[A Case of Rectal Neuroendocrine Carcinoma with Metachronous Liver Metastasis Treated with Multimodality Therapy].

A 6 2-year-old woman visited our hospital with a complaint of anal bleeding and was diagnosed with rectal cancer. She underwent low anterior resection and D3 lymphadenectomy. The pathological diagnosis was shown as follows: Ra, Circ, type 2, por1, pSS, ly3, v1, pN2, pStage III b, and KRAS wild type. UFT/UZEL with polysaccharide K(PSK)was initiated as adjuvant chemotherapy after the operation. However, multiple liver metastases were found on CT after 3 courses of UFT/UZEL with PSK, and pathological reexamination revealed that the primary tumor was a neuroendocrine carcinoma. She underwent chemotherapy with CBDCA combined with CPT-11, but bone marrow suppression was observed after 4 courses of the treatment. As second-line chemotherapy, FOLFOX4 plus panitumumab(Pmab)was administered. Although the disease remained stable through 10 courses of FOLFOX4 plus Pmab, Grade 3 peripheral neuropathy was observed. Hence, FOLFIRI plus bevacizumab(Bmab)was administered as third-line chemotherapy. Twenty-eight courses of FOLFIRI plus Bmab were administered, and transcatheter arterial chemoembolization(TACE)was performed during chemotherapy. However, her general condition worsened after the therapies, and she died 2 years 3 months after the initial chemotherapy.

Clinicopathological significance of androgen receptor, HER2, Ki-67 and EGFR expressions in salivary duct carcinoma.

BACKGROUND: Salivary duct carcinoma (SDC) is a highly aggressive disease which often metastasizes to distant sites, and there is no established standard therapy for this systemic disease. Given that SDC is biologically similar to breast and prostate cancer, anti-androgenic receptor (AR) and anti-human epidermal growth factor receptor 2 (HER2) therapies have the potential to exert effects, not only on patients with breast and prostate cancer but also on those with SDC. METHODS: The expression levels of HER2, epidermal growth factor receptor (EGFR), Ki-67, and AR were assessed in 32 patients with SDC, and their correlations with overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. SDC was classified into five subtypes using a method similar to that used for breast cancer. RESULTS: Anti-AR, HER2, and EGFR were positive in 23 (71.9 %), 14 (43.8 %), and 26 (81.3 %) cases, respectively. One or more of these 3 factors were positive in 30 (93.8 %) cases. The Ki-67 labeling index was greater than 15 % in all cases. While molecular status did not correlate with OS, EGFR and AR positivity were significantly associated with DFS in univariate analysis. Multivariate analysis revealed that EGFR was the only independent predictor of DFS. CONCLUSIONS: The statuses of some molecules are useful to predict DFS in patients with SDC. Ki-67 overexpression suggests that cytotoxic agents are effective for SDC. Since the majority of SDCs express AR, HER2, and/or EGFR, assessing and targeting these molecules are promising strategies to improve the prognosis of unresectable, metastatic or recurrent SDC, and a classification system according to the molecular expression status may be useful to select appropriate therapy.

Double pituitary neuroendocrine tumors in a patient with normal growth hormone level acromegaly: A case report and review of the literature.

Background: Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion caused by a pituitary neuroendocrine tumor (PitNET). However, some acromegaly patients show normal GH levels, and they can be a pitfall in clinical diagnosis. Moreover, rarely, synchronous true double or multiple PitNETs are encountered. Moreover, these PitNETs increase the risk of a left lesion during surgical exploration. Case Description: The patient, who was a 73-year-old female, was referred to our hospital with a chief complaint of headache. Assessment of basal anterior pituitary function revealed a slightly high level of insulin-like growth factor-1 (IGF-1) (standard deviation, 2.4), and her physical findings exhibited mild acromegalic features. The endocrine evaluation confirmed acromegaly and magnetic resonance imaging (MRI) showed a macro PitNET with suprasellar extension. Endoscopic endonasal surgery (EES) was performed to remove the macro PitNET. Although postoperative MRI showed complete removal of the macro PitNET, endocrinological testing indicated no improvement in GH or IGF-1 excess. Pathological examination of the surgical specimen revealed a gonadotropic PitNET. Therefore, we repeated the MRI scan and found a micro PitNET in the thin left normal pituitary gland. A second EES was successfully performed to remove the micro PitNET completely, and both endocrinological and pathological examinations confirmed that the disease was cured. Conclusion: Diagnosing acromegaly with low GH levels requires close monitoring. Double PitNETs are relatively rare and can cause incomplete remission of functional PitNETs.

Development of a human herpesvirus 8-negative effusion-based lymphoma during treatment with dasatinib for chronic myeloid leukemia.

We present the case of an 85-year-old male patient diagnosed with human herpesvirus 8 (HHV8)-negative effusion-based lymphoma (EBL) that developed from long-lasting pleural effusion (PE) induced by dasatinib treatment for chronic myeloid leukemia (CML). After the onset of this disorder, dasatinib treatment was discontinued and drainage was performed to regress the effusion. The major molecular response (MMR) was thus lost. The patient did not tolerate nilotinib treatment, but bosutinib was successful in restoring MMR. During these clinical courses, the patient suffered from a recurrence of EBL, which was treated with rituximab-based chemotherapy. The PE sample just before the 3rd cycle of chemotherapy revealed the proliferation of CD57-positive T cells, along with the disappearance of lymphoma cells. Anti-tumor immunity may have been activated following the immunochemotherapy in the undisturbed immunological environment when both EBL and CML almost regressed. After four cycles of R-CVP therapy, the patient has been in remission for 16 months and no longer requires drainage.

Utility of preoperative chemoradiotherapy for advanced esophageal carcinoma.

BACKGROUND AND AIMS: The most effective treatment would be neoadjuvant chemoradiotherapy (NACRT) plus surgery with three-field lymphadenectomy, if tolerability and complications are acceptable. The aim of this prospective study was to evaluate the tolerability of NACRT+ systematic three-field lymphadenectomy. METHODS: A total of 127 cases of advanced esophageal carcinoma were objected, among which 32 had NACRT, being the cases suspected to cT3-T4 or, < cT3 with multiple lymph node metastasis. ≥ T2 of 95 cases were treated by surgery alone (NACRT [-] case). The effect of NACRT was evaluated by histological examination and corrected with the clinicopathologic factors, including postoperative prognosis. After reports JCOG9907, we treated eight cases with neoadjuvant chemotherapy at stages II and III. We examined Musashi-1 staining for these eight cases. RESULTS: Histological good response to NACRT group showed good prognosis. Lymph node metastasis is a predictive factor for prognosis. In this additional study, Musashi-1 was positive after neoadjuvant chemotherapy in three cases. The histological response was grade 1 in all of them and recurrence was observed within a short period of time. Two cases of grade 3 were negative staining to Musashi-1 and showed no recurrence. CONCLUSIONS: This study shows that NACRT plus surgery with three-field lymphadenectomy is a feasible therapeutic approach for the cases with multiple lymph node metastases. Prognosis was significantly better in cases with marked histological improvement. It is important to find the predictive factors of histological improvement. Musashi-1 might be a candidate maker for histological response and prognosis, and further studies are needed to prove it.

[Two cases of ileocecal carcinoid found by total colonoscopy and a review of the literature on 16 cases].

We report 2 cases of ileocecal carcinoid with review of the literature recently reported in Japan. Both cases were diagnosed as carcinoid by colonoscopic biopsy after ileocecal tumors had been pointed out by computed tomography. We performed curative operation with lymph node dissection. Since multiple lymph node metastases were shown in both cases pathologically, they were closely followed after surgery, but no recurrence has been shown. Since SSTR2a stain was strongly positive in both cases, octreotide, the effectiveness of which was verified in the PROMID study might be administered if necessary. As ileocecal carcinoid has a tendency to metastasize to other organs, careful surveillance by colonoscopy and early detection are required. Furthermore, development of effective drugs following octreotide and further investigation including biological and histopathological analysis of neuroendocrine tumors including carcinoid are necessary.

Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.

Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.

Acquired amegakaryocytic thrombocytopenia after durvalumab administration.

Immune checkpoint inhibitors (ICIs), despite their ability to potentiate antitumor T-cell responses, may cause various immune-related adverse events. Most cases of thrombocytopenia induced by ICIs have revealed a pathophysiologic mechanism of immune thrombocytopenia with increased platelet destruction and preserved megakaryocytes. Acquired amegakaryocytic thrombocytopenic purpura (AATP) is an unusual disorder characterized by thrombocytopenia with markedly diminished bone marrow megakaryocytes in the presence of otherwise normal hematopoiesis. AATP caused by ICIs has not been reported on. Herein, we present the case of a 79-year-old man diagnosed with squamous cell carcinoma of the lung who developed AATP after two courses of durvalumab, a drug targeting programmed death-ligand 1. Two weeks after the second cycle, his platelet count decreased to 2.1 × 104/µL. After the patient underwent platelet transfusion, his platelet count increased to 8.1 × 104/µL the next day but subsequently decreased repeatedly even after the ICI was discontinued. Six weeks after the second cycle, he developed interstitial pneumonia and was administered prednisolone (50 mg/day). However, thrombocytopenia did not improve. Bone marrow biopsy showed scarce megakaryocytes (< 1 megakaryocyte/10 high-power fields) with preservation of myeloid and erythroid series. Myelodysplasia, myelofibrosis, or metastatic lesions were not observed. Cytogenetic analysis showed a normal male karyotype of 46XY. Hence, the patient received eltrombopag, a thrombopoietin receptor agonist, and his platelet count subsequently improved. After recovery, bone marrow aspiration revealed a normal number of megakaryocytes. AATP is rarely the type of thrombocytopenia induced by ICIs and may be successfully treated with thrombopoietin receptor agonists.

The pituitary function of androgen receptor constitutes a glucocorticoid production circuit.

Androgen receptor (AR) mediates diverse androgen actions, particularly reproductive processes in males and females. AR-mediated androgen signaling is considered to also control metabolic processes; however, the molecular basis remains elusive. In the present study, we explored the molecular mechanism of late-onset obesity in male AR null mutant (ARKO) mice. We determined that the obesity was caused by a hypercorticoid state. The negative feedback system regulating glucocorticoid production was impaired in ARKO mice. Male and female ARKO mice exhibited hypertrophic adrenal glands and glucocorticoid overproduction, presumably due to high levels of adrenal corticotropic hormone. The pituitary glands of the ARKO males had increased expression of proopiomelanocortin and decreased expression of the glucocorticoid receptor (GR). There were no overt structural abnormalities and no alteration in the distribution of cell types in the pituitaries of male ARKO mice. Additionally, there was normal production of the other hormones within the glucocorticoid feedback system in both the pituitary and hypothalamus. In a cell line derived from pituitary glands, GR expression was under the positive control of the activated AR. Thus, this study suggests that the activated AR supports the negative feedback regulation of glucocorticoid production via up-regulation of GR expression in the pituitary gland.

[Trends in gastroenteropancreatic neuroendocrine tumors].

Carcinoids were first reported approximately 100 years ago and proposed to be neuroendocrine tumors of hormonal origin some 50 years later. The first edition of the WHO classification included neuroendocrine tumors of the digestive organs and pancreas, but thereafter it was pointed that neuroendocrine cells are distributed throughout the body and thus that carcinoids occur in various other organs. The most recent edition of the WHO classification takes into account the occurrence of neuroendocrine tumors throughout the body. In addition, carcinoids were originally thought to be variants of a benign tumor type with a low malignancy rate, but thereafter metastases were observed. The term "neuroendocrine tumors" is now preferred instead of "carcinoids," and the malignant potential of such tumors is recognized. This paper reviews the classification and treatment of gastroenteropancreatic neuroendocrine tumors.

Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors.

BACKGROUND: We conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors (NETs) newly diagnosed in Japan from 2002 through 2004. METHODS: Data on 1541 patients, 514 pancreatic endocrine tumors (PETs) and 1027 gastrointestinal carcinoids (GICs), were collected and analyzed. RESULTS: Nonfunctioning tumors (NF-PET) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. The incidence of GICs was 28.8%, 5.2%, and 66.0% in foregut, midgut, and hindgut, respectively. Carcinoid syndrome and metastases were observed in only 1.7% and 5.6% of GICs, respectively. CONCLUSIONS: The incidence of NETs in Japan was clarified by this preliminary study. Comparatively large differences in GICs between Japan and Western nations were present with regard to the location, symptomatic status, and prevalence of malignancy.

Airway Obstruction Caused by Substernal Thyrotoxic Multinodular Goiter.

BACKGROUND: Substernal thyrotoxic multinodular goiter (MNG) shows signs and symptoms as a result of compression of adjacent organs and thyrotoxicosis. However, acute airway obstruction is rarely caused by substernal thyrotoxic MNG. CASE REPORT: We have described a 56-year-old Japanese woman who demonstrated acute airway obstruction because of compression of the airway by substernal thyrotoxic MNG. She had been diagnosed with substernal thyrotoxic MNG 6 years back. However, because she was unwilling to undergo surgery to remove substernal thyrotoxic MNG, she was treated with methimazole. The patient maintained normal thyroid function with this therapy for 6 years. However, after 6 years the patient was admitted to our hospital because of severe dyspnea. Physical examination revealed inspiratory stridor, which indicated an airway obstruction caused by substernal thyrotoxic MNG. Airway intubation and subtotal thyroidectomy were performed. After the surgery, the dyspnea ameliorated. The general condition of the patient remained good 6 months after the surgery. CONCLUSION: This case clearly demonstrates the need for careful monitoring of substernal thyrotoxic MNG, because it may lead to an airway obstruction.

Glucose transporter-1 expression in the thyroid gland: clinicopathological significance for papillary carcinoma.

Glucose transporter-1 (GLUT-1) expression was immunohistochemically analysed in a total of 268 cases of thyroid gland disease, including 129 cases of papillary carcinoma (PC), 60 cases of follicular carcinoma (FC), 57 cases of follicular adenoma, and 22 cases of adenomatous goitre. Seventy-one percent (91/129) of PC cases showed GLUT-1 expression, semi-quantitatively evaluated as: +, 21 cases (16%); 2+, 37 cases (29%); 3+, 33 cases (26%); and negative, 38 cases (29%). These positive cases were divided into two groups: 'membrane-like' pattern in 24 cases (19%), and 'cytoplasm-predominance' pattern in 67 cases (52%). GLUT-1 expression was observed in 5% (3/60) of FC cases, but all follicular adenomas and adenomatous goitres were negative for GLUT-1 (PC vs. FC, p<0.0001). Membrane-like expression was observed more frequently in non-organ-confined PCs (pT4) than in organ-confined PCs (pT1, 2, and 3) (p=0.0056). Seventy-five percent (18/24) of PC cases showing membrane-like expression were non-organ-confined. The membrane-like pattern was observed more frequently in PCs with lymph node (LN) metastasis compared to those without (p=0.0036). Ninety-two percent (22/24) of PC cases showing the membrane-like pattern were not organ-confined. Semi-quantitative analysis of glut-1 mRNA by RT-PCR showed a tendency toward higher expression in PCs compared to FCs, follicular adenomas and adenomatous goitres, and the mRNA expression in PCs with a membrane-like pattern was higher than those showing cytoplasm-predominance. We concluded that: 1) GLUT-1 is immunohistochemically useful in distinguishing PC from FC and benign diseases; 2) GLUT-1 may play an important role in the advancement of PC and LN metastasis, and its membrane-like expression is of more clinical significance than the cytoplasm-predominance pattern; and 3) glut-1 mRNA expression corresponds with the immunohistochemical expression profile.

Expression of carbohydrate antigens (SSEA-1, sialyl-Lewis X, DU-PAN-2 and CA19-9) and E-selectin in urothelial carcinoma of the renal pelvis, ureter, and urinary bladder.

Carbohydrate antigens and E-selectin play important roles in the invasion and metastasis of cancers. We examined the expression of these antigens and their ligand protein, E-selectin, in urothelial carcinomas to evaluate whether their staining is correlated with the grade and stage of cancer. We studied the expression of carbohydrate antigens (type 1 and type 2 blood-group antigens) and E-selectin in urothelial carcinomas of the renal pelvis, ureter, and urinary bladder in 52 patients by staining SSEA-1 (LeX), sialyl LeX (sLeX), DU-PAN-2, CA19-9, and E-selectin with 5 different monoclonal antibodies (MAbs) to evaluate whether their staining correlated with cancer grade and stage. The differences between organs with regard to the degree of expression of these antigens were not evident. Type 2 antigens (SSEA-1 and sialyl LeX) are frequently expressed in the tumor cells regardless of atypical grade. The expression level of type 1 antigens (DU-PAN-2 and CA19-9) is lower than that of type 2 antigens. However, the presence of DU-PAN-2 tends to correlate with the grade of atypia; however, that of CA19-9 is inversely proportional to the grade of atypia. The lack of CA19-9 and appearance of DU-PAN-2 in urothelial carcinoma implies a high malignant potential. The expression of E-selectin can be correlated with stage and grade of tumor atypia. Type 2 antigen and E-selectin may be involved in tumor invasion and metastasis.

[Schwannoma of the kidney with severe calcification: a case report].

Schwannoma arising from the kidney is a rare benign tumor, with only 20 cases reported in the English literature. We encountered a histopathologically typical Schwannoma of the kidney in a 39-year-old woman, which was characterized by marked calcification. Radical nephrectomy was performed under the diagnosis of renal cell carcinoma. The 21 reported cases of schwannoma of the kidney, including the present case, are reviewed in detail.

Unique properties of 189 amino acid isoform of vascular endothelial growth factor in tumorigenesis.

The 189 amino acid isoform of vascular endothelial growth factor (VEGF189) has been shown to be more strongly associated with the cell membrane than other isoforms of human VEGF (VEGF121, VEGF165). To analyze the biological activities of these VEGF isoforms on tumor growth, we transfected human VEGF121, VEGF165 or VEGF189 cDNA into the human colon cancer cell line SW-480, and established several clones overexpressing these VEGF isoforms. The total amounts of VEGF protein in the culture supernatants of the VEGF189-transfectants were less than those of VEGF121 and VEGF165-transfectants. These transfectants showed no significant differences in growth in culture. Nevertheless, the rate of in vivo tumor growth of VEGF189-transfectants was faster than or equivalent to that of VEGF121-transfectants, while the VEGF165-transfectant showed the greatest enhancement of tumor growth. The protein levels of VEGF were markedly increased only in the VEGF189-transfectants cultured in the presence of heparin. The enhanced in vivo tumor growth of VEGF189-transfectants can be partly explained by the cell-associated features of VEGF189 molecules. The VEGF189 molecule, which is strongly bound to the cell surface, has unique properties and high potential in local angiogenesis and tumor growth in the cancer inductive microenvironment.

Reversal of drug resistance mediated by hammerhead ribozyme against multidrug resistance-associated protein 1 in a human glioma cell line.

We examined the effects of suppressing multidrug resistance-associated protein 1 (MRP1) gene expression in a human glioma cell line U87MG. Hammerhead ribozymes, designed to cleave MRP1 mRNA (alphaMRP1-Rz), were transfected into the U87MG cells. The U87MG/alphaMRP1-Rz cells were significantly sensitive to nitrosourea (ACNU) and doxorubicin (DOX) compared with the U87MG cells (p<0.01 and p<0.05, respectively, unpaired t-test). There was no significant difference in the expression of other human genes between the U87MG/alphaMRP1-Rz and controls by cDNA array. The hammerhead ribozyme-mediated specific suppression of MRP1 was sufficient to reverse the resistance of ACNU and DOX in the human glioma cell line.

Interleukin-10 expression is closely correlated with the expression of granulocyte-macrophage colony-stimulating factor in non-small cell lung cancer.

It is unclear how the cytokine network contributes to the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in non-small cell lung cancer (NSCLC). We examined the gene expression of GM-CSF and interleukin (IL)-10 in 78 surgical specimens and 16 xenografts of NSCLC by reverse transcription-polymerase chain reaction. Forty-four of the 78 (56.4%) surgical specimens and 11 of the 16 (68.8%) xenografts of NSCLC showed GM-CSF gene expression. Forty-one of the 44 (93.2%) GM-CSF-positive NSCLC specimens showed IL-10 expression, and GM-CSF expression was significantly correlated with IL-10 expression (p < 0.0171, Mann-Whitney's U-test). These results suggested that IL-10 is one of the cytokines up-regulating the GM-CSF expression in NSCLC.

[Histopathology and tumor markers].

Serum tumor markers are useful for detection and diagnosis of cancer. Recent advances in cellular and molecular biology have developed procedures of immunohistochemistry including high sensitivity staining and epitope retrieval. Using the immunohistochemical analyses, we can detect various tumor markers, i.e., not only serum tumor markers (serum protein, carbohydrates), but also cellular skeletons, lymphocyte surface antigens, cytoplasmic markers, oncogene products and cell adhesion molecules. This article focuses on several immunohistochemical tumor markers. Carcinoembryonic antigen(CEA) is one of the good markers of colorectal cancer. Recent studies have demonstrated that CEA may function as a metastatic potentiator by different pathway, such as modulation of immune responses, facilitation of intercellular adhesion and cellular migration. CA19-9 (sialyl Le antigen), a member of a family of high molecular weight glycoproteins, was originally described as a gastrointestinal- and pancreatic-specific tumor marker. Recent studies have demonstrated that sialyl Le is a ligand for E-selectin and may play an important role in tumor metastasis. Stromal immunoreactivities of CEA or CA19-9 were correlated with lymph node metastasis and/or vascular invasion. p53 is one of the most important tumor suppressor genes, and the p53 gene product is known to regulate cell growth and proliferation. Mutation of the p53 gene can be detected immunohistochemically as overexpression of its protein in the nucleus. Diffuse p53 immunoreactivity was a histological marker of adenocarcinoma. In conclusion, immunohistochemical tumor markers are useful for histopathological diagnosis and can be prognostic predictors of cancer.

The current status of tailor-made medicine with molecular biomarkers for patients with clear cell renal cell carcinoma.

Appropriate use of multiple reliable molecular biomarkers in the right context will play a role in tailormade medicine of clear cell renal cell carcinoma (RCC) patients in the future. A total of 11,056 patients from 53 studies were included in this review. The article numbers of the each evidence levels, using the grading system defined by the Oxford Centre for Evidence-based Medicine, in 1b, 2a, 2b, and 3b were 5 (9%), 18 (34%), 29 (55%), and 1 (2%), respectively. The main goal of using biomarkers is to refine predictions of tumor progression, pharmacotherapy responsiveness, and cancer-specific and/or overall survival. Currently, carbonic anhydrase (CA9) and vascular endothelial growth factor (VEGF) in peripheral blood and p53 in tumor tissues are measured to predict metastasis, while VEGF-related proteins in peripheral blood are used to assess pharmacotherapy responsiveness with sunitinib. Furthermore, interleukin 8, osteopontin, hepatocyte growth factor, and tissue inhibitors of metalloproteinases-1 in peripheral blood enable assessment of responsiveness to pazopanib treatment. Other reliable molecular biomarkers include von Hippel­Lindau gene alteration, hypoxia-inducible factor-1a, CA9, and survivin in tumor tissues and VEGF in peripheral blood for predicting cancer-specific survival. In the future, studies should undergo external validation for developing tailored management of clear cell RCC with molecular biomarkers, since individual institutional studies lack the generalization and consistency required to maintain accuracy among different patient series.