Trifecta outcomes of robotic partial nephrectomy in obese patients: A comparison of body mass index <25, 25 to <30, and ≥30.

OBJECTIVE: We analyzed robotic partial nephrectomy (RPN) outcomes in obese patients based on body mass index (BMI) and trifecta achievement. METHODS: We retrospectively reviewed 296 patients who underwent RPN at Kansai Medical University Hospital between 2014 and 2022. The preoperative clinical data and perioperative outcomes were evaluated. Trifecta achievement (negative surgical margin, no major complications, and no acute kidney injury on postoperative day three) and its relationship to three BMI groups (<25, 25 to <30, and ≥30) were the primary outcome. The correlation between factors in achieving trifecta and BMI was evaluated. Univariate and multivariate analyses assessed variables for achieving the trifecta with logistic regression analysis. C-statistics quantitatively evaluated the prediction accuracy. RESULTS: Among 296 patients, 264 (89.2%) achieved trifecta (BMI categories were <25 [89.9%], 25 to <30 [89.4%], and ≥30 [82.6%]). There was no significant BMI-related difference (p = 0.566). Intraoperative blood loss increased with the BMI (p = 0.034). Multivariate analyses showed preoperative aspects and dimensions used for anatomic (PADUA) score independently predicted trifecta failure (odds ratio 1.71; 95% confidence interval 1.32-2.20; p < 0.001). The C-statistics of the PADUA score increased with increasing BMI. CONCLUSIONS: Higher BMI patients had more intraoperative blood loss during RPN. However, RPN remains safe and has acceptable quality and functional outcomes. Since patients with high PADUA scores combined with a high BMI may be at risk of trifecta failure, this should be explained before RPN.

Preoperative Factors Associated with Intraoperative Maximum Arterial Pressures in Patients with Pheochromocytoma and Paraganglioma.

Background: Surgery for pheochromocytoma and paraganglioma (PPGL) can lead to life-threatening complications, such as intraoperative hypertensive crises, even when adequate doses of preoperative α-receptor blockades are administered. Objectives: The aim of this study was to identify preoperative factors associated with intraoperative maximum arterial pressure (AP) in patients with PPGL. Methods: We retrospectively reviewed the cases of 61 PPGL patients who underwent surgical resection in our hospital between 2006 and 2020. The primary outcome was intraoperative maximum AP as a single index for continuous variables. Simple and multiple linear regression model were used for statistical analysis. Results: The median maximum systolic AP during surgery was 165 mmHg (interquartile range: 150 - 180 mmHg). Log24-h urinary-fractionated metanephrine (MN) and normetanephrine (NMN) was correlated with intraoperative maximum AP (R-squared = 0.218, P < 0.001). Multiple regression analyses showed that diabetes mellitus, one or more of the classic triad, and log24-h urinary-fractionated MN and NMN were independent factors associated with intraoperative maximum AP. Conclusions: Patients with PPGL accompanied by diabetes mellitus, one or more of the classic triad, and high log 24-h urinary-fractionated MN and NMN values may be at risk for hypertensive crises during surgery regardless of whether preoperative α-receptor blockades are used. Clinicians should manage these patients more carefully and effectively.

Histologic-Based Tumor-Associated Immune Cells Status in Clear Cell Renal Cell Carcinoma Correlates with Gene Signatures Related to Cancer Immunity and Clinical Outcomes.

The three-tier immunophenotype (desert, excluded, and inflamed) and the four-tier immunophenotype (cold, immunosuppressed, excluded, and hot) have been linked to prognosis and immunotherapy response. This study aims to evaluate whether immunophenotypes of clear cell renal cell carcinoma, identified on hematoxylin and eosin-stained slides, correlate with gene expression signatures related to cancer immunity, and clinical outcomes. We evaluated tumor-associated immune cells (TAICs) status using three methodologies: three-tier immunophenotype based on the location of TAICs, four-tier immunophenotype considering both the location and degree of TAICs and inflammation score focusing only on the degree of TAICs, using a localized clear cell renal cell carcinoma cohort (n = 436) and The Cancer Genome Atlas (TCGA)-KIRC cohort (n = 162). We evaluated the association of the TAICs status assessed by three methodologies with CD8 and PD-L1 immunohistochemistry and immune gene expression signatures by TCGA RNA-sequencing data. All three methodologies correlated with immunohistochemical and immune gene expression signatures. The inflammation score and the four-tier immunophenotype showed similarly higher accuracy in predicting recurrence-free survival and overall survival compared to the three-tier immunophenotype. In conclusion, a simple histologic assessment of TIACs may predict clinical outcomes and immunotherapy responses.

PBRM1 Immunohistochemical Expression Profile Correlates with Histomorphological Features and Endothelial Expression of Tumor Vasculature for Clear Cell Renal Cell Carcinoma.

Loss of the polybromo-1 (PBRM1) protein has been expected as a possible biomarker for clear cell renal cell carcinoma (ccRCC). There is little knowledge about how PBRM1 immunohistochemical expression correlates with the histomorphological features of ccRCC and the endothelial expression of tumor vasculature. The present study evaluates the association of architectural patterns with the PBRM1 expression of cancer cells using a cohort of 425 patients with nonmetastatic ccRCC. Furthermore, we separately assessed the PBRM1 expression of the endothelial cells and evaluated the correlation between the expression of cancer cells and endothelial cells. PBRM1 loss in cancer cells was observed in 148 (34.8%) patients. In the correlation analysis between architectural patterns and PBRM1 expression, macrocyst/microcystic, tubular/acinar, and compact/small nested were positively correlated with PBRM1 expression, whereas alveolar/large nested, thick trabecular/insular, papillary/pseudopapillary, solid sheets, and sarcomatoid/rhabdoid were negatively correlated with PBRM1 expression. PBRM1 expression in vascular endothelial cells correlated with the expression of cancer cells (correlation coefficient = 0.834, p < 0.001). PBRM1 loss in both cancer and endothelial cells was associated with a lower recurrence-free survival rate (p < 0.001). Our PBRM1 expression profile indicated that PBRM1 expression in both cancer and endothelial cells may be regulated in an orchestrated manner.

Development and validation of a vascularity-based architectural classification for clear cell renal cell carcinoma: correlation with conventional pathological prognostic factors, gene expression patterns, and clinical outcomes.

The prognostic significance of an architectural grading system for clear cell renal cell carcinoma (ccRCC) has recently been demonstrated. The present study aimed to establish a vascularity-based architectural classification using the cohort of 436 patients with localized ccRCC who underwent extirpative surgery and correlated the findings with conventional pathologic factors, gene expression, and prognosis. First, we assessed architectural patterns in the highest-grade area on hematoxylin and eosin-stained slides, then separately evaluated our surrogate score for vascularity. We grouped nine architectural patterns into three categories based on the vascular network score. "Vascularity-based architectural classification" was defined: category 1: characterized by enrichment of the vascular network, including compact/small nested, macrocyst/microcystic, and tubular/acinar patterns; category 2: characterized by a widely spaced-out vascular network, including alveolar/large nested, thick trabecular/insular, papillary/pseudopapillary patterns; category 3: characterized by scattered vascularity without a vascular network, including solid sheets, rhabdoid and sarcomatoid patterns. Adverse pathological prognostic factors such as TNM stage, WHO/ISUP grade, and necrosis were significantly associated with category 3, followed by category 2 (all p < 0.001). We successfully validated the classification using The Cancer Genome Atlas (TCGA) cohort (n = 162), and RNA-sequencing data available from TCGA showed that the angiogenesis gene signature was significantly enriched in category 1 compared to categories 2 and 3, whereas the immune gene signature was significantly enriched in category 3 compared to categories 1 and 2. In univariate analysis, vascularity-based architectural classification showed the best accuracy in pathological prognostic factors for predicting recurrence-free survival (c-index = 0.786). The predictive accuracy of our model which integrated WHO/ISUP grade, necrosis, TNM stage, and vascularity-based architectural classification was greater than conventional risk models (c-index = 0.871 vs. 0.755-0.843). Our findings suggest that the vascularity-based architectural classification is prognostically useful and may help stratify patients appropriately for management based on their likelihood of post-surgical recurrence.

Tumor volume and tumor crossing of the axial renal midline predict renal function after robotic partial nephrectomy.

There are several nephrometry scoring systems for predicting surgical complexity and potential perioperative morbidity. The R.E.N.A.L. scoring system, one of the most well-known nephrometry scoring systems, emphasizes the features on which it is based (Radius, Exophytic/endophytic, Nearness to collecting system or sinus, Anterior/posterior, and Location relative to polar lines). The ability of these nephrometry scoring systems to predict loss of renal function after robotic partial nephrectomy (RPN) remains controversial. Therefore, we verified which combination of factors from nephrometry scoring systems, including tumor volume, was the most significant predictor of postoperative renal function. Patients who underwent RPN for cT1 renal tumors in our hospital were reviewed retrospectively (n = 163). The preoperative clinical data (estimated glomerular filtration rate [eGFR], comorbidities, and nephrometry scoring systems including R.E.N.A.L.) and perioperative outcomes were evaluated. We also calculated the tumor volume using the equation applied to an ellipsoid by three-dimensional computed tomography. The primary outcome was reduced eGFR, which was defined as an eGFR reduction of ≥ 20% from baseline to 6 months after RPN. Multivariable logistic regression analyses were used to evaluate the relationships between preoperative variables and reduced eGFR. Of 163 patients, 24 (14.7%) had reduced eGFR. Multivariable analyses indicated that tumor volume (cutoff value ≥ 14.11 cm3, indicating a sphere with a diameter ≥ approximately 3 cm) and tumor crossing of the axial renal midline were independent factors associated with a reduced eGFR (odds ratio [OR] 4.57; 95% confidence interval [CI] 1.69-12.30; P = 0.003 and OR 3.50; 95% CI 1.30-9.46; P = 0.034, respectively). Our classification system using these two factors showed a higher area under the receiver operating characteristic curve (AUC) than previous nephrometry scoring systems (AUC = 0.786 vs. 0.653-0.719), and it may provide preoperative information for counseling patients about renal function after RPN.

Eosinophilic features in clear cell renal cell carcinoma correlate with outcomes of immune checkpoint and angiogenesis blockade.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) displays heterogeneity in appearance-a distinctive pale clear to eosinophilic cytoplasm; however, little is known about the underlying mechanisms and clinical implications. We investigated the role of these eosinophilic features in ccRCC on oncological outcomes and response to tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). METHODS: One-hundred and thirty-eight ccRCC cases undergoing radical surgery (cohort 1) and 54 metastatic ccRCC cases receiving either TKIs or ICIs (cohort 2) were included. After histological evaluation, all cases were divided into three phenotypes based on the eosinophilic features at the highest-grade area: clear, mixed, or eosinophilic type. Gene expression and immunohistochemical analyses were performed to explore the potential mechanisms of these phenotypes in cohort 1. Further, the association of the three phenotypes with the best objective response to TKI or ICI, clinical benefit (complete/partial response or stable disease), and overall survival (OS) was assessed in cohort 2. RESULTS: The clear type was significantly associated with increased hypoxia as well as angiogenesis gene signatures compared with the eosinophilic type. Gene signatures and protein expression related to effector T cell and immune checkpoint molecules were elevated to a greater extent in the eosinophilic type, followed by the mixed and clear types. The mixed and eosinophilic types exhibited greater PBRM1-negativity and increased prevalence of the epithelial-mesenchymal transition gene signature than the clear type. In the mixed/eosinophilic types of cohort 2, significant clinical benefit was observed in the ICI therapy group versus the TKI therapy group (p=0.035), and TKI therapy vs ICI therapy was an independent factor for worse prognosis of OS (HR 3.236; p=0.012). CONCLUSION: The histological phenotype based on the eosinophilic features, which are linked to major immunological mechanisms of ccRCC, was significantly correlated with therapeutic efficacy.

PD-L1 Expression and Clinicopathological Factors in Renal Cell Carcinoma: A Comparison of Antibody Clone 73-10 With Clone 28-8.

BACKGROUND/AIM: Expression of programmed death ligand-1 (PD-L1) is associated with poor prognosis in renal cell carcinoma (RCC). Although a new antibody clone for immunohistochemical assay, 73-10, has shown greater sensitivity than other assays (28-8, 22C3, SP142, and SP263) in non-small cell lung cancer, PD-L1 expression using 73-10 has never been assessed in RCC. Therefore, this study aimed to evaluate the association of clinicopathological factors with PD-L1 expression detected by clone 73-10 and compare it with that detected by 28-8. PATIENTS AND METHODS: Tissue microarray samples from 582 patients who underwent radical or partial nephrectomy for RCC were immunohistochemically assessed using clones 73-10 and 28-8. RESULTS: The positivity for PD-L1 expression in RCC by 73-10 was higher than that of 28-8 and significantly associated with worse pathological factors and a higher risk of cancer-specific mortality. CONCLUSION: Positivity for PD-L1 expression by 73-10, as compared to 28-8, was associated with worse clinicopathological factors and prognosis for patients with RCC.

Predictors of postoperative recurrence in patients with non-metastatic pT3a renal cell carcinoma.

OBJECTIVE: To analyze the effect of patterns of extrarenal tumor extension with other pathological factors on postoperative recurrence in patients with non-metastatic pT3a renal cell carcinoma. METHODS: We retrospectively reviewed 587 non-metastatic renal cell carcinoma patients who underwent radical surgery between 2006 and 2017 at Kansai Medical University Hospital, Hirakata, Osaka, Japan. We extracted a subset of 114 patients with pT3a of predominant histological types: 93 with clear cell renal cell carcinoma (81.6%), 13 with unclassified renal cell carcinoma (11.4%), six with chromophobe renal cell carcinoma (5.3%) and two with papillary renal cell carcinoma. The primary end-point was recurrence-free survival. The Kaplan-Meier method and Cox proportional hazards model were used for statistical analysis. RESULTS: Of the 114 patients with pT3a renal cell carcinoma, 42 patients (36.8%) experienced recurrence. Multivariate analysis showed that perinephric fat invasion (hazard ratio 2.36, P = 0.009), sarcomatoid or rhabdoid component (hazard ratio 2.88, P = 0.022) and necrosis (hazard ratio 2.34, P = 0.030) were independent factors for recurrence-free survival. The high-risk pT3a group, which had more than two independent predictors, had poor prognosis. Recurrence-free survival of the high-risk pT3a group and the pT3b or greater group were similar (median recurrence-free survival 23.0 and 10.8 months, respectively). CONCLUSIONS: Perinephric fat invasion, sarcomatoid or rhabdoid component and necrosis are independent predictors of recurrence-free survival in patients with pT3a-predominant renal cell carcinoma. Patients with more than two of these predictors have poor oncological outcomes. These findings will aid in risk stratification for predicting recurrence and provide prognostic information for patient counseling.

Association of intraductal carcinoma of the prostate detected by initial histological specimen and neuroendocrine prostate cancer: A report of three cases.

We present three cases of neuroendocrine prostate cancer (NEPC) and histologically investigate the association of intraductal carcinoma of the prostate (IDC-P) and NEPC. Case 1 was a 76-year-old man who had NEPC identified by repeated biopsy specimens when his prostate-specific antigen (PSA) level became elevated 8 years after the initiation of androgen deprivation therapy (ADT). Case 2 was a 70-year-old man who had NEPC detected when multiple bone metastases were found 3 years after the initiation of ADT. Case 3 was a 70-year-old man who was diagnosed with NEPC based on histological examination of transurethral resected specimens. The histological findings in these three cases showed mixed neuroendocrine carcinoma-acinar adenocarcinoma with various proportions of both components. In all three cases, the neuroendocrine carcinoma components were positive for synaptophysin and chromogranin A, whereas the adenocarcinoma components were positive for PSA and NKX3.1. When we retrospectively reviewed the initial hematoxylin and eosin-stained slides, IDC-P was detected in all three cases. Furthermore, we collected nine additional cases of NEPC and found that all six cases with initial biopsy specimens available had an IDC-P component. Detecting IDC-P on initial histological specimens of the prostate may predict transformation to NEPC.

Integration of NRP1, RGS5, and FOXM1 expression, and tumour necrosis, as a postoperative prognostic classifier based on molecular subtypes of clear cell renal cell carcinoma.

Molecular mechanisms of progression of clear cell renal cell carcinoma (ccRCC) have been proven with recent genomic or transcriptional analyses. However, it is still difficult to apply these analyses to daily clinical practice owing to economical and practical issues. Here, we established a pathology-based, postoperative prognostic classification based on the well-validated transcriptional classifier, ClearCode34, in ccRCC. A total of 342 cases with available tissue were identified and randomly allocated into a discovery cohort (n = 138) and a validation cohort (n = 204). Levels of mRNA were quantified using a nCounter Digital Analyzer, and the ccA/ccB subtypes were determined. Histological and immunohistochemistry (IHC) analyses were subsequently performed to establish a pathology-based classification based on the mRNA levels. Finally, the prognostic ability of the new classifier was evaluated in both the discovery and validation cohorts. Of 138 cases in the discovery cohort, 78 (56.5%) and 60 (43.5%) were assigned to the ccA and ccB subtypes, respectively. Proangiogenic genes, neuropilin 1 (NRP1) and regulator of G protein signalling 5 (RGS5), were especially overexpressed in all ccRCC samples and were enriched in ccA-assigned tumours. Histologically, tumour necrosis and the sarcomatoid feature were associated with the ccB subtype. In IHC analyses, expression of NRP1, RGS5, and forkhead box M1 (FOXM1), an epithelial-mesenchymal transition-related factor, significantly correlated with the ccA/ccB subtypes. Combining these three IHC factors and tumour necrosis, we developed the IHC/histology-based classifier, which showed good concordance with the ClearCode34 classifier with an accuracy of 0.80. The established classification significantly stratified relapse-free, cancer-specific, and overall survival rates in both the discovery and validation cohorts. The novel molecular pathology classifier integrating NRP1, RGS5, FOXM1, and tumour necrosis may enable the stratification of oncological outcomes for patients with ccRCC undergoing resection surgery.

The SSPN Score, a Novel Scoring System Incorporating PBRM1 Expression, Predicts Postoperative Recurrence for Patients with Non-metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND: The loss of PBRM1 expression (as identified by immunohistochemistry) is associated with a high risk of postoperative recurrence for patients with clear cell renal cell carcinoma (ccRCC). The authors developed a scoring system to predict recurrence based on clinicopathologic factors incorporating PBRM1 expression. METHODS: This study retrospectively reviewed 479 ccRCC patients who underwent radical surgery between 2006 and 2017. The study extracted a subset of 389 non-metastatic ccRCC patients for whom relevant clinicopathologic factors were available. The primary end point was recurrence-free survival (RFS). The Kaplan-Meier method and the Cox proportional hazards model were used for statistical analysis. Leibovich score, SSIGN score, and University of California, Los Angeles (UCLA) Integrated Staging System were included as conventional prediction models. RESULTS: Of the 389 patients, 53 (13.6%) experienced recurrence during a median period of 61 months. Multivariable analyses showed that that the independent factors for RFS were ≥ pT3 (hazard ratio [HR] 3.64; P < 0.001), sarcomatoid or rhabdoid component (HR 3.29; P = 0.005), PBRM1 negativity (HR 3.39; P = 0.001), and necrosis (HR 3.60; P < 0.001). A scoring system calculated with these factors, named the SSPN (stage, sarcomatoid, PBRM1 expression, and necrosis) score, showed significant differences in RFS among the following four groups; low-risk group (0 factors), intermediate-risk group (1 factor), high-risk group (2 to 3 factors), and very high-risk group (4 factors) (P < 0.001). The authors' model also showed a greater predictive accuracy for 5-year RFS than the conventional models (0.841 vs 0.747-0.792). CONCLUSIONS: The SSPN score, which integrates clinicopathologic findings and PBRM1 expression, can accurately predict postoperative recurrence for patients with non-metastatic ccRCC after radical surgery.

Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study.

Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic ß-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.

Laparoendoscopic Single-Site Surgery for Urachal Remnants: A Single-Center Experience.

INTRODUCTION: Urachal remnants are relatively rare. Generally, urachal remnants are detected in young people, and the removed specimen is small, comprising a good indication for laparoscopic surgery. Laparoendoscopic single-site surgery (LESS) for urachal remnants is considered to be safe and result in an excellent cosmetic outcome. Therefore, we report our single-center experience with LESS for urachal remnants. METHODS: We retrospectively reviewed 30 patients with urachal remnants who underwent LESS from January 2011 to December 2017. The patients' characteristics, surgical data, postoperative pain, and cosmetic assessment results were retrospectively collected and analyzed. RESULTS: Mean total operative time was 151 min, mean pneumoperitoneal surgery time was 83 min, and mean estimated blood loss was 5.0 mL. All patients were started on an oral diet and began ambulating on postoperative day 1. Mean hospital stay was 5.5 days. LESS was completed successfully in all patients, with no conversion to conventional or open surgery. CONCLUSIONS: LESS is a viable option for the surgical treatment of urachal remnants. This technique may result in less pain than conventional techniques. Further accumulation of surgical outcomes (especially regarding safety and cosmesis) is required for LESS to become an established treatment for urachal remnants.

Pheochromocytoma arising from an ectopic adrenal tissue in multiple endocrine neoplasia type 2A.

SUMMARY: A 21-year-old woman was referred to our hospital to treat bilateral pheochromocytomas (PCCs) after a diagnosis of multiple endocrine neoplasia type 2A (MEN2A). We performed bilateral laparoscopic adrenalectomy. One year after the operation, urinary fractionated metanephrines in 24-h urine increased. MRI showed a 30 mm tumor on the interaortocaval region and 123I-MIBG concentrated in this area. We excised the tumor and performed para-aortic lymphadenectomy. Histopathologic examination confirmed a PCC arising from ectopic adrenal tissue. Urinary fractionated metanephrines in 24-h urine declined to basal levels immediately after the operation. We detected no recurrence of paraganglioma or PCC for 5 years after the treatment. LEARNING POINTS: Most ectopic adrenal tissue is associated with no symptoms and contains only the adrenal cortex. Adrenocortical tumors sometimes arise from ectopic adrenal tissues similarly to in the normal adrenal gland. PCC arising from ectopic adrenal tissue occurs infrequently. MEN2-related PCC is accompanied by adrenal medullary hyperplasia, which might be part of tumorigenesis.

Intestinal stem cells contribute to the maturation of the neonatal small intestine and colon independently of digestive activity.

The murine intestine, like that of other mammalians, continues to develop after birth until weaning; however, whether this occurs in response to an intrinsic developmental program or food intake remains unclear. Here, we report a novel system for the allotransplantation of small intestine and colon harvested from Lgr5 EGFP-IRES-CreERT2/+; Rosa26 rbw/+ mice immediately after birth into the subrenal capsule of wild-type mice. By histological and immunohistochemical analysis, the developmental process of transplanted small intestine and colon was shown to be comparable with that of the native tissues: mature intestines equipped with all cell types were formed, indicating that these organs do not require food intake for development. The intestinal stem cells in transplanted tissues were shown to self-renew and produce progeny, resulting in the descendants of the stem cells occupying the crypt-villus unit of the small intestine or the whole crypt of the colon. Collectively, these findings indicate that neonatal intestine development follows an intrinsic program even in the absence of food stimuli.

[Improvement in Hyperglysemia Following Unilateral Adrenalectomy for ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH) : A Case Report].

Adrenal corticotropin (ACTH) -independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing's syndrome. Bilateral adrenalectomy is the treatment of choice, but lifetime steroid replacement is essential. Here we report a case of AIMAH whose hyperglycemia was improved following unilateral adrenalectomy. A 42-year-old woman with serious intellectual disability and intractable epilepsy presented with polydipsia. Casual blood glucose and hemoglobin A1c (HbA1c) were 322 mg/dl and 8.5%, respectively. The cortisol level was high and ACTH level was low. Abdominal computed tomography and magnetic resonance imaging revealed unsuspected macronodular enlargement of bilateral adrenal glands (left 8 cm, right 4 cm in maximal diameter) and she was diagnosed with AIMAH. Both adrenal glands showed intense 131 I-adosterol accumulation predominantly in the left side and left-unilateral laparoscopic adrenalectomy was performed. Both insulin and oral antidiabetic drugs could be cancelled postoperatively, and HbA1c decreased to 5.7%. Steroid was not replaced but she never experienced adrenal crisis. We conclude that unilateral adrenalectomy is a safe and effective treatment for certain cases of AIMAH.

Intestinal cancer stem cells marked by Bmi1 or Lgr5 expression contribute to tumor propagation via clonal expansion.

Although the existence of cancer stem cells in intestine tumors has been suggested, direct evidence has not been yet provided. Here, we showed, using the multicolor lineage-tracing method and mouse models of intestinal adenocarcinoma and adenoma that Bmi1- or Lgr5- positive tumorigenic cells clonally expanded in proliferating tumors. At tumor initiation and during tumor propagation in the colon, the descendants of Lgr5-positive cells clonally proliferated to form clusters. Clonal analysis using ubiquitous multicolor lineage tracing revealed that colon tumors derived from Lgr5-positive cells were monoclonal in origin but eventually merged with neighboring tumors, producing polyclonal tumors at the later stage. In contrast, the origin of small intestine tumors was likely polyclonal, and during cancer progression some clones were eliminated, resulting in the formation of monoclonal tumors, which could merge similar to colon tumors. These results suggest that in proliferating intestinal neoplasms, Bmi1- or Lgr5-positive cells represent a population of cancer stem cells, whereas Lgr5-positive cells also function as cells-of-origin for intestinal tumors.

Bmi1-positive cells in the lingual epithelium could serve as cancer stem cells in tongue cancer.

We recently reported that the polycomb complex protein Bmi1 is a marker for lingual epithelial stem cells (LESCs), which are involved in the long-term maintenance of lingual epithelial tissue in the physiological state. However, the precise role of LESCs in generating tongue tumors and Bmi1-positive cell lineage dynamics in tongue cancers are unclear. Here, using a mouse model of chemically (4-nitroquinoline-1-oxide: 4-NQO) induced tongue cancer and the multicolor lineage tracing method, we found that each unit of the tumor was generated by a single cell and that the assembly of such cells formed a polyclonal tumor. Although many Bmi1-positive cells within the tongue cancer specimens failed to proliferate, some proliferated continuously and supplied tumor cells to the surrounding area. This process eventually led to the formation of areas derived from single cells after 1-3 months, as determined using the multicolor lineage tracing method, indicating that such cells could serve as cancer stem cells. These results indicate that LESCs could serve as the origin for tongue cancer and that cancer stem cells are present in tongue tumors.