Imaging and Clinical Findings of Xanthogranulomatous Inflammatory Disease of Various Abdominal and Pelvic Organs: A Pictorial Essay.

Xanthogranulomatous (XG) inflammatory disease is a rare benign disease involving various organs, including the gallbladder, bile duct, pancreas, spleen, stomach, small bowel, colon, appendix, kidney, adrenal gland, urachus, urinary bladder, retroperitoneum, and female genital organs. The imaging features of XG inflammatory disease are nonspecific, usually presenting as a heterogeneous solid or cystic mass. The disease may also extend to adjacent structures. Due to its aggressive nature, it is occasionally misdiagnosed as a malignant neoplasm. Herein, we review the radiological features and clinical manifestations of XG inflammatory diseases in various organs of the abdomen and pelvis.

Myxoid Liposarcoma of the Breast Mimicking Phyllodes Tumor: A Case Report.

Myxoid liposarcoma is an extremely rare malignant breast tumor. We report the case of a 44-year-old woman who had myxoid liposarcoma of the breast with a history of phyllodes tumor and describe the imaging findings on US, mammography, and MRI. Before surgery, the mass was considered to be a recurrent phyllodes tumor. However, using US, we retrospectively identified some differences between myxoid liposarcomas and phyllodes tumors.

Mesonephric-like Adenocarcinoma of the Uterine Corpus: Comprehensive Analyses of Clinicopathological, Molecular, and Prognostic Characteristics With Retrospective Review of 237 Endometrial Carcinoma Cases.

BACKGROUND/AIM: Uterine mesonephric-like adenocarcinoma (MLA) is a rare malignant tumor of the female genital tract. PATIENTS AND METHODS: We reviewed 237 endometrial carcinoma cases and investigated the clinicopathological and molecular characteristics of uterine MLA. RESULTS: We found that 3.0% (7/237) of the endometrial carcinoma cases were MLAs. Compared to endometrial endometrioid carcinoma, MLA showed larger tumor size, deeper myometrial invasion, increasingly advanced-stage disease, and more frequent lymphovascular space invasion. All MLAs exhibited architectural diversity, compactly aggregated small tubules, eosinophilic intraluminal secretions, overlapped and angulated nuclei, scant cytoplasm, and presence of spindle cells. All the MLAs expressed at least two mesonephric markers. All except one MLA harbored activating Kirsten rat sarcoma viral oncogene homolog mutations. All patients with MLA developed postoperative metastases. MLA had the lowest progression-free survival rate among different histological types of endometrial carcinoma. CONCLUSION: Uterine MLA is a highly aggressive gynecological malignancy, showing unique morphological and molecular features, frequent recurrences and metastases, as well as poor prognosis.

The antioncogenic effect of Beclin-1 and FOXP3 is associated with SKP2 expression in gastric adenocarcinoma.

ABSTRACT: An overexpression of S-phase kinase-associated protein 2 (SKP2) is frequently observed in human cancer progression and metastasis, and evidence suggests that SKP2 plays a proto-oncogenic role both in vitro and in vivo. However, the function of SKP2 in gastric adenocarcinoma remains largely obscure. We investigated SKP2 expression in human gastric carcinomas.Tissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected from 2006 to 2012. Immunohistochemical staining for SKP2, Beclin-1, and forkhead box protein P3 (FOXP3) was performed. Pearson chi-square test was used to evaluate the associations among clinicopathological variables. The Kaplan-Meier method, the log-rank test, and the Cox proportional-hazards model were used in the analysis of the overall survival (OS) and disease-free survival (DFS).As a result, SKP2 overexpression in gastric adenocarcinomas showed a significant correlation with several favorable clinical factors, including the tumor size, T category, N category, lymphatic invasion, vascular invasion, OS, and DFS. SKP2 expression was positively correlated with the tumoral FOXP3, Beclin-1 expression, and regulatory T cell (Treg) infiltration. The difference in DFS between the SKP2 positive and negative group was attenuated by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration. Attenuation of the difference in OS by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration was not significant. In multivariable analysis, SKP2 expression was not correlated with OS and DFS.Our study showed a complex interrelationship between SKP2 and Beclin-1 and FOXP3 expression in gastric adenocarcinoma. The antioncogenic effect of Beclin-1 and FOXP3 expression in gastric adenocarcinoma is related to SKP2 expression.

Tubulocystic Renal Cell Carcinoma Is Not an Indolent Tumor: A Case Report of Recurrences in the Retroperitoneum and Contralateral Kidney.

Tubulocystic renal cell carcinoma (RCC) is a rare subtype of RCC that was recently included in the 2016 World Health Organization classification of tumors of the kidney. Most of these tumors exhibit indolent behavior with low metastatic potential. However, here we report a case of recurrent tubulocystic RCC with aggressive features in the retroperitoneum and contralateral kidney treated with targeted agents and radiofrequency ablation.

Clinical Significance of Receptor-Interacting Protein 3 and Parkin, Essential Molecules for Necroptosis, in Breast Cancer.

PURPOSE: Receptor-interacting protein 3 (RIP3) is the main initiator of necroptosis. Parkin prevents the formation of the RIP1-RIP3 complex by promoting polyubiquitination of RIP3. However, the mechanism by which necroptosis affects the clinical features of breast cancer and prognosis is not known. Here, we aimed to study the effect of necroptosis on the clinical features and prognosis of breast cancer by assessing the expression of RIP3 and Parkin. METHODS: Tissue microarrays (TMAs) were constructed from 257 cases of breast cancer. Immunohistochemistry was performed on 4-µm tissue sections from each TMA block. The χ² test, Kaplan-Meier survival analysis with log-rank test, and Cox regression proportional hazard model were used for statistical analysis. RESULTS: Low RIP3 expression resulted in a large tumor size and high nuclear grade. Low RIP3 expression was correlated with human epidermal growth factor receptor 2 positivity, short overall survival (OS), and short disease-free survival (DFS). The triple negative breast cancer group with low RIP3 expression and lymph node (LN) positive group with low RIP3 expression had the shortest OS. High Parkin expression was associated with high histological grade, estrogen and/or progesterone receptor negativity, and lymphatic emboli, but was not correlated with OS and DFS. OS was correlated with LN metastasis and RIP3 loss and DFS with large tumor size, LN metastasis, and RIP3 loss. CONCLUSION: Low RIP3 and high Parkin expression are associated with aggressive clinical features in breast cancer. RIP3, a molecular marker of necroptosis, is an independent factor associated with survival in breast cancer. Further in-depth studies are needed to investigate the role of necroptosis in breast cancer development, metastasis, and treatment in the future.

Adenosine A2A Receptor Agonist Polydeoxyribonucleotide Alleviates Interstitial Cystitis-Induced Voiding Dysfunction by Suppressing Inflammation and Apoptosis in Rats.

BACKGROUND: Interstitial cystitis (IC) is a chronic disorder that indicates bladder-related pain or discomfort. Patients with IC often experience urination problems, such as urinary frequency and urgency, along with pain or discomfort in the bladder area. Therefore, new treatments based on IC etiology are needed. Polydeoxyribonucleotide (PDRN) is a biologic agonist of the adenosine A2A receptor, and PDRN has anti-inflammatory effect and inhibits apoptosis. In the current study, the effect of PDRN on cyclophosphamide-induced IC animal model was investigated using rats. METHODOLOGY: To induce the IC animal model, 75 mg/kg of cyclophosphamide was injected intraperitoneally once every 3 days for 10 days. The rats in the PDRN-treated groups were intraperitoneally injected with 0.5 mL physiological saline containing 8 mg/kg PDRN, once a day for 10 days after IC induction. RESULTS: Induction of IC by cyclophosphamide injection caused voiding dysfunction, bladder edema, and histological damage. Cyclophosphamide injection increased secretion of pro-inflammatory cytokines and enhanced apoptosis. In contrast, PDRN treatment alleviated voiding dysfunction, bladder edema, and histological damage. Secretion of pro-inflammatory cytokines and expressions of apoptotic factors were suppressed by PDRN treatment. These changes indicate that treatment with PDRN improves voiding function by ultimately promoting the repair of damaged bladder tissue. CONCLUSION: The conclusion of this experiment suggests the possibility that PDRN could be used as an effective therapeutic agent for IC.

ERG and nestin: useful markers of immature vessels and novel prognostic markers in renal cell carcinoma.

OBJECTIVES: Renal cell carcinoma (RCC) accounts for approximately 90% of all renal malignancy. Because a rich vasculature is an outstanding feature of RCC, information on the blood vessels of RCC might explain its tumor characteristics. Several researchers have noted the effects of tumor vessels on the clinicopathologic characteristics and prognosis of tumors; however, a clear association has not been established. We hypothesized that the immaturity of the neovasculature may be an important clinicopathologic characteristic forprognosis of RCC patients. ERG and nestin are new vascular markers that regulate vascular homeostasis and angiogenesis. Therefore, in the present study, we investigated how ERG and nestin were expressed with respect to tumor characteristics. MATERIALS AND METHODS: IHC staining for ERG, nestin, CD31, and CD34 was performed for 217 renal tumors, including clear-cell RCC (ccRCC; n = 184), papillary RCC (pRCC; n = 14), chromophobe RCC (chRCC; n = 14), and oncocytoma (n = 5). RESULTS: Vascular endothelial cells from normal kidney consistently showed strong nuclear expression of ERG and nestin. Conversely, a loss of ERG and nestin expression was observed in endothelial cells of some tumor blood vessels, which was associated with tumor progression. In particular, the loss of ERG expression was significantly associated with progression-free survival and overall survival (univariate analyses: P = 0.027 and P = 0.004, respectively; multivariate analyses: P = 0.030 and P = 0.046, respectively). CONCLUSION: A loss of ERG and nestin expression is associated with tumor progression, and loss of ERG is a powerful prognostic marker for ccRCC.

Solitary, Endobronchial Metastasis from Renal Cell Carcinoma 20 Years after Nephrectomy.

Late recurrence over 10 years after surgery and endobronchial metastasis are some of the specific biological behaviors of renal cell carcinoma (RCC). The current report describes a case of solitary endobronchial metastasis at a subsegmental bronchus that developed 20 years after curative nephrectomy for RCC. A 71-year-old male was admitted to our hospital for pneumonia. Chest radiography showed multifocal ill-defined nodular opacities in the right lower lung zone, suggesting pneumonia. Subsequent chest CT confirmed pneumonic infiltration in the right lung. However, a 4.3-cm, well-defined, elongated mass with a branching pattern was also identified in the right lower lobe, and a right nephrectomy scar was detected on the covered upper abdomen. The patient had undergone right nephrectomy 20 years ago due to clear cell RCC. After right lower lobectomy, the postoperative pathological diagnosis was endobronchial metastatic clear cell RCC. Endobronchial metastasis should be considered in a patient with a history of RCC who presents with a suspected endobronchial tumor, even decades after curative surgery.

Bicameral Gallbladder With Chronic Cholecystitis on Hepatobiliary Scintigraphy.

Bicameral gallbladder, also known as segmental adenomyomatosis, is not a rare benign condition with the lumen divided into 2 interconnected chambers. Here we present 2 interesting cases of the bicameral gallbladder, which shows unremarkable findings on hepatobiliary scintigraphy at first appearance. However, the CT scan revealed that the fundal chamber was not visualized on the scintigraphy unlike the ductal chamber. These cases suggest that the findings of the bicameral gallbladder on hepatobiliary scintigraphy can lead to misdiagnosis without carefully correlating with anatomic imaging findings.

Protective Effect of Polydeoxyribonucleotide Against CCl4-Induced Acute Liver Injury in Mice.

PURPOSE: Polydeoxyribonucleotide (PDRN) is a substance known to suppress inflammation and accelerate wound healing. In this experiment, the effect of PDRN treatment on carbon tetrachloride (CCl4)-evoked acute liver injury (ALI) was investigated using mice. METHODS: We analyzed the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and conducted hematoxylin and eosin staining in accompany with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Western blot analysis was also conducted to assess the expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, adenosine A2A receptor, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). The mice were received intraperitoneal injection of 10-mL/kg CCl4, 4 times, once every 2 days. The mice in the PDRN treatment groups received intraperitoneal injection of 200-µL distilled water comprising each concentration of PDRN for 7 days starting 1 day after first CCl4 injection. RESULTS: ALT and AST concentrations in the serum were reduced and TNF-α, IL-1ß, and IL-6 expressions were decreased by PDRN injection in CCl4-evoked ALI mice. PDRN injection suppressed Bax versus Bcl-2 ratio and reduced the percentage of TUNE-positive cells in CCl4-evoked ALI mice. PDRN injection overexpressed adenosine A2A receptor in CCl4-evoked ALI mice. CONCLUSION: The therapeutic efficacy of PDRN also can be expected for CCl4-evoked acute urogenital injury in addition to ALI. The current research suggests that PDRN may be used for the therapeutic agent of CCl4-evoked ALI.

Mesonephric Adenocarcinoma of the Uterine Fundus Exhibiting High 18F-FDG Uptake.

Mesonephric adenocarcinoma is a rare tumor that is considered to develop from mesonephric remnants of the female genital tract. This tumor usually occurs in the lateral wall of the uterine cervix. Herein, we present an exceptionally rare case of mesonephric adenocarcinoma located in the uterine fundus. The tumor exhibited intense hypermetabolism on 18F-FDG PET/CT. Based on the characteristic histologic features and immunohistochemical phenotypes, the diagnosis of mesonephric adenocarcinoma was confirmed. The patient underwent hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node dissection, and no lymph node or distant metastasis was identified. After 20 months of surveillance without adjuvant therapy, she remains free of relapse.

Early Prediction of Tumor Response to Neoadjuvant Chemotherapy and Clinical Outcome in Breast Cancer Using a Novel FDG-PET Parameter for Cancer Stem Cell Metabolism.

Cancer stem cells (CSCs) contribute to chemoresistance and tumor relapse. By using the distinct metabolic phenotype of CSC, we designed novel PET parameters for CSC metabolism and investigated their clinical values. Patients with breast cancer who underwent 18F-FDG PET/CT before neoadjuvant chemotherapy (NAC) were retrospectively included. We developed a method to measure CSC metabolism using standardized uptake value histogram data. The predictive value of novel CSC metabolic parameters for pathologic complete response (pCR) was assessed with multivariable logistic regression. The association between the CSC parameter and disease-free survival (DFS) was also determined. We identified 82 patients with HER2-positive/triple-negative subtypes and 38 patients with luminal tumors. After multivariable analysis, only metabolic tumor volume for CSC (MTVcsc) among metabolic parameters remained the independent predictor of pCR (OR, 0.12; p = 0.022). MTVcsc successfully predicted pathologic tumor response to NAC in HER2-positive/triple-negative subtypes (accuracy, 74%) but not in the luminal subtype (accuracy, 29%). MTVcsc was also predictive of DFS, with a 3-year DFS of 90% in the lower MTVcsc group (<1.75 cm3) versus 72% in the higher group (>1.75 cm3). A novel data-driven PET parameter for CSC metabolism provides early prediction of pCR after NAC and DFS in HER2-positive and triple-negative subtypes.

Hippo pathway and tumoral FOXP3 expression correlate with tumor growth in squamous cell carcinoma of the lung.

BACKGROUND: Expression of FOXP3 in tumors is associated with proliferation, migration, and invasion, has been implicated in cancer prognosis, and may be related to metastatic potential. The Hippo signaling pathway is known to regulate tissue homeostasis and organ size through cell proliferation and apoptosis. We investigated tumoral FOXP3, Lats2, and YAP expression related to the Hippo pathway in squamous cell carcinoma (SCC) of the lung. METHODS: Between 1983 and 2006, 149 cases of SCC were diagnosed and surgically resected at Kyung Hee University Hospital. Immunohistochemical staining for FOXP3, YAP, and Lats2 was done. RESULTS: Tumor size was inversely correlated with tumoral FOXP3 expression (p = 0.015), Treg count (p < 0.0001), and positive Lats2 expression (p = 0.028). YAP expression was inversely correlated with lymph node metastasis (p = 0.039). Positive tumoral FOXP3 expression was significantly associated with infiltrated Treg count (p = 0.001) and positive Lats2 expression (p = 0.007). CONCLUSION: Tumoral FOXP3 has the potential to suppress tumor function in SCC of the lung. The decrease or loss of FOXP3 expression in cancer cells is thought to contribute to SCC tumorigenesis and progression in the lung. The tumor suppressor function of FOXP3 in SCC of the lung was related to Lats2 and YAP expression in the Hippo pathway.

Clear cell chondrosarcoma of the talus in Von Hippel-Lindau disease: a rare tumor in an unusual location and uncommon co-presentation.

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome. Clear cell chondrosarcoma (CCCS) is a rare variant of chondrosarcoma. Here, we report a case of CCCS in the talus occurring in a patient with VHL disease. A 32-year-old man presented with ankle pain for 2 years. MRI revealed a 4.2 cm mass in the talus, and needle biopsy was performed. The patient underwent curettage but the final diagnosis was CCCS. Adjuvant radiation therapy was performed without additional talectomy and the patient was alive without recurrence for a follow-up period of 2 years. To our knowledge, this is the first case in the English medical literature of a co-presentation of this rare disease and condition: i.e. CCCS with VHL disease in the unusual location of the talus. We cautiously suggest that CCCS may be associated with VHL disease based on their histologic similarity.

Expression of Beclin-1, an autophagy-related protein, is associated with tumoral FOXP3 expression and Tregs in gastric adenocarcinoma: The function of Beclin-1 expression as a favorable prognostic factor in gastric adenocarcinoma.

BACKGROUND: Autophagy, which is stimulated by cellular or environmental stresses, is involved in several distinct biological processes, and the regulation mechanism is complex. Autophagy has been reported to modulate immune system components. In the present study, the expression of Beclin-1 and LC3, an autophagy-related proteins, and its relationship with FOXP3 expression were investigated in gastric adenocarcinoma cells and FOXP3+T cells (regulatory T cells). METHODS: Tissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected at Kyung Hee University Hospital at Gangdong from 2006 to 2012. Immunohistochemical staining for Beclin-1, LC3, FOXP3, and CD8 was performed. RESULTS: Consequently, positive Beclin-1 expression was significantly associated with a smaller tumor size, mixed histologic type, better histologic grade, lower T category, lower N category, lower recurrence rate, less lymphatic invasion, less vascular invasion, and less neural invasion. Positive tumoral FOXP3 expression was significantly associated with a lower T category, lower N category, lower recurrence rate, and less lymphatic invasion. The cases of more infiltrated Tregs (≥ 25/high power field, HPF) significantly correlated with a lower N category, lower recurrence rate, less lymphatic invasion, more infiltrated CD8+T cells, and a higher number of tumor-infiltrating lymphocytes. Beclin-1 and LC3 expression were positively correlated with tumoral FOXP3 overexpression. In addition, Beclin-1 expression was significantly associated with a greater number of infiltrated Tregs in gastric adenocarcinoma. Both the positive Beclin-1 expression and positive tumoral FOXP3 expression cases showed significantly better disease-free and overall survival. In addition, the patients with an increased number of infiltrated Tregs (≥ 25/HPF) showed better disease-free and overall survival rates. CONCLUSION: In conclusion, the autophagic function of Beclin-1 in gastric adenocarcinoma cells was associated with an increased number of infiltrated Tregs and tumoral FOXP3 containing tumor suppressor function. Therefore, the favorable effects of Beclin-1 expression in gastric adenocarcinoma is associated with the regulation of Tregs and tumoral FOXP3 expression.

Milk Fat Globule-EGF Factor 8 Contributes to Progression of Hepatocellular Carcinoma.

Milk fat globule-EGF factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates a wide spectrum of pathophysiological processes. MFG-E8 has been studied as a key regulator of cancer cell invasion, migration, and proliferation in different tissues and organs. However, potential roles of MFG-E8 in the growth and progression of liver cancer have not been investigated to date. Here, we analyzed 33 human hepatocellular carcinoma (HCC) samples and found that levels of MFG-E8 expression were significantly higher in HCC cells than in normal liver tissues. In addition, our in vitro gain-of-function study in three different HCC cell lines revealed that overexpression of MFG-E8 promoted the proliferation and migration of HCC cells, as determined by RT-qPCR, MTT assays, and wound healing analyses. Conversely, an MFG-E8 loss-of function study showed that proliferation capacity was significantly reduced by MFG-E8 knockdown in HCC cells. Additionally, MFG-E8 activity-neutralizing antibodies profoundly inhibited both migration and proliferation of HCC cells, attenuating their tumorigenic properties. These reductions in migration and proliferation were rescued by treatment of HCC cells with recombinant MFG-E8 protein. Furthermore, an in vivo HCC xenograft study showed that the number of proliferating HCC cells and tumor volume/weight were all significantly increased by MFG-E8 overexpression, compared to control mice. These results clearly show that MFG-E8 plays an important role in HCC progression and may provide a basis for future mechanistic studies and new strategies for the treatment of liver cancer.

Circulating Tumor DNA in Saliva in an Orthotopic Head and Neck Cancer Mouse Model.

AIM: To evaluate the feasibility of conducting studies of saliva circulating tumor DNA (ctDNA) as a biomarker of metastasis or recurrence in our orthotopic head and neck cancer (HNC) mouse model. MATERIALS AND METHODS: A mouse model of recurrence or metastasis after tongue cancer resection was developed. Blood and saliva were collected at baseline and at the establishment of recurrence or metastasis. Real-time polymerase chain reaction was performed to quantify human long interspersed element (hLINE) in samples to assess the amount of ctDNA. RESULTS: In our model, salivary hLINE increased as the cancer developed and decreased after surgery. Plasma hLINE was significantly elevated in mice with metastasis. The presence of tongue cancer recurrence in mice was more correlated with hLINE concentration in saliva than in plasma. CONCLUSION: In our orthotopic model, salivary ctDNA better reflected tumor development and recurrence than did plasma ctDNA.

Clinicopathologic analysis of intraductal papillary neoplasm of bile duct: Korean multicenter cohort study.

BACKGROUND: IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. METHODS: Among 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. RESULTS: Of 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the "Jang & Kim's modified anatomical classification," 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010-4.433]). CONCLUSIONS: This is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.

Groin abnormalities: ultrasonographic and clinical findings.

Groin lesions can be classified as neoplastic or non-neoplastic. Neoplastic lesions include lipoma, epidermoid cyst, angiomyofibroblastoma-like tumor, liposarcoma, and synovial sarcoma, as well as metastases from lymphoma, neuroendocrine carcinoma, and carcinomas of the lung, breast, urinary bladder, ovary, vulva, and colon. Non-neoplastic lesions include hernias, round ligament varices, endometriosis, Kimura disease, Castleman disease, hematoma, and inflammation. Because the clinical implications and therapeutic strategies for groin lesions vary depending on the cause, the ability to noninvasively differentiate among etiologies is very important. Although there is substantial overlap in ultrasonographic findings across various groin lesions, some ultrasonographic features, along with clinical characteristics, may suggest a specific diagnosis. Familiarity with the ultrasonographic and clinical features of various groin lesions facilitates accurate diagnosis and treatment.