Keeney, Michael G.

ABSTRACT Purpose We studied histologic Ewing sarcoma (ES) tumor response at local control surgery to explore associations between histologic response and chemotherapy practice changes over time and confirm its prognostic significance in the modern era. Methods We reviewed clinical data for 126 patients with ES treated at Mayo Clinic from 1977 to 2022, analyzing the percentage necrosis as a prognostic factor across chemotherapy regimens (including modern interval‐compressed VDC‐IE). Results In the historical cohort, 5‐year event‐free survival (EFS) and overall survival (OS) for patients with ≤5% versus greater than 5% viable tumor were 76% versus 59% ( p = 0.01) and 83% versus 62% ( p = 0.01). Review of 104 specimens by two pathologists identified the percentage remaining viable tumor as more reproducible than the percentage necrosis and/or fibrosis. On multivariable analysis of patients with localized disease ( n = 87), pelvic tumors and greater than 5% viable tumor remained independent risk factors for poor survival (EFS: hazard ratio [HR] 3.1, p < 0.01; OS: HR 2.1, p = 0.048). The modern cohort consisted of 22 patients. No patients with tumor size less than 8 cm at diagnosis and 100% necrosis after surgery had events; four of seven with tumors greater than 8 cm had events despite 100% necrosis. Conclusions Our results validate the historical threshold of greater than 5% viable tumor with older chemotherapy regimens but not with modern interval‐compressed VDC‐IE. In addition, inter‐rater reliability for the percentage viable is more reproducible than the percentage necrosis. Although numbers are small, tumors less than 8 cm with no viable tumor appear to be a favorable subgroup and suggest risk stratification using a combination of tumor size and any viable tumor should be evaluated in ES.

Background and ObjectivesAdenoid cystic carcinoma (ACC) is a rare, typically triple‐negative, breast cancer reported to have a favorable prognosis and low rate of nodal metastasis. No consensus guidelines exist for axillary staging and treatment.MethodsWe identified all patients with ACC evaluated at our institution from January 1994 to August 2016. Patient, tumor, and treatment variables were abstracted and analyzed.ResultsWe identified 20 pure ACCs (0.13% of all invasive breast cancers) with size range 0.2‐4.8 cm, in 19 women, median age 59 years. Preoperative axillary ultrasound was normal in 10/13 women and suspicious in 3/13 who had a subsequent negative lymph node fine needle aspiration (FNA). Fifteen patients (75%) had sentinel lymph node surgery and were pathologically node‐negative, while the remaining five had no axillary surgery. With 3.6 years median follow‐up (range 0.2‐38.6 years), three patients experienced an in‐breast recurrence at 2, 16, and 17 years, respectively, while none recurred in regional nodes.ConclusionsWe observed no cases of nodal metastasis in 20 consecutive cases of ACC of the breast. Preoperative axillary ultrasound with FNA of suspicious nodes accurately predicted pathologic nodal stage. These data suggest axillary surgery might be omitted safely in patients with pure ACC and a clinically negative axilla.

Background and ObjectivesCurrent randomized controlled trials are investigating the outcomes of non‐surgical treatment for patients with ductal carcinoma in situ (DCIS). We sought to evaluate pre‐operative factors associated with no residual disease at definitive resection following a core needle biopsy (CNB) diagnosis of DCIS.MethodsEight hundred and thirty‐four operations for DCIS were performed at our institution between January 2004 and October 2014. We evaluated patient and biopsy tumor characteristics to determine pre‐operative factors associated with no residual disease at surgical resection using uni‐ and multivariable analyses.ResultsSixty‐nine patients (8%) had no residual disease on final pathology. On multivariable analysis, low‐ or intermediate‐grade lesions, <1 cm in size on mammography, and lesions where ≥90% of calcifications were removed correlated with finding no residual disease on final pathology, c‐statistic 0.84. Of the 14 patients with all three low‐risk factors, 36% had no residual disease on final pathology.ConclusionsAlthough our multivariable analysis performed well, its clinical utility would be limited as we were unable to identify a subset of patients with DCIS in whom the probability of finding no residual disease is low enough to consider routine use of non‐surgical management.

ObjectiveHuman adipose‐derived mesenchymal stem cells (ADSCs) were used to rehabilitate bone damaged by osteoradionecrosis (ORN) in an established animal model.Study DesignProspective animal study.SettingAcademic department laboratory.Subjects and MethodsAfter institutional review board and Institutional Animal Care and Use Committee approval, 24 athymic nude rats were divided into 5 groups: 4 groups irradiated (20 Gy) by brachytherapy catheter placed at the left hemimandible and 1 mock irradiation control (n = 4). For all groups, ORN was initiated by extraction of the central molar 1 week later. After 28 days, animals (n = 5/group) received injection at the extraction site with saline (SAL), ADSCs, platelet‐rich plasma and collagen (PRP/COL), or ADSCs + PRP/COL. Rats were sacrificed 28 days later and their mandibles harvested for histopathology analysis (osteoblasts, osteoclasts, and fibrosis) and bone volume measurement using 3‐dimensional micro–computed tomography.ResultsAll but 1 rat survived the experiment period (23/24). Radiographic and histological analysis revealed 60% bone loss in the SAL group compared with the nonirradiated control. Injection of ADSCs increased jaw region bone volume by up to 36% (P <. 01). All experimental groups (ADSC, PRP/COL, and ADSC + PRP/COL) showed dramatically decreased osteoclast counts (P <. 001) while injection of PRP/COL with or without ADSCs increased osteoblasts. Increased fibrosis was observed after ADSC injection (P <. 05).ConclusionThe application of human ADSCs to an induced mandibular osteoradionecrosis model in athymic rats results in increased deposition or preservation of bone, demonstrated both histologically and radiographically. This offers an encouraging possible treatment option for translational research in this difficult disease.

ObjectiveWe aim to create a model of mandibular osteoradionecrosis in athymic rats. Athymic rats provide an immunosuppressed environment whereby human stem cells and biomaterials can be used to investigate regenerative solutions for osteoradionecrosis, bridging the gap between in vivo testing and clinical application.Study DesignProspective animal study.SettingAcademic otolaryngology department laboratory.Subjects and MethodsAfter Institutional Animal Care and Use Committee approval, 10 athymic nude rats were divided into 2 groups. The experimental group (n = 6) underwent irradiation (20 Gy), while the control group (n = 4) underwent sham irradiation catheter placement only. All 10 rats underwent extraction of the second mandibular molar 7 days later. The rats were sacrificed 28 days after dental extraction, and their mandibles were harvested. The mandibles were examined with histologic analysis and bone volume analysis based on 3‐dimensional micro–computed tomography.ResultsAll 10 rats survived the experiment period. Radiographic and histologic analysis revealed decreased bone formation in the experimental group compared with the control group. Jaw region volume ratio was 0.83 for the experimental group versus 0.97 in the control group (P =. 003). The region‐of‐interest volume ratio was 0.75 in the experimental group and 0.97 in the control group (P =. 005). Histologically, there were increased osteoclasts (P =. 02) and decreased osteoblasts (P =. 001) as well as increased fibrosis in the experimental group versus the control group.ConclusionMandibular osteoradionecrosis can be effectively and reproducibly produced in an athymic rat model. This will allow further research to study regenerative medicine in an athymic rat model.

ObjectiveAssess human papilloma virus (HPV) transcriptional activity in inverted Schneiderian papillomas (IPs).Study DesignCase series with chart review.SettingAcademic tertiary care center.Subjects and MethodsRetrospective clinicopathologic review of 19 cases of IP in patients undergoing surgical excision from 1995 to 2013 at Mayo Clinic in Rochester, Minnesota. Surgical pathology archival material was histopathologically reviewed using hematoxylin and eosin–stained slides. Formalin‐fixed, paraffin‐embedded material from each case was evaluated for p16 expression using immunohistochemistry as well as HPV DNA and E6/E7 messenger RNA (mRNA) transcription using polymerase chain reaction (PCR) and in situ hybridization (via RNAscope technology), respectively.ResultsEight patients were female (42%), with an average age of 53 years (range, 23‐82 years). Three demonstrated malignancy, and 5 subsequently recurred. Average follow‐up was 49 months (range, 0‐200 months), and 1 patient died from squamous cell carcinoma arising from the IP. RNAscope detected HPV mRNA transcripts exclusively within IP in 100% of cases; however, in 11 patients (58%), less than 1% of cells exhibited transcriptional activity. Only 2 of 19 cases (11%) demonstrated mRNA activity in 50% or more cells. HPV DNA was detected in only 2 specimens by PCR.ConclusionsThis study reveals wide prevalence but limited transcriptional activity of HPV in IP. No correlation between HPV transcriptional activity and progression, recurrence, or malignant transformation was identified. These data suggest that transcription of HPV may contribute to the pathogenesis of IP, but prospective data are needed to definitively demonstrate this connection. These results also suggest that RNAscope may be more sensitive than PCR in detecting HPV activity in IP.