Cystic Features in Renal Epithelial Neoplasms and Their Increasing Clinical and Pathologic Significance.

Most cystic renal tumors after resection (Boniak IIF to IV cysts) have an indolent course despite the significantly higher proportion of malignant [ie, renal cell carcinoma (RCC)] diagnosis. Most cystic renal tumors have clear cell histology that include cystic clear cell RCC and multilocular cystic renal neoplasm of low malignant potential (MCNLMP). There is growing evidence to suggest that MCNLMP, cystic clear cell RCC, and noncystic clear cell RCC form a cystic-to-solid biological spectrum with MCNLMP representing the most indolent form and with cystic clear cell RCC behaving better than noncystic (solid) clear cell RCC. Extensively (>75%) cystic clear cell RCC also has an excellent outcome similar to MCNLMP stressing the need to reevaluate the histologic criteria that separate these 2 cystic clear cell tumors. Other tumors with clear cells that can be extensively cystic such as the recently reclassified noncancerous clear cell papillary renal tumor and the newly described MED15::TFE3 RCC also have indolent course and may mimic MCNLMP. Cystic features occur also in renal tumors with nonclear cell histology including tumors capable of metastasis such as acquired cystic disease-associated, tubulocystic, fumarate hydratase-deficient, and eosinophilic solid and cystic RCCs. Cystic imaging presentation of some renal tumors such as papillary RCC can be attributed in part to pseudocystic necrosis and hemorrhage. It is important to know that tubulocystic RCC may have a lower Bosniak class presentation that overlaps with benign renal cysts (Bosniak I to IIF) that are managed conservatively. This review highlights the cystic renal tumors with clear cell and nonclear cell morphologies including some novel RCC subtypes that may have cystic features. The presence of cystic features and their extent may aid in the classification and prognostication of renal neoplasms underscoring its increasing importance in the pathologic diagnosis and reporting of renal neoplasia.

Risk Factors of Vasopressor-Induced Symmetrical Peripheral Gangrene.

BACKGROUND: Symmetrical peripheral gangrene (SPG) is an uncommon syndrome showing symmetrical gangrene in acral regions without evidence of large-vessel occlusion or vasculitis. Intravenous vasopressors are frequently used to manage hemodynamically unstable patients. There have been few reports about SPG after using inotropics. However, risk factors for SPG have not been extensively studied. Therefore, the objective of this study was to analyze several cases of SPG and identify risk factors for SPG. METHODS: From October 2013 to October 2016, 36 patients with SPG after using vasopressors were included in this study. SPG is an extremely rare disease entity. Therefore, this work was designed as a matched case-control study. For the control group, 42 patients (25 men and 17 women) with similar age, admission department, sex, and vasopressor usage in intensive care unit patients during the same period were selected. Retrospective chart review was performed to identify risk factors within the following categories: medical conditions, vasopressor-related factors, and Sequential Organ Failure Assessment scores. RESULTS: Differences between the 2 groups concerning medical condition-related variables did not exist. Statistically significant differences were found in intensive care unit duration (P = 0.0011) and survival. All vasopressor-related factors were adjusted according to weights of patients. Weight-compensated mean dose of dopamin significantly (P = 0.028) affected the occurrence of SPG. Weight-compensated peak dose of norpin, dopamin, and epinephrine also significantly contributed to SPG. CONCLUSIONS: Symmetrical peripheral gangrene is a rare clinical syndrome related with a high mortality and up to 70% of patients who survive require amputation. Several studies have mentioned that there are several factors affecting the result of SPG. Few studies on SPG have been reported and most of them are case reports. In this study, we revealed the influence of vasopressors to the occurrence of SPG, and this was the first matched case-control study based on the analysis of multiple risk factors.

Analysis of Malpractice Claims Associated with Surgical Site Infection in the Field of Plastic Surgery.

Postoperative infections are rare after plastic surgery; however, when present, they can affect the aesthetic outcome. Currently, many malpractice lawsuits are associated with surgical site infection. The present study aimed to analyze malpractice claims associated with surgical site infection in the field of plastic surgery through a review of Korean precedents. We analyzed the type of procedure, associated complications, and legal judgment in these cases. Most claimants were women, and claims were most often related to breast surgery. The common complications related to surgical site infection were deformity, scar, and asymmetry. Among the 40 cases, 34 were won by the plaintiff, and the mean claim settlement was 2,832,654 KRW (USD 2,636.6). The reasons for these judgements were as follows: 1) immediate bacterial culture tests were not performed and appropriate antibiotics were not used; 2) patients were not transferred to a high-level hospital or the infection control department was not consulted; 3) surgical site infection control measures were not appropriate; and 4) surgical procedures were performed without preoperative explanation about surgical site infection. The number of claims owing to surgical site infection after surgery is increasing. Infection handling was one of the key factors that influenced the judgement, and preoperative explanation about the possibility of infection is important. The findings will help surgeons achieve high patient satisfaction and reduce liability concerns.

Expression and function of transcription factor AP-2? in early embryonic development of porcine parthenotes.

Transcription factor AP-2? (TFAP2C) is a member of the transcription factor activating enhancer binding protein (AP) family. In the present study we determined the temporal and spatial expression patterns of TFAP2C in porcine parthenotes during preimplantation development. Porcine TFAP2C transcripts were expressed at all stages of preimplantation development, with highest expression at the 8-cell stage. In contrast with the mouse, TFAP2C protein was not restricted to the trophectoderm and was also detected in the ICM in blastocyst stage porcine parthenotes. In knockdown (KD) experiments, most TFAP2C-depleted embryos were arrested before the compacted 8-cell stage. This developmental failure is attributed to abnormal expression of genes involved in cell adhesion, tight junction biogenesis and cell proliferation. Interestingly, although the conserved region 4 (CR4) of the porcine OCT4 5? upstream regionlacked the AP2C-binding motif, OCT4 transcript levels were elevated in porcine TFAP2C-KD 8-cell embryos, suggesting TFAP2C may be involved in the regulation of OCT4 in porcine embryos through other mechanisms. In summary, the results suggest that TFAP2C is necessary for the transition from de novo transcript synthesis by activation to compaction and further development, and the different expression patterns of TFAP2C in porcine embryos may reflect species-specific functions during preimplantation embryo development.

The association of mitochondrial potential and copy number with pig oocyte maturation and developmental potential.

ATP is critical for oocyte maturation, fertilization, and subsequent embryo development. Both mitochondrial membrane potential and copy number expand during oocyte maturation. In order to differentiate the roles of mitochondrial metabolic activity and mtDNA copy number during oocyte maturation, we used two inhibitors, FCCP (carbonyl cyanide p-(tri-fluromethoxy)phenyl-hydrazone) and ddC (2'3-dideoxycytidine), to deplete the mitochondrial membrane potential (Δφm) and mitochondrial copy number, respectively. FCCP (2000 nM) reduced ATP production by affecting mitochondrial Δφm, decreased the mRNA expression of Bmp15 (bone morphogenetic protein 15), and shortened the poly(A) tails of Bmp15, Gdf9 (growth differentiation factor 9), and Cyclin B1 transcripts. FCCP (200 and 2000 nM) also affected p34(cdc2) kinase activity. By contrast, ddC did not alter ATP production. Instead, ddC significantly decreased mtDNA copy number (P < 0.05). FCCP (200 and 2000 nM) also decreased extrusion of the first polar body, whereas ddC at all concentrations did not affect the ability of immature oocytes to reach metaphase II. Both FCCP (200 and 2000 nM) and ddC (200 and 2000 µM) reduced parthenogenetic blastocyst formation compared with untreated oocytes. However, these inhibitors did not affect total cell number and apoptosis. These findings suggest that mitochondrial metabolic activity is critical for oocyte maturation and that both mitochondrial metabolic activity and replication contribute to the developmental competence of porcine oocytes.

Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia.

ABSTRACT: Therapeutic vaccination has long been a promising avenue for cancer immunotherapy but is often limited by tumor heterogeneity. The genetic and molecular diversity between patients often results in variation in the antigens present on cancer cell surfaces. As a result, recent research has focused on personalized cancer vaccines. Although promising, this strategy suffers from time-consuming production, high cost, inaccessibility, and targeting of a limited number of tumor antigens. Instead, we explore an antigen-agnostic polymeric in situ cancer vaccination platform for treating blood malignancies, in our model here with acute myeloid leukemia (AML). Rather than immunizing against specific antigens or targeting adjuvant to specific cell-surface markers, this platform leverages a characteristic metabolic and enzymatic dysregulation in cancer cells that produces an excess of free cysteine thiols on their surfaces. These thiols increase in abundance after treatment with cytotoxic agents such as cytarabine, the current standard of care in AML. The resulting free thiols can undergo efficient disulfide exchange with pyridyl disulfide (PDS) moieties on our construct and allow for in situ covalent attachment to cancer cell surfaces and debris. PDS-functionalized monomers are incorporated into a statistical copolymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after IV administration. There, the compound initiates an anticancer immune response, including T-cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice.

Radiologic and pathologic correlation of a renal venous hemangioma.

Renal hemangiomas, including the rare subtype of venous hemangioma, are typically non-cancerous, often asymptomatic, and usually discovered incidentally during imaging studies. Here, we report a unique case of a 59-year-old African-American female with a renal venous hemangioma that initially mimicked papillary-type renal cell carcinoma (RCC-pt) on imaging studies. The patient's presentation included a long history of rectal bleeding and an incidental discovery of a hypoattenuating mass in the left kidney during a contrast-enhanced CT scan. Renal MRI revealed a 3.5 cm left renal lower pole mass, presenting as heterogeneously hyperintense on T1-weighted images and hypointense on T2-weighted images, with gradual mild enhancement post-contrast. Subsequent total nephrectomy confirmed the histopathological diagnosis of a venous hemangioma. This case underlines the need for recognizing unique imaging features of renal venous hemangiomas, contributing to the differential diagnosis of T2 dark hypoenhancing renal masses. Correct interpretation may prevent unnecessary invasive procedures and operations, thereby improving patient management and outcomes.

Preservation of Circumferential and Radial Left Ventricular Function as a Mitigating Mechanism for Impaired Longitudinal Strain in Early Cardiac Amyloidosis.

BACKGROUND: In patients with cardiac amyloidosis (CA), left ventricular ejection fraction (LVEF) is frequently preserved, despite commonly reduced global longitudinal strain (GLS). We hypothesized that nonlongitudinal contraction may initially serve as a mitigating mechanism to maintain cardiac output and studied the relationship between global circumferential (GCS) and radial (GRS) strain with LVEF and extracellular volume (ECV), a marker of amyloid burden. METHODS: Patients with CA who underwent cardiac magnetic resonance (CMR; n = 140, 70.7 ± 11.5 years, 66% male) or echocardiography (n = 67, 71 ± 13 years, 66% male) and normal controls (CMR, n = 20; echocardiography, n = 45) were retrospectively identified, and GCS, GLS, and GRS were quantified using feature-tracking CMR or speckle-tracking echocardiography and compared between CA patients with preserved and reduced LVEF (CAHFpEF, CAHFrEF) and controls. The prevalence of impaired strain (magnitudes <2.5th percentile of the controls) was compared between CAHFpEF and CAHFrEF and between ECV quartiles. RESULTS: While echocardiography-derived GLS was impaired in both CAHFpEF (-13.4% ± 3.1%, P < .003) and CAHFrEF (-9.1% ± 3.2%, P < .003), compared with controls (-20.8% ± 2.4%), GCS was more impaired in CAHFrEF compared with both controls (-15.6% ± 5.0% vs -32.3% ± 3.3%, P < .003) and CAHFpEF (-30.4% ± 5.7%, P < .003) and did not differ between CAHFpEF and controls (P = .24). The prevalence of abnormal CMR-derived GCS (P < .0001) and GRS (P < .0001) but not GLS (P = .054) varied significantly across ECV quartiles. CONCLUSIONS: Among CA patients with preserved LVEF, preserved GCS and GRS, despite near-universally impaired GLS, may be explained by an initial predominantly subendocardial involvement, where mostly longitudinal fibers are located. If confirmed in future studies, these findings may facilitate identification of patients with early stages of CA, when treatments may be most effective.

Deep learning generates synthetic cancer histology for explainability and education.

Artificial intelligence methods including deep neural networks (DNN) can provide rapid molecular classification of tumors from routine histology with accuracy that matches or exceeds human pathologists. Discerning how neural networks make their predictions remains a significant challenge, but explainability tools help provide insights into what models have learned when corresponding histologic features are poorly defined. Here, we present a method for improving explainability of DNN models using synthetic histology generated by a conditional generative adversarial network (cGAN). We show that cGANs generate high-quality synthetic histology images that can be leveraged for explaining DNN models trained to classify molecularly-subtyped tumors, exposing histologic features associated with molecular state. Fine-tuning synthetic histology through class and layer blending illustrates nuanced morphologic differences between tumor subtypes. Finally, we demonstrate the use of synthetic histology for augmenting pathologist-in-training education, showing that these intuitive visualizations can reinforce and improve understanding of histologic manifestations of tumor biology.

Esculetin has therapeutic potential via the proapoptotic signaling pathway in A253 human submandibular salivary gland tumor cells.

Esculetin is a natural lactone that is commonly derived from coumarins. According to previous experiments using human cancer cells, esculetin has potent antitumor activity; it also inhibits proliferation and induces the apoptosis of cancer cells. In the present study, the anti-proliferative effect of esculetin on the submandibular salivary gland tumor cell line, A253, was evaluated via in vitro and in vivo analyses. Furthermore, the anti-cancer effects of esculetin in A253 cells and a xenograft model of salivary gland tumors were determined using 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide and TUNEL assay, apoptosis protein array, quantitative polymerase chain reaction and western blot analysis. Esculetin (50-150 µM) was demonstrated to have an anti-proliferative effect in the A253 cell line in vitro; this observed effect was dependent on the dose and duration of treatment. Esculetin also increased the levels of Bax, cleaved caspase-3, cleaved-9 and cleaved poly (ADP-ribose) polymerase apoptosis-related proteins, and decreased the expression levels of the Bcl-2 anti-apoptotic protein. With respect to apoptosis regulation, esculetin significantly decreased the proliferation of tumor cells in a xenograft model (100 mg/kg/day) for 18 days. Overall, esculetin could be a potential oral anticancer drug against salivary gland cancer.

Effect of Human Placental Extract Treatment on Random-Pattern Skin Flap Survival in Rats.

Background: Human placental extract (HPE), prepared from the placentas of healthy, postpartum females, displays various physiological activities, including antioxidative properties. In this study, a dorsal skin flap model was used to investigate the effect of HPE on flap viability in rats. Materials and methods: Forty male Sprague-Dawley rats underwent random-pattern skin flap surgeries. The animals were randomly divided among a control group and three treatment groups (localized injection (LI), 10 mg/kg/d localized HPE injections; low-dose treatment (LT), 10 mg/kg/d systemic HPE injections; high-dose treatment (HT), 40 mg/kg/d systemic HPE injections). Surviving skin flap areas were measured 7 days after surgery and tissue samples were stained with hematoxylin and eosin; vascular endothelial growth factor expression was determined immunohistochemically. To evaluate the antioxidant and antiapoptotic effects of HPE, malondialdehyde, glutathione peroxidase, and caspase-3 levels were examined. Results: Seven days after surgery, HPE-treated animals had significantly reduced necrotic areas, rats receiving the highest HPE dose demonstrated the greatest flap survival. In the HPE groups, the histopathological scores were lower than for the control group. Immunohistochemistry showed markedly more numerous vascular endothelial growth factor-positive cells in the HT group than in the C group. Malondialdehyde levels were significantly lower and glutathione peroxidase levels were higher in the HT group than in the C group. HPE treatment significantly inhibited apoptosis by lowering caspase-3 activity. Conclusions: HPE treatment yielded positive effects on flap survival, due to its antioxidant and antiapoptotic properties. These results suggest a new therapeutic approach for enhancing flap viability and accelerating wound repair.

Analysis of the Legal Effect of Settlement Agreements Prepared in Medical Litigation Following Plastic Surgery in Korea.

BACKGROUND: Settlements between doctors and patients provide a solution to complicated disputes. However, some disputes may be renewed as a result of negligence by both parties. The purpose of this study was to review the legal issues that may potentially arise during the preparation of settlement agreements and to propose a list of requirements for ensuring the effectiveness of these settlement agreements. METHODS: Data from 287 civil cases concerning aesthetic surgery that took place between 2000 and 2015 were collected from a court database in South Korea. Factors that influenced the effectiveness of settlement agreements were analyzed. RESULTS: Among the 287 court precedents, there were 68 cases of covenant not to sue. Eighteen cases were dismissed because the settlement agreements were recognized as effective, and 50 cases were sent forward for judgment on their merits because the agreements were not recognized as effective. The types of surgery and types of complications were classified by frequency. We evaluated the geographical distribution of the precedents, the settlement timing, and the effectiveness and economic impact of the settlements. We found that there was no statistically significant relationship among these factors. Four major factors that made a settlement agreement legally effective were identified, and the data showed that fee-free reoperations were not considered by the court in determining the compensation amount. CONCLUSIONS: When preparing a settlement agreement, it is advisable to review the contents of the agreement rather than to take the preparation of a settlement agreement per se to be legally meaningful.

Centriolin, a centriole-appendage protein, regulates peripheral spindle migration and asymmetric division in mouse meiotic oocytes.

Unlike somatic cells mitosis, germ cell meiosis consists of 2 consecutive rounds of division that segregate homologous chromosomes and sister chromatids, respectively. The meiotic oocyte is characterized by an absence of centrioles and asymmetric division. Centriolin is a relatively novel centriolar protein that functions in mitotic cell cycle progression and cytokinesis. Here, we explored the function of centriolin in meiosis and showed that it is localized to meiotic spindles and concentrated at the spindle poles and midbody during oocyte meiotic maturation. Unexpectedly, knockdown of centriolin in oocytes with either siRNA or Morpholino micro-injection, did not affect meiotic spindle organization, cell cycle progression, or cytokinesis (as indicated by polar body emission), but led to a failure of peripheral meiotic spindle migration, large polar body emission, and 2-cell like oocytes. These data suggest that, unlike in mitotic cells, the centriolar protein centriolin does not regulate cytokinesis, but plays an important role in regulating asymmetric division of meiotic oocytes.

The Effect of Botulinum Toxin on an Iatrogenic Sialo-Cutaneous Fistula.

A sialo-cutaneous fistula is a communication between the skin and a salivary gland or duct discharging saliva. Trauma and iatrogenic complications are the most common causes of this condition. Treatments include aspiration, compression, and the administration of systemic anticholinergics; however, their effects are transient and unsatisfactory in most cases. We had a case of a patient who developed an iatrogenic sialo-cutaneous fistula after wide excision of squamous cell carcinoma in the parotid region that was not treated with conventional management, but instead completely resolved with the injection of botulinum toxin. Based on our experience, we recommend the injection of botulinum toxin into the salivary glands, especially the parotid gland, as a conservative treatment option for sialo-cutaneous fistula.

Polymerase subunit gamma 2 affects porcine oocyte maturation and subsequent embryonic development.

Deoxyribonucleic acid polymerase subunit gamma (POLG) is an enzyme encoded by the mitochondrial Polg gene. Polymerase (DNA directed), gamma 2, accessory subunit, also known as POLG2, is involved in mitochondrial replication. In the present study, we examined the role of Polg2 in the maturation of porcine oocytes. After Polg2 knockdown, the mitochondrial DNA copy number was significantly (P < 0.05) lower than that in the control group. However, there was no decrease in mitochondrial membrane potential. The decrease in mitochondrial DNA copy number led to reductions in adenosine-5'-triphosphate content (P < 0.05) and the maturation rate (P < 0.05) of oocytes. Furthermore, in the Polg2-knockdown group, maturation-promoting factor activity was decreased (P < 0.05) and the percentage of oocytes displaying abnormal actin filaments and microtubules was significantly increased (P < 0.05). This likely led to the reduced development rate and number of cells per blastocyst in this group (P < 0.05). In conclusion, Polg2 seems to be critical for mitochondrial replication and regulation of adenosine-5'-triphosphate content and affects porcine oocyte maturation and subsequent embryonic development.

Zinc regulates meiotic resumption in porcine oocytes via a protein kinase C-related pathway.

Zinc is an extremely important trace element that plays important roles in several biological processes. However, the function of zinc in meiotic division of porcine oocytes is unknown. In this study, we investigated the role of zinc during meiotic resumption in in vitro matured porcine oocytes. During meiotic division, a massive release of zinc was observed. The level of free zinc in the cytoplasm significantly increased during maturation. Depletion of zinc using N, N, N', N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+ chelator, blocked meiotic resumption in a dose dependent manner. The level of phosphorylated mitogen activated protein kinase (MAPK) and p34cdc2 kinase activity were reduced when zinc was depleted. Moreover, zinc depletion reduced the levels of phosphorylated protein kinase C (PKC) substrates in a dose dependent manner. Real-time PCR analysis showed that expression of the MAPK- and maturation promoting factor related genes C-mos, CyclinB1, and Cdc2 was downregulated following zinc depletion. Treatment with the PKC agonist phorbol 12-myristate 13-acetate (PMA) increased phosphorylation of PKC substrates and MAPK and increased p34cdc2 kinase activity. This rescued the meiotic arrest, even in the presence of TPEN. Activation of PKC by PMA increased the level of zinc in the cytoplasm. These data demonstrate that zinc is required for meiotic resumption in porcine oocytes, and this appears to be regulated via a PKC related pathway.