Esophagitis as a complication of the combination of lenvatinib and pembrolizumab for advanced endometrial cancer: A case report.

Background: Pembrolizumab is a monoclonal antibody targeting the programmed cell death protein 1 (PD-1). It is used in the management and treatment of various oncologic conditions. To name a few: refractory and advanced melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma and gastric cancer. It is also approved for metastatic mismatch repair deficient (dMMR) endometrial carcinoma after failure of front-line chemotherapy. Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-a, RET, and KIT. The combination of lenvatinib and pembrolizumab has proven to be more effective together than as monotherapy. Here, we present the case of a patient who probably developed lenvatinib-related esophagitis, a complication not previously described in the literature to our knowledge.Case presentation.We describe a 65 years old female with metastatic endometrial cancer who presented dysphagia after a few months of lenvatinib plus pembrolizumab treatment. Upper endoscopy results revealed a very fragile upper esophageal mucosa with mucosal lacerations, consistent with grade 2 esophagitis. The biopsy showed esophagitis with mixed lymphocytic and eosinophilic inflammation and apoptotic component. Pembrolizumab was then stopped pending the results of the biopsy, following the recommendations of the gastroenterologist. Dysphagia, however, remained unchanged. In the meantime, the lenvatinib had to be stopped due to a dental procedure, and the patient noted a marked improvement in her symptoms. After discussion with the gastroenterologist, pembrolizumab was resumed and lenvatinib was suspended. The patient was also started on a PPI twice daily since the first digestive exploration. 1 month later, upper endoscopy showed complete recovery, the patient's symptoms improved, and lenvatinib was resumed. However, symptoms of dysphagia resumed a few days later. Lenvatinib was finally resumed at a reduced dose without reappearance in her symptoms. Conclusions: We present a case of oesophagitis as a likely complication of lenvatinib for advanced endometrial cancer. The initiation of PPI and dose reduction of the lenvatinib allowed the patient to successfully go back on treatment.

Epstein-Barr Virus-Associated Lymphoepithelial Carcinoma Arising in a Salivary Sebaceous Lymphadenoma.

BACKGROUND: Lymphadenomas are rare benign tumors of the major salivary glands that are further classified as sebaceous and non-sebaceous. No association with viruses has been reported so far. Little is known about the mechanisms that allow lymphadenomas to undergo malignant transformation. Among these rare instances, there has never been a malignant transformation to Epstein-Barr virus (EBV)-associated lymphoepithelial carcinoma. METHODS: Clinical data of the reported case were retrieved from the patient's electronic medical record. Hematoxylin & eosin-stained slides, immunohistochemical tests, and in situ hybridization performed for routine diagnostic purposes were reviewed. RESULTS: We report a salivary gland sebaceous lymphadenoma in which the luminal components were mostly replaced by malignant epithelial cells with markedly atypical nuclear features. Presence of EBV was demonstrated in all components by EBER. The morphological and immunohistochemical findings were consistent with a lymphoepithelial carcinoma arising from a sebaceous lymphadenoma. CONCLUSION: We report the first case of an Epstein-Barr virus-associated lymphoepithelial carcinoma arising from a sebaceous lymphadenoma.

Programmable self-regulated molecular buffers for precise sustained drug delivery.

Unlike artificial nanosystems, biological systems are ideally engineered to respond to their environment. As such, natural molecular buffers ensure precise and quantitative delivery of specific molecules through self-regulated mechanisms based on Le Chatelier's principle. Here, we apply this principle to design self-regulated nucleic acid molecular buffers for the chemotherapeutic drug doxorubicin and the antimalarial agent quinine. We show that these aptamer-based buffers can be programmed to maintain any specific desired concentration of free drug both in vitro and in vivo and enable the optimization of the chemical stability, partition coefficient, pharmacokinetics and biodistribution of the drug. These programmable buffers can be built from any polymer and should improve patient therapeutic outcome by enhancing drug activity and minimizing adverse effects and dosage frequency.

Learning curve for completely thoracoscopic anatomic sublobar resection.

BACKGROUND: Minimally invasive anatomic sublobar resection is increasingly being considered as an alternative to lobectomy in selected cases. However, this remains a technically challenging procedure and only 5 studies evaluating learning curves have been published to date. The aim of this study was to evaluate a single surgeon's learning curve for completely thoracoscopic anatomic sublobar resection. METHODS: A retrospective review was conducted of all thoracoscopic anatomic sublobar resections by one surgeon proficient in VATS lobectomy between January 2015 and January 2020. The primary outcome was operative time. Secondary outcomes were perioperative complications, duration of chest tube drainage and length of stay. RESULTS: There were 67 thoracoscopic anatomic sublobar resections performed in 66 patients. A Time-series plot and Cumulative Sum analysis of operative times showed a drop off after case 32, suggesting achievement of competency. After case 32, mean operative times were decreased (128.59±32.42 min. vs. 153.63±40.16 min, P=0.013) and there was a trend toward decreased blood loss (124.26±76.0 vs. 175.0±141.99 mL, P=0.073). A percentage 13.6% of patients had postoperative complications other than air leak and 88,9% of these were Clavien-Dindo class 1-2; postoperative complications were evenly distributed before and after case 32. Cumlulative Sum curves for the duration of chest tube drainage and length of stay did not show any significant change during the study period. CONCLUSIONS: This study suggests that for a surgeon proficient in VATS lobectomy, competency in completely thoracoscopic anatomic sublobar resection can be achieved after 32 cases and can be accomplished in a way that does not compromise perioperative outcomes.

RB1, p16, and Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma.

While P16 immunohistochemistry (IHC) is a well-established surrogate marker of Human Papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC), Retinoblastoma 1 (RB1) loss may lead to p16 overexpression in the absence of HPV. We determined the proportion of p16-positive/HPV-negative OSCC with RB1 loss and other alterations in RB1/p16 pathway, and tested RB1 IHC as a prognostic biomarker for OSCC, along with the 8th edition of AJCC staging manual. P16 and RB1 IHC and HPV DNA in situ hybridization (ISH) were performed on 257 OSCC. High risk HPV RNA ISH, RB1 fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) were done on p16-positive/HPV DNA ISH-negative OSCC. Disease free survival (DFS) was used as an endpoint. In the entire cohort and in p16-positive (n = 184) and p16-negative (n = 73) subgroups, AJCC 8th edition staging correlated with DFS (p < 0.01). RB1 IHC showed RB1 loss in p16-positive OSCC only (79/184, 43%). RB1 loss by IHC is associated with a better DFS, without providing additional prognostic information for patients with p16-positive OSCC. HPV RNA ISH was positive in 12 of 14 HPV DNA ISH-negative cases. RB1 IHC showed loss in 10 of 15 HPV DNA ISH-negative cases and in 1 of 2 HPV RNA ISH-negative cases. Overall, only one case of p16-positive/HPV RNA ISH-negative OSCC showed RB1 loss by IHC (1/184, 0.5%). Of the 10 p16-positive and HPV DNA ISH-negative cases with RB1 loss by IHC, 2 had RB1 hemizygous deletion and 3 showed Chromosome 13 monosomy by FISH. No RB1 mutations were detected by NGS. Other molecular alterations in p16-positive/HPV DNA ISH-negative cases included TP53 and TERT mutations and DDX3X loss. HPV-independent RB1 inactivation rarely results in false positive p16 IHC. RB1 inactivation by high risk HPV E7 oncoprotein may co-exist with RB1 deletion. RB1 loss is a favorable prognosticator and occurs exclusively in p16-positive OSCC. The 8th edition of the AJCC staging manual satisfactorily predicts DFS of OSCC patients.

Sebaceous Epithelial-Myoepithelial Carcinoma With Aggressive Behavior and Evidence of Preexisting Pleomorphic Adenoma.

Epithelial-myoepithelial carcinoma (EMCA) is a rare low-grade carcinoma of the salivary glands with multiple morphological variants. One such variant, sebaceous EMCA (SEMCA), has been reported in the literature. Distinguishing it from other tumors such as sebaceous carcinoma is crucial, as SEMCA typically behaves more indolently. We present a case of a SEMCA in the right parotid of a 71-year-old man that shows features of aggressive behavior such as facial nerve invasion and extraparenchymal extension. Also, we report evidence of preexisting pleomorphic adenoma within this tumor.

Heat production during pulmonary artery sealing with energy vessel-sealing devices in a swine model.

OBJECTIVES: Energy vessel-sealing devices are being increasingly utilized to seal pulmonary artery (PA) branches during lobectomy. Heat from these devices can potentially injure surrounding tissues. We evaluated heat production from devices in a live animal model. METHODS: PA branches were sealed in pigs with 4 energy vessel-sealing devices: 2 ultrasonic (US), 1 advanced bipolar or 1 mixed US and bipolar (mixed) device. Thermocouples were implanted in tissue surrounding the PA branch being sealed to measure tissue temperature. A thermal camera measured the sealing site and the temperatures of the instruments. Pathological analysis was performed on PA stumps to identify thermal damage. RESULTS: A total of 37 PA branches were sealed in 4 pigs. Maximum tissue heat measured by the thermocouples for the 2 US, advanced bipolar and mixed devices was 42, 39, 42 and 46°C, respectively. The mean tissue temperatures at the site of the sealing measured with the thermal camera were 78, 75, 70 and 82°C (P = 0.834) and the mean instrument blade temperatures were 224, 195, 83 and 170°C (P = 0.000005) for the 2 US, advanced bipolar and mixed devices, respectively. The mean diameter of the region with tissue reaching 60°C or more measured with the thermal camera was between 4 and 6 mm for the 4 devices (P = 0.941). On pathological analysis, PA stumps had either thermal damage on the adventitia and external media (26/37) or transmural damage (11/37) at 1 mm from sealed site. CONCLUSIONS: A 3-mm safety margin between the instrument blades and vital structures is recommended. Instrument blades can reach high temperatures that may cause tissue damage.

Periapical Cyst and Odontogenic Remnants on Osseous Mandibulectomy Margins: Two Diagnostic Pitfalls.

In this article, we describe 2 high-stake diagnostic pitfalls that occurred in a single patient having undergone partial glossectomy and marginal mandibulectomy for invasive squamous cell carcinoma. Margins were grossly uninvolved. Histopathology showed a moderately differentiated squamous cell carcinoma. Microscopic evaluation of margins was challenging, as the inferior osseous margin submitted en face showed spongiotic epithelium with mixed chronic and acute inflammation, representing a periapical cyst after correlation with the gross examination. Another section of the osseous margin showed a small non-atypical epithelial nest, consistent with an odontogenic epithelial rest. We wish to raise awareness of these diagnostic pitfalls as a bone margin with such epithelial foci could be misinterpreted as positive, with serious therapeutic consequences.

Measuring Depth of Invasion in Early Squamous Cell Carcinoma of the Oral Tongue: Positive Deep Margin, Extratumoral Perineural Invasion, and Other Challenges.

The 8th edition of American Joint Committee on Cancer (AJCC 8th) staging manual incorporated depth of invasion (DOI) into pT stage of oral cavity cancer. The aim of this study was to characterize several histological findings that may complicate measurement of DOI in early conventional squamous cell carcinomas (SCC) of the oral tongue: (1) lack of or minimal residual carcinoma following biopsy; (2) positive deep margin; (3) extratumoral perineural invasion (PNI); and (4) lymphatic or vascular invasion. Conventional SCC of the oral tongue (n = 407) with the largest dimension of ≤ 4 cm and with a negative elective cervical lymph node dissection (pN0) were reviewed. A clear plastic ruler was used to measure DOI by dropping a "plumb line" to the deepest point of the invasive tumor from the level of the basement membrane of the normal mucosa closest to the invasive tumor. Examples of identifying  reference point on the mucosal surface of oral tongue from which to measure the DOI are illustrated. In the experience of one contributing institution, the residual carcinoma was absent in 14.2% of glossectomies (34/239), while in 4.8% of cases (10/205) there was only minimal residual carcinoma. In 11.5% (21/183) of pT2 cases the deep margin was positive and thus DOI and pT may be underestimated. Of all cases with PNI, extratumoral PNI was identified in 23.1% (31/134) of cases, but represented the deepest point of invasion in only two cases. In one case, lymphatic invasion represented the deepest point of invasion and could have led to upstaging from pT1 to pT2. In conclusion, DOI measurement for SCC of the oral tongue may require re-examination of the diagnostic biopsy in up to 20% of cases due to the absence or only minimal residual carcinoma in glossectomy specimens. In 11.5% of apparently pT2 cases, DOI may be underestimated due to the positive deep margin. Rarely, extratumoral PNI or lymphatic invasion may be the deepest point of invasion. Overall, two issues (absent or minimal residual disease and positive deep margin) may confound DOI measurement in early SCCs of oral tongue.

Plesiomonas shigelloides: An Unusual Cause of Septic Abortion.

Plesiomonas shigelloides, the only oxidase-positive Enterobacteriaceae, is an inhabitant of freshwater and estuary ecosystems. We report the first possible case of Plesiomonas shigelloides-induced septic abortion. This 24-year-old female was successfully treated by dilatation and curettage as well as antimicrobial therapy.

Cutaneous Apocrine Carcinoma With an In Situ Component and Histiocytoid and Signet-Ring Cells.

We present a case of cutaneous apocrine carcinoma arising in the axilla of a 71-year-old man. The tumor had a significant component of histiocytoid and signet-ring cells as well as in situ carcinoma within the apocrine glands. The cells expressed GATA3, gross cystic disease fluid protein 15, androgen receptor, and E-cadherin. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 were negative. Clinical correlation was required to rule out a metastasis from the breast or the gastrointestinal tract. Although most cutaneous apocrine carcinomas do not behave aggressively, our patient developed bone metastases and eventually died of his disease. It is debated whether histiocytoid and signet-ring cell cutaneous carcinomas should be classified as apocrine neoplasm. The presence of in situ carcinoma associated with this kind of tumor has been reported only once in the literature. This characteristic and the immunohistochemical profile are in favor of apocrine differentiation.

Differences in Patient Characteristics among Men Choosing Open or Robot-Assisted Radical Prostatectomy in Contemporary Practice - Analysis of Surveillance, Epidemiology, and End Results Database.

OBJECTIVE: To examine characteristics of robot-assisted (RARP) and open radical prostatectomy (ORP) patients. PATIENTS AND METHODS: We relied on the Surveillance, Epidemiology, and End Results-Medicare-linked database and focused on prostate cancer patients between 2008 and 2009. In multivariable logistic regression analyses, we predicted RARP. RESULTS: Of 5,915 patients, 3,476 (58.8%) underwent RARP and 2,439 (41.2%) ORP. Patients within intermediate (OR 1.4, p = 0.01) or highest (OR 1.5, p = 0.02) education strata and those treated by surgeons with a high volume (OR 2.2, p < 0.001) were more likely to undergo RARP. Conversely, those residing in rural areas (OR 0.7, p = 0.005) and those with clinical stage T2 or higher (OR 0.7, p = 0.006) were less likely to undergo RARP. Additionally, patients from the Southwest were less likely to undergo RARP (OR 0.4, p < 0.001), but those from the Northern Plains were more likely to undergo RARP (OR 1.4, p = 0.02) than their counterparts from the East. Finally, RARP patients were neither younger nor healthier than ORP patients. CONCLUSIONS: Several patient characteristics such as education, region of residence and population density affect the likelihood of RARP vs. ORP treatment. Similarly, clinical stage and surgeon characteristics also affect the assignment to one or other treatment modality.

Suboptimal use of pelvic lymph node dissection: Differences in guideline adherence between robot-assisted and open radical prostatectomy.

INTRODUCTION: Our aim was to assess adherence to National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) guidelines for pelvic lymph node dissection (PLND) at the time of either robot-assisted (RARP) or open radical prostatectomy (ORP). METHODS: We relied on the Surveillance, Epidemiology, and End Results-Medicare linked database and focused on localized prostate cancer (PCa) patients who were treated with either RARP or ORP between October 2008 and December 2009. Categorical and multivariable logistic regression analyses targeted two endpoints: 1) probability of guideline-recommended PLND; and 2) probability of no PLND, when not guideline-recommended. RESULTS: Among 5268 PCa patients, adherence to NCCN PLND guideline was 56.9% during RARP and 76.5% during ORP (odds ratio [OR] 0.4, 95% confidence interval [CI] 0.3‒0.6). AUA PLND guideline adherence was 68.1% during RARP and 82.4% during ORP (OR 0.7, 95% CI 0.5‒0.9). When PLND was not recommended, it was more frequently performed during ORP according to either NCCN (OR 3.7, 95% CI 3.5‒3.9) or AUA (OR 2.7, 95% CI 2.6‒2.8). According to the NCCN guideline, at recommended PLND in ORP patients, 6.3% harboured lymph node invasion (LNI) (number needed to treat [NNT] 16) vs. 3.2% at RARP (NNT 31). According to the AUA guideline, at recommended PLND in ORP patients, 12.3% harboured LNI (NNT 8) vs. 5.1% RARP (NNT 19). CONCLUSIONS: Adherence to NCCN and AUA PLND guidelines was lower during RARP than during ORP when PLND was recommended. The rate of non-recommended PLND was also higher during ORP than during RARP. Technical considerations may be at play.

Pulmonary Artery Sealing With an Ultrasonic Energy Device in Video-Assisted Thoracoscopic Surgery Lobectomy: An Animal Survival Study.

BACKGROUND: Pulmonary artery (PA) sealing in video-assisted thoracoscopic surgery (VATS) lobectomy is typically accomplished using vascular endostaplers. Endostaplers may be associated with iatrogenic PA branch injury, especially in short, small PA branches. We evaluated PA branch sealing with the HARMONIC ACE +7 (ACE) shears (Ethicon, Cincinnati, OH) in VATS lobectomy in a canine survival model. METHODS: Ten adult dogs underwent VATS lobectomy. Standard VATS lobectomy operative technique was used for the entire operation, except for PA branch sealing. The ACE was used for all PA branch sealing. Dogs were kept alive for 30 days. RESULTS: The 10 dogs underwent VATS right upper (n = 5) and right lower (n = 5) lobectomy. The ACE was used to seal 21 PA branches. No PA branch was divided with an endostapler. There were no intraoperative complications or conversions to thoracotomy. Mean in vivo PA diameter was 5.6 mm (range, 2 to 12 mm). One 10-mm PA branch had a partial seal failure immediately at the time of sealing. The device was reapplied on the stump, and the PA branch was successfully sealed. All dogs survived 30 days without hemothorax. Necropsy at 30 days did not reveal any signs of postoperative bleeding. Pathology of the sealed PA branches at 30 days revealed fibrosis, giant cell reaction, neovascularization, and thermal changes of the vessel wall. CONCLUSIONS: The use of the ACE for PA branch sealing in VATS lobectomy is safe and effective in an animal survival model. Human studies are needed to determine the clinical safety of ultrasonic PA branch sealing before widespread clinical use.

Spindle Cell Epithelioma of the Vagina: Report of Two Cases, Literature Review, and New Immunohistochemical Markers.

Spindle cell epitheliomas of the vagina are rare benign tumors of uncertain histogenesis. It has been hypothesized that they originate from a pluripotent cell population. Here, we report 2 cases of spindle cell epitheliomas of the vagina. Both patients presented with a painless vaginal nodule. The resected lesions were solid, well circumscribed, and composed of a proliferation of epithelioid or epithelial cells admixed with spindle cells without atypia. The 2 cellular populations expressed epithelial and mesenchymal markers. Based on these morphologic and immunohistochemical findings, a diagnosis of spindle cell epithelioma was rendered in both cases. Furthermore, we describe for the first time the expression of WT-1 (Wilms' tumor protein 1) and calretinin in addition to the previously defined immunohistochemical profile.

BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs.

BACKGROUND: Axolotls have the unique ability, among vertebrates, to perfectly regenerate complex body parts, such as limbs, after amputation. In addition, axolotls pattern developing and regenerating autopods from the anterior to posterior axis instead of posterior to anterior like all tetrapods studied to date. Sonic hedgehog is important in establishing this anterior-posterior axis of limbs in all tetrapods including axolotls. Interestingly, its expression is conserved (to the posterior side of limb buds and blastemas) in axolotl limbs as in other tetrapods. It has been suggested that BMP-2 may be the secondary mediator of sonic hedgehog, although there is mounting evidence to the contrary in mice. Since BMP-2 expression is on the anterior portion of developing and regenerating limbs prior to digit patterning, opposite to the expression of sonic hedgehog, we examined whether BMP-2 expression was dependent on sonic hedgehog signaling and whether it affects patterning of the autopod during regeneration. RESULTS: The expression of BMP-2 and SOX-9 in developing and regenerating axolotl limbs corresponded to the first digits forming in the anterior portion of the autopods. The inhibition of sonic hedgehog signaling with cyclopamine caused hypomorphic limbs (during development and regeneration) but did not affect the expression of BMP-2 and SOX-9. Overexpression of BMP-2 in regenerating limbs caused a loss of digits. Overexpression of Noggin (BMP inhibitor) in regenerating limbs also resulted in a loss of digits. Histological analysis indicated that the loss due to BMP-2 overexpression was the result of increased cell condensation and apoptosis while the loss caused by Noggin was due to a decrease in cell division. CONCLUSION: The expression of BMP-2 and its target SOX-9 was independent of sonic hedgehog signaling in developing and regenerating limbs. Their expression correlated with chondrogenesis and the appearance of skeletal elements has described in other tetrapods. Overexpression of BMP-2 did not cause the formation of extra digits, which is consistent with the hypothesis that it is not the secondary signal of sonic hedgehog. However, it did cause the formation of hypomorphic limbs as a result of increased cellular condensation and apoptosis. Taken together, these results suggest that BMP-2 does not have a direct role in patterning regenerating limbs but may be important to trigger condensation prior to ossification and to mediate apoptosis.