttreatment. A pair-wise comparison of NLR and PLR between CP patients at baseline and posttreatment was significant. Correlation analyses were not remarkable. Receiver operating characteristics analyses provided significant NLR and PLR predictive cutoff values to differentiate between CP patients at baseline and posttreatment. CONCLUSION: NLR and PLR may serve as potential biomarkers of the SIR to CP to bridge the association between periodontal and systemic conditions.

Immunohistochemical expression of tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible immediate early response protein 14 in oral squamous cell carcinoma and its implications.

AIM: To study the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible immediate early response protein 14 (Fn14) in oral squamous cell carcinoma (OSCC), to elucidate the possible role of TWEAK-Fn14 in OSCC development. METHODS: Immunohistochemistry for TWEAK-Fn14 was performed on 61 oral mucosal samples: healthy oral mucosa (HOM; N = 15); oral dysplastic lesions (ODL; N = 15); and OSCC (N = 31). Extent of staining (ES) and immunoreactive score (IRS) were assessed. The data was statistically analyzed. RESULTS: All OSCC expressed TWEAK, and the Fn14 expression was noted in 90% of OSCC. A significant difference in the TWEAK and Fn14 expression was noted among the groups. ES and IRS of TWEAK-Fn14 significantly increased in OSCC compared with ODL and HOM. ES of TWEAK was significantly higher than Fn14 in all 3 groups. ES of TWEAK-Fn14 was significantly higher at the invasive tumor front (ITF) than in the whole tumor. TWEAK-Fn14 showed a significant association with clinicopathological parameters of prognostic significance. CONCLUSION: Findings suggest that TWEAK and Fn14 may participate in the growth and progression of OSCC. Increased expression of TWEAK-Fn14 at the ITF may facilitate increased proliferation, altered differentiation and invasion.

Serum sTWEAK levels in chronic periodontitis and type 2 diabetes mellitus.

AIM: The two-way relationship between diabetes mellitus and periodontitis has been extensively studied with various interconnected biomarkers sharing a link. Soluble Tumour Necrosis Factor-like Weak inducer of apoptosis (sTWEAK) is gaining attention as an important mediator in chronic inflammatory diseases. Thus, the aim of this study was to detect, estimate and compare the levels of sTWEAK in the serum of health, chronic periodontitis (CP), and CP with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Forty-five participants between 18 and 65 years were divided into groups of 15 each as Group 1: healthy, Group 2: CP, and Group 3: CP + T2DM. Clinical periodontal parameters and glycemic status were assessed. sTWEAK in serum was estimated using a commercially available ELISA kit. The data was statistically analyzed. RESULTS: sTWEAK was detected in all participants. Significant differences were observed between the groups for sTWEAK; highest in health, lower in CP and lowest in CP + T2DM. In the diseased groups, the clinical and glycemic parameters correlated positively with each other, whereas sTWEAK correlated negatively with each of the parameters. CONCLUSION: The literature reports lower concentrations of systemic sTWEAK in T2DM which may be comparable to our observations in CP + T2DM when compared to health and its negative correlation with all the parameters suggesting an association with both clinical periodontal parameters and glycemic levels. However, serum sTWEAK levels may not be necessarily elevated in periodontitis as previously reported, and hence has the potential to be studied extensively for clarification with its association with T2DM.

A retrospective study of clinicopathological features of oral squamous cell carcinoma with and without oral submucous fibrosis.

CONTEXT: Oral submucous fibrosis (OSF) is strongly associated with areca nut usage; the existence of OSF in patients with oral squamous cell carcinoma (OSCC) is an indicator of areca nut-induced carcinogenesis. As areca nut follows a discrete molecular path for oral carcinogenesis, this could be the basis why OSCC patients with OSF are different and are currently projected to constitute a distinct clinicopathologic entity. AIM: This study aims to analyze and compare the demographics, risk factors and clinicopathologic features of OSCC patients with and without OSF. MATERIALS AND METHODS: A retrospective review of OSCC cases treated in the institution from 2008 to 2013 was done. Sixty OSCC of buccal mucosa were selected, of which 30 were with concomitant OSF and 30 without OSF. Demographics, risk factors and clinicopathological features were studied. The data were analyzed by SPSS-20 software, using the Pearson Chi-square, Fisher's exact and Mann-Whitney U-tests. RESULTS: OSCC cases with OSF were younger (mean age 40.5 vs. 54 years) compared to those without OSF (P < 0.05). Risk factors and other clinicopathological parameters did not differ between the two groups. There was significant difference in the two groups with regard to tumor differentiation (P = 0.000). Tumors in OSCC with OSF were more likely to be well differentiated. CONCLUSION: Although majority of OSCC patients with OSF were young with a better grade of tumor differentiation, other clinicopathologic features having prognostic significance did not differ significantly between the two groups. Therefore, OSCC arising in background OSF as a distinct entity is uncertain.

Tumor necrosis factor-like weak inducer of apoptosis expression in healthy oral mucosa, oral dysplasia and oral squamous cell carcinoma.

OBJECTIVE: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of cancer, as it participates in the progression of internal malignancies. However, its role in the biology of squamous cell carcinoma (SCC) is uncertain. Studies regarding TWEAK in SCC have shown inconsistent results. We aimed to study the expression of TWEAK in healthy oral mucosa, oral dysplastic lesions and in oral SCC (OSCC). METHODS: Immunohistochemistry for TWEAK was performed on one hundred oral mucosal tissues, healthy control (HC) (n = 20), oral dysplasia (OD) (n = 20) and OSCC (n = 60). Staining intensity, extent of staining (ES) and immunoreactive Score (IRS) were assessed for each sample. Kruskal-Wallis ANOVA, Mann-Whitney U, Chi-square and Spearman's rank correlation coefficient were applied. RESULTS: TWEAK was expressed in 55% of HC, 90% of OD and in all cases of OSCC, with variable intensities. A significant difference in the ES and IRS of TWEAK was noted among the three groups. ES and IRS were highest in OSCC group. ES of TWEAK was significantly higher at invasive tumor front (ITF) than in the whole tumor, with a significant positive correlation. TWEAK expression showed a significant association with invasive front grading, pattern of invasion and surgical margins of OSCC. CONCLUSIONS: TWEAK may contribute to the progression of OSCC. It might also sustain altered differentiation, invasion and migration of tumor cells at ITF.

Pattern of invasion as a factor in determining lymph node metastasis in oral squamous cell carcinoma.

CONTEXT: Lymph node metastasis (LNM) influences survival of oral squamous cell carcinoma (OSCC). Evidence supports the value of prognostic information provided by most aggressive cells that lie in the tumor invasive front. AIMS: This study evaluated the clinical and histological parameters (C and HP) that would best associate with LNM in OSCC. SETTINGS AND DESIGN: A review of records and histological examination of nonrecurrent surgically treated 182 cases. SUBJECTS AND METHODS: A review of records and histological examination according to the Bryne's invasive front grading system of nonrecurrent surgically treated 182 cases (pN- =100; pN+ =82) was undertaken. The data were subjected to suitable statistical analysis to check the agreement between observers, association of the parameters to LNM, and to identify the best among all of them. STATISTICAL ANALYSIS USED: Kappa statistics, Pearson's Chi-square, Fisher's exact test, multiple logistic regression analysis. RESULTS: None of the C and HP, with the exception of pattern of invasion (PI) (P = 0.000), modified degree of keratinization and nuclear polymorphism (P = 0.041, 0.022), and total malignancy score for survival (P = 0.013) showed a significant association with nodal status. PI was identified as the most influencing parameter of all. CONCLUSIONS: Factor that is primarily the manifestation of tumor and its microenvironment has taken the prime seat followed by the ones that are dictated by the tumor. The factors that are basically quantified were not able to show association. Site influences the nodal status alongside PI.

Serum alkaline phosphatase in oral squamous cell carcinoma and its association with clinicopathological characteristics.

CONTEXT: Biochemical changes occur in biological fluids and tissues of different types of malignancies. Tumor markers in serum, tissue, and other body fluids during neoplastic process are of clinical value in the management of patients with cancers. Serum alkaline phosphatase (ALP) activity is potentially a useful indicator for detection of malignancies, but its status in oral squamous cell carcinoma (OSCC) is less explored. AIMS: The aim of this study is to evaluate the serum level of ALP in OSCC patients and assess its relation with the clinicopathological features. SETTINGS AND DESIGN: A total of 175 participants (145 OSCC patients and 30 healthy controls) were included in the study. One hundred and forty-five patients with OSCC who underwent treatment at our institution were included to obtain the clinicopathological data. MATERIALS AND METHODS: Fasting blood ALP activity was evaluated using ALP assessment kit and biochemistry analyzer. STATISTICAL ANALYSIS USED: The data were analyzed by SPSS-21 software (SPSS Statistics for Windows, Version 21.0, Armonk, NY, USA), using t-test, Mann-Whitney U, and Kruskal-Wallis tests. RESULTS: Raised ALP was seen in 24% of OSCC patients. The mean ALP in OSCC was significantly higher than the control. ALP level in patients with advanced stage was significantly higher than with early stage. The serum ALP level in OSCC patients with bone involvement (BI) by local extension of tumor was significantly higher than without BI. CONCLUSION: ALP showed statistically significant differences in relation to tumor stages and BI. Hence, ALP could be useful in advanced stage disease for expressing the endurance of patient and tumor expansion. Elevated ALP in OSCC patients may indicate BI.

Histological Assessment of the Carotid Sheath in Patients With Oral Squamous Cell Carcinoma.

PURPOSE: During surgical management of the neck using various types of neck dissection, the carotid sheath is removed, in particular, the part adjacent to the jugular lymph node chain, with the intention of preventing recurrence from the lymphatics present within it. The role of the carotid sheath as a potential origin for nodal recurrence has not been proved thus far. Working in a tissue plane between the carotid sheath and the neurovascular structures of the neck can lead to a greater chance of damage to these structures. Also, the carotid sheath is a strong fibroelastic tissue barrier that shields the internal jugular vein and carotid artery from saliva and local infection during the postoperative period. Thus, this study investigated the histopathology of the carotid sheath in patients with oral squamous cell carcinoma (OSCC) and assessed the pathologic infiltration of the carotid sheath when grossly uninvolved. PATIENTS AND METHODS: Pathologic infiltration and histopathologic characteristics of the entire length of the carotid sheath were assessed in 30 biopsy-proved cases of OSCC; these patients underwent surgical excision of the lesion in addition to neck dissection from 2013 to 2015 in the craniofacial unit of the authors' institution. RESULTS: The carotid sheath consisted of fibrofatty tissue and interspersed nerve bundles. Neutrophilic infiltration and dilated lymphatic channels were seen in all 30 cases. Miniature lymph nodes adherent to the carotid sheath were seen in 5 cases and some lymphoid aggregates were seen in 15 cases. The carotid sheath in all 30 cases (metastatic and nonmetastatic) was free from tumor deposit and lymphatic tumor emboli, which are indicators of tumor cell infiltration. CONCLUSION: Indicators of tumor cell infiltration were not found in any of the 30 cases. The result did not vary with the age or gender of the patient, tumor size, location, staging or grading of the tumor, or even when there were metastatic lymph nodes in the gross specimen. Hence, the role of the carotid sheath as a potential origin for nodal recurrence is questionable and its removal needs reconsideration.

Preoperative platelet lymphocyte ratio is superior to neutrophil lymphocyte ratio to be used as predictive marker for lymph node metastasis in oral squamous cell carcinoma.

OBJECTIVE: To assess whether the neutophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) before complete surgical staging will provide information on lymph node metastasis (LNM) in oral squamous cell carcinoma (OSCC) patients and to evaluate the relation of NLR and PLR with the various clinicopathologic characteristics. METHODS: The clinicopathological data and the preoperative complete blood investigation details were obtained from 68 OSCC patients who underwent surgical treatment. Receiver operating characteristics (ROC) curve analysis was used to evaluate cut-off, sensitivity, and specificity values for preoperative NLR and PLR in order to predict LNM. RESULTS: Lymph node involvement was detected in 24 (35%) patients. The best cut-off value for predicting LNM was 128.5 for the PLR, with 75% sensitivity and 70.45% specificity (P < 0.05). Fifty-five percent of patients had PLR ≤ 128.5 and 45% had PLR > 128.5. The PLR was higher in the lymph-node-positive group than in the negative group (147.63 ± 35.49 vs. 120.51 ± 42.5) (P < 0.05). There was an association between PLR cut-off and tumor stage. The best cut-off value for predicting LNM was 1.77 for NLR, with sensitivity of 87.5% and 25% specificity (P = 0.92). CONCLUSION: Preoperative PLR is directly associated with nodal involvement status of OSCC. Preoperative PLR is superior to NLR for predicting LNM in OSCC.

Assessment of ABO blood grouping and secretor status in the saliva of the patients with oral potentially malignant disorders.

BACKGROUND: Secretor status may possibly be one of the factors in the etiopathogenesis of oral precancerous lesions and subsequently cancer. Studies have shown the relationship between the pathogenesis of disease and secretor status. They have made known that secretor status is a possible factor influencing disease status. Studies have revealed the association between blood groups and specific diseases. AIMS: To assess any association of ABO blood grouping with oral potentially malignant disorders (OPMDs) and to examine whether there is any difference in the saliva secretor status in the patients with OPMDs and healthy controls. MATERIALS AND METHODS: The study consisted of 90 subjects, with 45 patients assigned to two groups (a) Patients with potentially malignant disorders and (b) healthy controls. ABO blood grouping was done and 1 ml of unstimulated saliva was collected in a sterile test tube. The Wiener agglutination test was performed to analyze the secretor status in both the groups. Chi-square test and odd ratio were used to assess the relationship between ABO blood group and OPMDs. Chi-square test was performed to assess the relationship between secretor status and OPMDs. Probability level was fixed at <0.05. RESULTS: The results demonstrated a statistically significant relation between OPMDs and secretor status (P = 0.00). Eighty-seven percent of patients with OPMDs were nonsecretors, while in the control group sixteen percent of them were nonsecretors. There was no statistically significant relationship between ABO blood groups and OPMDs (P > 0.05). CONCLUSIONS: The study confirms the inability to secrete blood group antigens in the saliva of patients with OPMDs which could be regarded as a host risk factor. Results could not propose a relationship between ABO blood group and OPMDs.

Oral pulse or hyaline ring granuloma: A case report and a brief review.

Pulse or hyaline ring granulomas are rare but are well-defined oral and extraoral lesions due to implantation of the cellulose moiety of plant foods in contrast starch components. A unique form as reactive gingival growth showing histologic features of oral pulse or hyaline ring granuloma (OPHRG) which had resulted from implantation of food particles of plant or vegetable origin into the periodontium has been illustrated. Such a presentation is attributable to compromised periodontal health and poor oral hygiene favoring the implantation of food particles has been described here along with a literature update on OPHRG.

Intraoral salivary duct carcinoma: A case report and a brief review.

Salivary duct carcinoma (SDC) is a rare, extremely aggressive malignancy arising in the ductal epithelium of the salivary glands. SDC occurs almost exclusively in the major salivary glands with parotid gland predominantly affected. Only isolated cases involving minor salivary glands have been reported in the literature. We report an unusual case of extensive SDC occupying the right cheek and the maxillary sinus, possibly arising from the minor glands of the buccal mucosa or from the mixed glands of the maxillary sinus in a 71-year-old man. The case was subjected to a panel of immunohistochemical markers like pan cytokeratin, low molecular weight cytokeratin (LMW CK), high molecular weight cytokeratin (HMW CK), CK 7, CK 20, CD 117, carcinoembryonic antigen (CEA), S-100, p63, Gross cystic disease fluid protein (GCDFP-15) and estrogen receptor (ER) to arrive at a definitive diagnosis.

Comparing the efficacy of coconut oil and xylene as a clearing agent in the histopathology laboratory.

BACKGROUND: The commonly used clearing agent, xylene is supposed to be highly toxic and carcinogenic. As previous research studies have shown the effectiveness of different vegetable oils as clearants, this study was designed to evaluate the efficacy of coconut oil. MATERIALS AND METHODS: Two equal halves of 60 soft tissue specimens were processed simultaneously in xylene and coconut oil as clearing agents. The Xylene-treated specimens (XY-S) and Coconut oil-treated specimens (CO-S) were checked for gross and histological features and comparison was done between the two groups. RESULTS: Significant shrinkage was noted in XY-S compared to that in CO-S. No difference was found in either of the sections when checked for cellular details and staining quality. Morphometrically, there was significant reduction in the mean cell area in XY-S compared to that in CO-S. CONCLUSION: Coconut oil may be substituted for the highly hazardous xylene as a clearing agent without compromising the quality of histological details.

Focal cemento-osseous dysplasia masquerading as benign cementoblastoma: A diagnostic dilemma.

CONTEXT: Focal cemento-osseous dysplasia (FCOD) is a fibro-osseous lesion that is a nonneoplastic reactive lesion. CASE REPORT: A case of 47-year-old female patient presenting with a diagnostic dilemma to the clinician is reported. Methods to achieve definitive diagnosis are discussed. CONCLUSIONS: FCOD can present with features of periapical pathology or other osseous lesions. Hence, to arrive at a definitive diagnosis biopsy and histopathologic examination is imperative.

Oral eumycetoma of infancy: a rare presentation and a brief review.

Mycetoma is a chronic granulomatous infection of skin and subcutaneous tissue, which may involve bone. The disease is caused by true fungi (eumycetoma) or filamentous bacteria (actinomycetoma). Both types of organism are important soil saprophytes, and therefore infection is normally acquired by traumatic inoculation of the skin by contaminated material. Clinically, mycetomas are characterized by tumefaction, draining sinuses and discharging grains. The grains are aggregates of fungal hyphae or bacterial filaments, and grain size, colour and consistency provide the initial clue to the causative organism. To our knowledge, this probably is the first case report of oral eumycetoma of infancy. Review of literature shows only ten cases of eumycetoma involving the head and neck, including the present case. Histological examinations of the biopsies were the cornerstone in the diagnosis of mycetoma. The distinction between eumycetoma and actinomycetoma is essential for treatment. Direct microscopic examination of the grain and histopathological examination, using histochemical staining will distinguish between the two. Treatment consists of long courses of antifungals and antibacterials agents, often combined with surgery.