Faculty Bibliography

There is no consensus on the true meaning of clinical regenerative endodontics, and there is confusion over the concept and the term. Commonly used terms include revitalization and revascularization. The clinical methods for endodontic revitalization procedures and the tissue engineering concept differ depending on whether there is exogenous delivery of cells - called cell therapy, or not. Here, in this review, the difference is clarified by emphasizing the correct terminology: cell-free versus cell-based regenerative endodontic therapy (CF-RET versus CB-RET). The revitalization procedures practised clinically do not fit into the modern tissue engineering concepts of pulp regeneration but can be categorized as CF-RET. The modern tissue engineering concept in pulp regeneration is a CB-RET, which so far is at the clinical trial stage. However, histological examination of teeth following regenerative endodontic treatments reveals healing with repair derived from stem cells that originate from the periodontal, bone and other tissues. The aim of regenerative endodontics is regeneration of the pulp-dentine complex. This review discusses why CF-RET is unlikely to regenerate a pulp-dentine complex with current protocols. The American Association of Endodontists and the European Society of Endodontology have not yet recommended autologous stem cell transplantation (CB-RERT) which aspires for regeneration. Therefore, an understanding of the concept, term, difficulties and differences in current protocols is important for the clinician. However, rather than being discouraged that ideal regeneration has not been achieved to date, repair can be an acceptable outcome in clinical regenerative endodontics as it has also been accepted in medicine. Repair should also be considered in the context that resolution of the clinical signs/symptoms of pulp necrosis/apical periodontitis is generally reliably obtained in clinical regenerative endodontics.

Background: Gender affirming surgery is part of a multidisciplinary approach in the gender transition process, allowing patients to align their physical anatomy to their internal sense of identity. Our study evaluates the cytology and histopathology of transmasculine gynecological specimens. A deeper examination of the pathologic findings may strengthen care for transmasculine individuals and increase our understanding of the influence of hormonal therapy in specific organs.
Design(s): This is an IRB-approved retrospective study that included all transmasculine individuals undergoing a gender-affirming gynecological surgery from January 2015 to June 2020. All surgical pathology and cytology slides were reviewed. Clinical data were retrieved from electronic health records.
Result(s): Forty patients were identified with a median age of 26.5 years (range 17-56) and a median body mass index of 25.38 kg/m2 (range 18.9 - 43.4). The majority of patients were white (52%), were receiving androgen therapy for at least 6 months (95%) and had a previous bilateral mastectomy (92%). The histologic samples comprised of 40 uteri, 40 bilateral fallopian tubes and 36 bilateral ovaries. The overall findings are summarized in table 1. The majority of the endometria were inactive (75%) with significant stromal fibrosis (80%). Some patients showed evidence of cycling endometrium with proliferative (17.5%) and secretory (7.5%) patterns. The most common findings in the ovaries were the presence of multiple bilateral cystic follicles (50%), stromal hyperplasia (14%) and of corpora lutea (14%). The most common findings in the cervix was transitional metaplasia (42.5%). Of the 8 available cervical cytology specimens, 2 were unsatisfactory, 4 were negative for intraepithelial lesion or malignancy and 2 had atypical squamous cells of undetermined significance (ASC-US).
Conclusion(s): Despite prolonged use of androgens, endometria in transmasculine individuals may show cycling activity with proliferative and secretory patterns. The presence of multiple bilateral cystic ovarian follicles provides evidence that androgens can result in abnormal follicular development, similar to polycystic ovary syndrome. The chronic use of androgens in young individuals seems to induce transitional metaplasia in the cervix, which can impact cervical cytology results including increase the percentage of unsatisfactory samples and ASC-US and has the potential to mimic high-grade squamous dysplasia

Background: Clear cell carcinoma of ovary (CCCO) accounts for 5-25% of ovarian carcinomas. Considered a high-grade malignancy by default, the role of histological grading for assessing clinical outcome is not established in CCCO. We aimed to evaluate histopathological features predictive of clinical outcome in patients with CCCO.
Design(s): Pathology database was searched after IRB approval. A total of 69 cases of CCCO were studied. Slides from primary tumor resection were reviewed blinded to outcome. The original diagnosis of CCCO was confirmed and the following histopathologic features were recorded: percentage of solid component, degree of nuclear atypia, mitotic activity, intratumoral inflammation, presence of small tumor nests (intratumoral single cells or clusters of <5 cells in non-hyalinized stroma, Figure 1A-B), tumor budding (peritumoral single cells or clusters of <5 cells), lymph node involvement and endometriosis. Information regarding age at diagnosis, clinical stage, treatment and followup was obtained from medical charts. Kaplan-Meier survival curves with log rank test, Fisher's exact test and Mann-Whitney test were used for statistical analysis.
Result(s): Median patient age was 52 years (range 26-75 years). Forty-nine (71%) tumors were associated with endometriosis and 37 (53%) presented at stage I. Ten (15%) patients died of disease, 14 (20%) were alive with active disease and 45 (65%) had no evidence of disease at last follow-up (median follow-up: 34.2 months, range 1.2 - 230.6). Advanced stage, positive lymph nodes and presence of small tumor nests were significantly associated with shorter overall survival (p=0.006, p<0.001, p=0.004, respectively; Figure 2A-C) and recurrence/progression despite treatment (p<0.0001, p=0.0011, p=0.0003, respectively; table 1). Also, within the cohort of low stage patients (stage I and II), presence of small tumor nests was associated with recurrence/disease progression (p=0.0014; table 1). None of the other studied features reached statistical significance for assessment of prognosis.
Conclusion(s): Besides the classic prognostic factors of stage and lymph node status, presence of small tumor nests seems to be associated with poorer outcome in patients with CCCO. Specifically, in patients with early stage disease, evaluation of small tumor nests may help to better determine prognosis. These findings should be further evaluated in larger studies

Background: In addition to respiratory distress, GI symptoms have been reported in COVID-19 patients at various stages of the disease. Among the GI symptoms that have been reported, diarrhea, nausea, vomiting, abdominal pain and GI bleeding were often seen. Age and comorbid conditions such as obesity, HTN, DM and/or CAD have been considered as risk factors for COVID-19 patients for severe disease. GI manifestations in COVID-19 patients appeared to act as a sign for a serious condition. The virus has been identified in the stool and in rectal swabs of some infected patients, even after a negative nasopharyngeal test. There is a lack of reports on pathological alterations of the GI tract in COVID-19 infected patients.
Design(s): 16 PCR confirmed COVID-19 patients (11 males and 5 females) were included in the study. Biopsy or resection specimens were taken from the esophagus (4), stomach (6), small intestine (5), appendix (3), colon (5) and gallbladder (3). Clinical information including demographics, comorbidities, GI symptoms, related laboratory tests were collected. Histopathologic evaluation was performed and correlated with clinical properties.
Result(s): The age of the patients ranged from 10 to 84 years old, with an average of 47 years. Eight (50%) patients had at least one comorbid condition, two patients (12.5%) had prior history of cancer, and six patients had no significant medical history. Abdominal pain and GI bleeding were the most common presenting symptoms. Histologically, acute and chronic inflammation was seen in 14 of 16, and 15 of 16 cases, respectively. Eight cases showed severe acute inflammation with ulceration. The mucosal changes included nonspecific reactive change, hypermucinous, atrophic/ischemic changes, and necrosis, were indiscriminately noticed in these cases. Four cases showed intraepithelial lymphocytosis. Viral like inclusions were found in four cases. Microthrombi were identified in 5 cases with an average patient age of 60 years. Notably, microthrombi were seen in about 5 out of 8 (62%) patients with comorbidities. The patients with microthrombi had a higher D dimer test value than those without thrombus. Three patients died shortly after operation, and two of them showed microthrombi in the tissue specimens.
Conclusion(s): Acute and chronic inflammation were indiscriminately seen in these cases. Microthrombi were dominantly found in aging patients with comorbidities, suggesting microthrombi in the GI tract may be a histologic indication for severe COVID-19 patients with GI symptoms

Background: Digestive symptoms are often seen in COVID-19 patients with poor outcomes. The Viral RNA is mostly positive in the stool of these patients, and has a longer delay before viral clearance. However, its diagnostic value and significance for guiding clinical treatment remain unknown. And the pathologic alterations in the GI tract in COVID-19 patients have not been well defined. We evaluated rectal swab SAS-CoV-2 test and histopathologic changes in the small intestine in autopsy patients.
Design(s): 18 autopsy cases with confirmed SAS-CoV2 infection were included. Nasal, bronchial, and rectal swab SARS-CoV-2 PCR were performed at the time of autopsy. Clinical information included demographics, comorbidities, presenting symptoms, related laboratory tests were collected. Histopathologic evaluation was performed and correlated with clinical properties.
Result(s): 83% (15/18) of patients were male. Median age is 50 years. 7/18 (38.9%) patients had diarrhea in addition to cough, fever and other symptoms. Except in one case, all patients had underlying comorbidities of diabetes, hypertension and /or obesity. In the small intestine, acute inflammation was not seen in any cases. 5/18 displayed mild and one showed moderate chronic inflammation. Hypermucinous change was found in six patients but not associated with diarrhea. 3 cases had microthrombi identified in the sections. Notably, obviously increased D dimer in lab tests were noticed in all patients. Postmortem 17/17 (100%) nasal, 18/18 (100%) bronchial and 7/16 (43.8%) rectal swabs showed SARS-CoV-2 PCR positivity. 3 of 7 (42.9%) patients with diarrhea are positive in rectal swab for SARS-CoV-2.
Conclusion(s): There are no specific COVID-19 changes in the small intestine. More investigations are needed, especially on tissues from different locations of the GI tract. Data from rectal swab testing suggests that it is not ideal for diagnosing COVID-19, guiding treatment, or predicting small intestinal pathology

External root resorption (ERR) is often a complication of traumatic injury to the teeth. Traditionally, external inflammatory root resorption is treated with calcium hydroxide. The outcome of ERR, especially replacement resorption, is unpredictable. The purpose of the present case report was to describe regenerative endodontic procedures (REPs) for 1 replanted avulsed tooth with severe external root resorption and root perforation (tooth #9) and 1 extruded tooth (tooth #8). A 9-year-old girl was referred for the treatment of teeth #8 and #9 4 months after the initial trauma. Clinical examination showed that tooth #9 had a sinus tract present near the periapical area, was tender to percussion and palpation, and did not respond to pulp sensibility tests. Tooth #8 responded to pulp sensibility tests. Periapical radiographic and cone-beam computed tomographic examination showed that tooth #9 had a periapical radiolucent lesion and severe ERRs with a root perforation. Tooth #9 was diagnosed with a necrotic pulp and symptomatic apical periodontitis. Regenerative endodontic procedures (REPs) were initiated. Tooth #8 became nonresponsive to pulp sensibility tests and developed a periapical lesion 12 months after REPs of tooth #9 and was also treated with REPs. The clinical symptoms and apical lesions resolved for both teeth after REPs. The severe ERRs were arrested, and root perforation was repaired for tooth #9. Teeth #8 and #9 underwent canal obliteration by hard tissue formation after REPs and were in function at 18 months and 30 months, respectively. REPs may be used to manage traumatized immature permanent teeth with a necrotic pulp and apical periodontitis associated with severe ERR and root perforation.

Background Potent antivirals can reduce HCC incidence in CHB. TDF and TAF are first-line treatments, and in Phase 3 studies through 3 years, TAF has shown antiviral efficacy similar to TDF, higher rates of ALT normalization, and no resistance. We evaluated HCC incidence in patients participating in these ongoing studies. Methods HBeAg-positive (n=1039) and -negative (n=593) patients with HBV DNA 20,000 IU/mL and ALT >60 U/L (males) or >38 U/L (females) were randomized (2:1) to TAF 25 mg QD or TDF 300 mg QD for up to 3 years, followed by open-label TAF through Year 8. Patients with hepatic decompensation, co-infection with HCV/HDV/HIV, or evidence of HCC were excluded. HCC was assessed at 6 monthly intervals by hepatic ultrasonography beginning after Week 96 and by local standards of care. The standardized incidence ratio (SIR) for HCC was calculated for observed cases relative to predicted cases using the REACH-B model. Results 1632 patients were followed for up to 4 years; HCC was seen in 16 patients (0.98%; 7 TAF; 9 TDF); median time to onset was 568 days. At baseline HCC patients were older (median age 53 vs 40 y; p<0.001), had lower median HBV DNA (6.2 vs 7.3 log10 IU/mL; p=0.041) and were more likely to have cirrhosis (FibroTest score 0.75; 31% vs 10%; p=0.004). For study patients, the overall SIR was significantly reduced with TAF or TDF treatment 0.45 (95% CI 0.278 -0.740) (table 1). HCC incidence was significantly reduced (SIR 0.42, 95% CI 0.23 to 0.75) in noncirrhotic patients (n=11 vs 26.5 predicted), but not for cirrhotic patients (n=5 vs 8.1 predicted). The SIR was significantly reduced in noncirrhotic patients receiving TAF (n=5), but not in those with TDF (n=6). Conclusions In CHB patients treated with TAF or TDF for up to 4 years, HCC incidence was reduced, particularly in noncirrhotic patients. Additional follow up is needed to further characterize the impact of longer-term treatment on HCC risk reduction

The American Association of Endodontists (AAE) Consensus Conference Recommended Diagnostic Terminology states that mature permanent teeth clinically diagnosed with irreversible pulpitis are treated with pulpectomy and root canal filling because inflamed vital pulp is not capable of healing. Histological studies have demonstrated that clinically diagnosed irreversible pulpitis does not involve the entire pulp. A recent International Endodontic Journal Editorial suggested clinical diagnosis of pulp disease should be reassessed because of the poor correlation between clinical symptoms and pulp sensibility testing and the actual histological status of the pulp. This review identified studies in a PubMed search that provide evidence for vital pulp therapy (VPT) of mature permanent teeth with irreversible pulpitis is predictable if correctly diagnosed and properly treated. A narrative review was undertaken to outline the correlation between the clinical symptoms/signs and pulp sensibility testing and the histological findings of the pulp. Treatment procedures for permanent teeth are outlined.

The current American Association of Endodontists clinical considerations for a regenerative endodontic procedure state that a regenerative procedure is suitable for immature permanent teeth with necrotic pulp when the pulp space is not needed for a post/core in the final restoration. Therefore, many immature permanent teeth with necrotic pulp that have sustained a substantial loss of coronal tooth structure either from caries or trauma are treated by apexification or mineral trioxide aggregate/Biodentine (Septodent, Lancaster, PA) apical barrier techniques in which no further root maturation would occur. This case series presents 10 immature permanent teeth with necrotic pulp in which a post/core was likely required in the future for adequate coronal restoration because of loss of substantial coronal tooth structure and a modified apexification procedure was used. All 10 cases after the modified apexification procedure showed no clinical symptoms/signs and showed radiographic evidence of healed/healing of periapical lesion after a 2-year review. Eight cases showed increased thickness of the apical root canal walls, increased apical root length, and apical closure. The overall percentage change in root length was 7.52%, in root width at the apical one third it was 18.89%, and in radiographic root area it was 15.04% at the 24- to 72-month follow-up period. This modified apexification procedure allows for the tooth to be restored with a post/core if required for the final restoration in the future as well as continued root development.

Three immature permanent teeth with pulp necrosis and apical periodontitis were treated with regenerative endodontic therapy (RET), which included root canal disinfection with sodium hypochlorite irrigation, intra-canal medication with calcium hydroxide paste, 17% EDTA rinse, induction of periapical bleeding into the canal, collagen matrix and MTA coronal seal, and composite resin restoration of access cavities. After different periods of follow-up, it was observed that continued root maturation, especially apical closure occurred despite persistent apical periodontitis of immature permanent teeth after failed RET. This finding is of interest as the secondary goal of further root maturation occurred despite failure of the primary goal of elimination of clinical symptom/sign and periapical inflammation. The possible biological mechanisms that could allow for further root maturation to occur in spite of persistent root canal infection of immature permanent teeth are discussed. Based on these observations, the biology of wound healing of immature permanent teeth after injury is not fully understood and should be further investigated. This case report demonstrates that whilst further root maturation is considered a successful outcome for teeth treated with RET, the primary objective must be the resolution of the signs and symptoms of apical periodontitis.