A 2-center review of histopathology of variants of upper urinary tract urothelial carcinoma and their impact on clinical outcomes.

INTRODUCTION: Similar to bladder cancer, about one third of upper tract urothelial carcinoma (UTUC) present variant histology (VH). We aim to evaluate the incidence, clinical characteristics and the impact on outcomes of VH in UTUC. METHODS: We consecutively enrolled 77 patients treated between 2009 and 2022 by radical surgery for UTUC from a secondary and a tertiary referral center. A pathology review of all specimens was performed by 1 independent uropathologist for each center. We compared pure UTUC and UTUC with VH and the accuracy of endoscopic biopsy. Descriptive and comparative analysis was performed to assess the association with clinical characteristics and the Kaplan-Meier estimator to compare outcomes. RESULTS: Median follow-up after surgery was 51 months. VH was present in 21/77 (28%) patients and 4/21 (19%) patients had multiple variants. The most frequent VH was squamous 12/21 (57%), followed by glandular 7/21 (33%) and micropapillary 3/21 variants (14%). Neuroendocrine carcinoma was present in 2 patients. Nested variant was found in 1 patient. Muscle invasive tumor (≥pT2) was present in 30/56 (54%) patients with pure UTUC and in 18/21 (86%) patients with VH (P < 0.05). Presence of carcinoma in situ was seen in 24/56 (43%) patients with pure UTUC and in 16/21 (76%) with VH (P < 0.05). Cumulative 8/56 (14%) with pure UTUC had a nonintravesical recurrence (6 patients with local and 2 distant recurrence) compared to 8/21 (38%) (3 local, 3 nodal, 2 distant) in the subgroup with VH (P < 0.05). Opposite effect was noted for bladder recurrence: 60% for pure UTUC vs. 29% for tumors with VH (P < 0.05). Review of preoperative endoscopic biopsy did not show the presence of VH in any patients. Differences in outcomes did not reach significance: 3yr-OS 63% vs. 42% (P 0.28) and 3yr-CSS 77% vs. 50% (P 0.7). CONCLUSION: Almost a third of UTUC present VH. Presence of VH is related to more aggressive tumor characteristics and associated with unfavorable outcomes. Due to a higher rate of extravesical recurrences in UTUC with VH, Follow-up controls should include cross sectional imaging and cystoscopy.

Findings in ancient Egyptian mummies from tomb KV64, Valley of the Kings, Luxor, with evidence of a rheumatic disease.

OBJECTIVE: In 2011, a spectacular find was made in the Valley of the Kings, Egypt - a well-known archaeological site, where pharaohs were buried during the New Kingdom (ca. 1500-1100 BCE). A team from the University of Basel's Kings' Valley Project discovered a tomb (KV64) containing two mummies that were buried in different time episodes (unidentified elite burial, 18th dynasty, and Nehemesbastet, 22nd dynasty). METHOD: Anthropological investigations of the mummies were performed using portable X-ray and photographic documentation. RESULTS AND CONCLUSION: The first burial was an adult individual with bilateral pathological changes at the temporomandibular joints (TMJs), most likely of inflammatory origin, possibly psoriatic arthritis. Investigations of the second burial revealed an intact body of a younger female individual.

Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

First-line surgery in prolactinomas: lessons from a long-term follow-up study in a tertiary referral center.

CONTEXT: Although consensus guidelines recommend dopamine agonists (DAs) as the first-line approach in prolactinomas, some patients may opt instead for upfront surgery, with the goal of minimizing the need for continuation of DAs over the long term. While this approach can be recommended in selected patients with a microprolactinoma, the indication for upfront surgery in macroprolactinomas remains controversial, with limited long-term data in large cohorts. We aimed at elucidating whether first-line surgery is equally safe and effective for patients with micro- or macroprolactinomas not extending beyond the median carotid line (i.e., Knosp grade ≤ 1). METHODOLOGY: Retrospective study of patients with prolactinomas Knosp grade ≤ 1 treated with upfront surgery. The primary endpoint was patients' dependence on DAs at last follow-up. The secondary endpoint was postoperative complications. Independent risk factors for long-term dependence on DAs were analyzed. RESULTS: A microadenoma was noted in 45 patients (52%) and a macroadenoma in 41 (48%), with 17 (20%) harboring a Knosp grade 1 prolactinoma. Median follow-up was 80 months. First-line surgery resulted in long-term remission in 31 patients (72%) with a microprolactinoma and in 18 patients (45%) with a macroprolactinoma (p = 0.02). DA therapy was ultimately required in 11 patients (24%) with microadenomas vs. 20 (49%) with macroadenomas (p = 0.03). As for the latter, DA was required in 13 patients (76%) with Knosp grade 1 macroadenomas vs. 7 patients (29%) with Knosp grade 0 macroadenomas (p = 0.004). There was no mortality, and morbidity was minimal. Knosp grade 1 prolactinomas (OR 7.3, 95% CI 1.4-37.7, p = 0.02) but not adenoma size (i.e., macroprolactinomas) were an independent predictor of long-term dependence on DAs. CONCLUSIONS: First-line surgery in patients with microprolactinomas or macroprolactinomas Knosp grade 0 resulted in a good chance of non-dependency on DA therapy. However, in patients with prolactinomas Knosp grade 1, first-line surgery cannot be recommended, as adjuvant DA therapy after surgery is required in the majority of them over the long term.

[Molecular tumor board-urothelial cancer]. / Molekulares Tumorboard ­ Urothelkarzinom.

BACKGROUND: Molecular tumor boards (MTB) are becoming more common. There are several molecular alterations in urothelial cancer a molecular tumor board can potentially rely on. OBJECTIVES: The aim is to specify molecular alterations and their correlations with different clinical endpoints and to highlight potential questions addressed to a MTB for urothelial cancer. MATERIALS AND METHODS: Descriptive review of the literature based on PubMed. RESULTS: The landscape of molecular alterations in urothelial cancer is heterogeneous. Thus, recent biomarker research has been focusing on biomarker panels and classifiers instead of single biomarkers. Recently, molecular subtypes of urothelial cancer have been identified and correlated with different clinical endpoints. Furthermore, circulating tumor cells and tumor DNA are under investigation as potential biomarkers. In addition to treatment response and prognosis, molecular markers are also needed to improve clinical staging prior to radical cystectomy or for proper patient selection for neoadjuvant chemotherapy. Erdafitinib is the first targeted therapy (fibroblast growth factor receptor [FGFR] alteration) in urothelial cancer that was recently approved (in the USA). CONCLUSIONS: Due to the lack of external validation, none of the identified biomarkers is currently established in clinical routine. In addition, there is no single driver mutation in urothelial cancer that facilitates the development of biomarkers and targeted therapies.

Dental investigation of mummies from the Capuchin Catacombs of Palermo (circa 18th-19th century CE).

Within the framework of the Sicily Mummy Project, the orofacial complex of a significant sample of individuals (n=111) from the Capuchin Catacombs of Palermo, Italy, was inspected. The heads and dentitions of the mummies were documented and the recorded findings described: the state of preservation of skeletal and soft tissues; dental pathologies such as carious lesions and alveolar bone loss; enamel hypoplasia; and ante- and post-mortem tooth loss. Despite limitations in data collection, the oral health of these mummies was assessed and the frequencies of pathologies were compared to those of similar populations. From their position within the corridors of the Catacombs, sex and social status of the mummies were also inferred, allowing the dental pathologies to be specified in the social and historical context. Most interestingly, the rate of oral health problems did not differ between the groups of the members of the Capuchin Order and the laymen of the city of Palermo, despite their different lifestyles.

Morphological and molecular characteristics of HER2 amplified urothelial bladder cancer.

Several (pre-) clinical trials are currently investigating the benefit of HER2-targeted therapy in urothelial bladder cancer (UBC). Patients with HER2 amplified UBC could potentially profit from these therapies. However, little is known about histomorphology, HER2 protein expression patterns and occurrence of alterations in the HER2 gene in their tumors. Among 150 metastasizing primary UBC, 13 HER2 amplified tumors were identified. Their histopathological features were compared with 13 matched, non-amplified UBC. HER2 protein expression was determined by immunohistochemistry. The 26 tumors were screened for mutations in exons 19 and 20 of the HER2 gene. UBC with HER2 amplification presented with a broad variety of histological variants (median 2 vs. 1), frequently featured micropapillary tumor components (77 % vs. 8 %) and demonstrated a high amount of tumor associated inflammation. Immunohistochemically, 10 of 13 (77 %) HER2 amplified tumors were strongly HER2 protein positive. Three tumors (23 %) were scored as HER2 negative. One of the HER2 amplified tumors harbored a D769N mutation in exon 19 of the HER2 gene; all other tested tumors were wild type. In conclusion, HER2 amplified UBC feature specific morphological characteristics. They frequently express the HER2 protein diffusely and are, therefore, promising candidates for HER2 targeted therapies. The detection of mutations at the HER2 locus might add new aspects to molecular testing of UBC.

The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression.

Epigenetic silencing of tumour suppressor genes is an important mechanism involved in cell transformation and tumour progression. The Set and RING-finger-associated domain-containing protein UHRF1 might be an important link between different epigenetic pathways. Here, we report that UHRF1 is frequently overexpressed in human prostate tumours and has an important role in prostate cancer pathogenesis and progression. Analysis of human prostate cancer samples by microarrays and immunohistochemistry showed increased expression of UHRF1 in about half of the cases. Moreover, UHRF1 expression was associated with reduced overall survival after prostatectomy in patients with organ-confined prostate tumours (P < 0.0001). UHRF1 expression was negatively correlated with several tumour suppressor genes and positively with the histone methyltransferase (HMT) EZH2 both in prostate tumours and cell lines. UHRF1 knockdown reduced proliferation, clonogenic capability and anchorage-independent growth of prostate cancer cells. Depletion of UHRF1 resulted in reactivation of several tumour suppressor genes. Gene reactivation upon UHRF1 depletion was associated with changes in histone H3K9 methylation, acetylation and DNA methylation, and impaired binding of the H3K9 HMT Suv39H1 to the promoter of silenced genes. Co-immunoprecipitation experiments showed direct interaction between UHRF1 and Suv39H1. Our data support the notion that UHRF1, along with Suv39H1 and DNA methyltransferases, contributes to epigenetic gene silencing in prostate tumours. This could represent a parallel and convergent pathway to the H3K27 methylation catalyzed by EZH2 to synergistically promote inactivation of tumour suppressor genes. Deregulated expression of UHRF1 is involved in the prostate cancer pathogenesis and might represent a useful marker to distinguish indolent cancer from those at high risk of lethal progression.

[The development of a questionnaire for the assessment of integrated health-care programmes from the patients' perspective (BIGPAT)]. / Die Entwicklung eines Fragebogens zur Beurteilung integrierter Gesundheitsversorgungsprogramme durch die Patienten (BiGPAT)*

AIMS: The aim of the study is the development of a questionnaire for the assessment of health care from the patients' perspective. METHODS: In the framework of a bottom-up approach, 8 focus groups of patients with diabetes or cardiovascular diseases from two different regions have been conducted. Results of the focus groups have been analysed by means of qualitative content analysis. On the basis of the results of the qualitative content analysis, a pool of 125 questions has been developed which constitute the starting point of a stepwise process for the selection of 44 items for a field test questionnaire. The field test questionnaire has been completed by 195 patients from three regions. The dimensional structure and the psychometric properties of the questionnaire have been analysed by means of exploratory and confirmatory factor analyses and by means of item-response-theory (IRT) models. RESULTS: The final questionnaire consists of 18 items belonging to the five dimensions "physician treatment", "treatment equity", "consultation by pharmacists", "preventive care" and "waiting times". The results of the confirmatory factor analysis reveal a good fit of the five factor model. Results of IRT analyses confirm that all subscales have at least an ordinal scale level. The reliability of the five subscales ranges between 0.70 and 0.91. CONCLUSIONS: A questionnaire for the assessment of health care from the patients' perspective has been developed. The new instrument can be applied in the evaluation of interventions for the improvement of the organisational aspects of health care for patients with chronic conditions.

Lhermitte-Duclos disease with atypical vascularization--case report and review of the literature.

OBJECTIVE: A case of Lhermitte-Duclos disease (LDD, dysplastic gangliocytoma) with atypical vascularization is reported. LDD is a rare cerebellar mass lesion which may be associated with Cowden's syndrome and the PTEN germline mutation. CASE MATERIAL: A 61-year-old male presented 15 years before with a transient episode of unspecific gait disturbance. Initial magnetic resonance (MR) imaging revealed a right-sided, diffuse, nonenhancing cerebellar mass lesion. No definitive diagnosis was made at that time, and the symptoms resolved spontaneously. 15 years later, the patient presented with acute onset of vomiting associated with headache and ataxic gait. MR imaging showed a progression of the lesion with occlusive hydrocephalus. The lesion depicted a striated pattern characteristic for LDD with T1-hypointense and T2-hyperintense bands, nonenhancing with contrast. After resection of the mass lesion, the cerebellar and hydrocephalic symptoms improved rapidly. The pathological examination confirmed the diagnosis of dysplastic gangliocytoma (WHO Grade I) with enlarged granular and molecular cell layers, reactive gliosis and dysplastic blood vessels. No other clinical features associated with Cowden's syndrome were present. CONCLUSIONS: This case illustrates that LDD with atypical vascularization is a slow-growing posterior fossa mass lesion which may remain asymptomatic for many years. Timing of surgical treatment and extent of resection in patients with LDD is controversial. The typical features on standard T1-/T2-weighted MR imaging allow a diagnosis without surgery in most cases. The authors believe that the decision to treat in these cases should be based on clinical deterioration.

Contribution of the apparent diffusion coefficient in perilesional edema for the assessment of brain tumors.

OBJECTIVES: Diffusion-weighted MRI is sensitive to molecular motion and has been applied to the diagnosis of stroke. Our intention was to investigate its usefulness in patients with brain tumor and, in particular, in the perilesional edema. METHODS: We performed MRI of the brain, including diffusion-weighted imaging and mapping of the apparent diffusion coefficient (ADC), in 16 patients with brain tumors (glioblastomas, low-grade gliomas and metastases). ADC values were determined by the use of regions of interest positioned in areas of high signal intensities as seen on T2-weighted images and ADC maps. Measurements were taken in the tumor itself, in the area of perilesional edema and in the healthy contralateral brain. RESULTS: ADC mapping showed higher values of peritumoral edema in patients with glioblastoma (1.75 x 10(-3)mm(2)/s) and metastatic lesions (1.61 x 10(-3)mm(2)/s) compared with those who had low-grade glioma (1.40 x10(-3)mm(2)/s). The higher ADC values in the peritumoral zone were associated with lower ADC values in the tumor itself. CONCLUSIONS: The higher ADC values in the more malignant tumors probably reflect vasogenic edema, thereby allowing their differentiation from other lesions.

Lack of microbial DNA in tissue specimens of patients with abdominal aortic aneurysms and positive Chlamydiales serology.

In a case-control study that included a total of 98 patients and 83 controls, the possible link between various pathogens and abdominal aortic aneurysms was investigated. For 68 patients with abdominal aortic aneurysm and age-matched controls, no differences were detected in the levels of immunoglobulin (Ig)A and IgG Chlamydiaceae and Chlamydophila pneumoniae antibodies. Patients with IgA titers positive for Chlamydophila pneumoniae showed progressive disease (defined as an annual increase of the aneurysm diameter of > or = 0.5 cm) more frequently than patients with negative IgA titers (p = 0.046). Polymerase chain reactions performed to detect DNA for Chlamydophila pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, human cytomegalovirus, Borrelia burgdorferi and Helicobacter pylori in tissue specimens of 30 patients and 15 controls were negative. In summary, Chlamydophila pneumoniae may contribute to aortic aneurysm disease progression, but DNA of this and other pathogens was not found in patients' specimens.

Morbidity in 201 patients with small sized meningioma treated by microsurgery.

BACKGROUND: The management of patients with small, often asymptomatic meningiomas is controversial and includes observation, microsurgery (MS) and stereotactic radiosurgery (SRS). The purpose of this retrospective study was to analyze the morbidity and the extent of removal after MS for small (< or =3 cm) intracranial meningiomas and compare these results to those of SRS reported in the literature. METHODS: All patients with an intracranial meningioma with a maximum diameter up to 3 cm operated on in our institution over a 10 year period (1992-2002) were included in the study and retrospectively analyzed. Patients were grouped into asymptomatic and symptomatic and according to tumor location as: group I (cranial vault, parasagittal, lateral sphenoid), group II (falx, frontobasal, medial sphenoid, parasellar and tentorial), group III (cavernous sinus, petroclival, petrosal, CPA and foramen magnum). FINDINGS: There were a total of 201 patients, of whom 102 were asymptomatic and 99 were symptomatic. The overall risk of permanent neurological morbidity was 4.9% in asymptomatic and 23.2% in symptomatic patients. The combined risk in asymptomatic and symptomatic patients was 5.4% in group I, 11.5% in group II, and 39.9% in group III lesions. Radical removal was achieved in all patients in group I, in 93.7% of group II, and 80% of group III lesions. There was no disease related mortality. CONCLUSIONS: MS provides excellent efficacy and morbidity results in groups I and II meningiomas, especially in asymptomatic patients and might therefore be considered the first choice of treatment for these patients. The results of MS in group III were worse than those of SRS reported in the literature.

Technical and clinical success of infrarenal endovascular abdominal aortic aneurysm repair: A 10-year single-center experience.

OBJECTIVE: The aim of our retrospective study was to review our single-center experience with aortic abdominal aneurysm (AAA) repair retrospectively. MATERIAL AND METHODS: From 1995 to 2005, 70 consecutive patients affected by AAA were treated by endovascular stent-graft repair. Mean follow-up was 23.9 months. Follow-up investigations were performed at 6 and 12 months and yearly thereafter. Five different stent-graft designs were compared to each other. Primary technical success (PTS), assisted primary technical success (APTS), primary clinical success (PCS) and secondary clinical success (SCS) were evaluated. RESULTS: All over PTS was achieved in 94.3%, APTS in 97.1%, PCS in 61.4%, APCS in 64.3% and SCS in 70%. There were 3 type I endoleaks, 25 type II endoleaks, 4 type III endoleaks, 8 limb problems, 5 conversions to open surgery, 10 aneurysm sac expansions and 14 device migrations. Patients with newer generation devices showed better results than patients with first generation prosthesis. In addition results were better for grafts with suprarenal fixation (versus infrarenal fixation) and grafts with barbs and hooks (versus grafts without barbs and hooks). Patients with bad anatomic preconditions showed a higher complication rate. CONCLUSION: Contrary to first generation products, new stent-graft designs show acceptable technical and clinical results in endovascular AAA aneurysm repair. However, this therapy still should be reserved only for patients with significant comorbities and suitable anatomic conditions.

[Simultaneous defect of visual fields and loss of libido--a coincidence?]. / Gleichzeitiger Gesichtsfelddefekt und Libidoverlust - Zufall?

We present the case of a 60 year old male patient with incidentally detected visual abnormalities. Detailed personal history revealed a hypogonadism that had been present for several years. Further investigations established the diagnosis of an infiltrative macroadenoma. Medical treatment with cabergoline led to a rapid regression of ophthalmologic symptoms and, subsequently, of tumor size. In male subjects symptoms of hypogonadism are often reported only late in the course of the disease, thereby leading to a generally larger tumor size at the point of diagnosis. In contrast to other pituitary tumors that are mainly treated by surgery, medical treatment with dopamine agonists is the principal therapeutic option in prolactinomas.

Cerebral revascularization model in a swine.

The purpose of this study was to analyze the suitability of the cerebral vasculature of the pig regarding a revascularization procedure. In two 60 kg pigs the femoral artery was exposed and canulated for selective angiography and interventional procedures. After the angiography, the pigs were brought to the animal OR for craniotomy and analysis of the intracranial cerebral arteries and the surgical exposure of the carotid arteries under the microscope. Angiography demonstrated the presence of a true internal-, external carotid artery and vertebral arteries. Both the vertebral and internal carotid arteries are feeding a rete mirabilis both at the cranial base and the cranio-cervical junction. At these sites further advancement of the angiography catheter was not possible. Out of these rete mirabilis, an intracranial carotid artery and an intracranial vertebral artery were formed, respectively. The intracranial cerebral vessels were of the dimension of 1 mm and less. The extracranial portion of the internal carotid artery was 2.5 mm of diameter. From these findings, we conclude that a direct cerebral revascularization procedure of the intracranial vessels is not possible in the swine. However, a global revascularization procedure on the extracranial portion of the internal carotid artery is thus feasible, both using a low- and high-flow anastamosis technique.

Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, characterized by a prominent loss of GABA-ergic medium-sized spiny neurons in the caudate putamen. There is evidence that impaired energy metabolism contributes to neuronal death in HD. Creatine is an endogenous substrate for creatine kinases and thereby supports cellular ATP levels. This study investigated the effects of creatine supplementation (5 mm) on cell survival and neuronal differentiation in striatal cultures. Chronic creatine treatment resulted in significant increased densities of GABA-immunoreactive (-ir) neurons, although total neuronal cell number and general viability were not affected. Similar effects were seen after short-term treatment, suggesting that creatine acted as a differentiation factor. Inhibitors of transcription or translation did not abolish the creatine-mediated effects, nor did omission of extracellular calcium, whereas inhibition of mitogen-activated protein kinase and phosphatidylinositol-3-kinase significantly attenuated the creatine induced increase in GABA-ir cell densities. Creatine exhibited significant neuroprotection against toxicity instigated either by glucose- and serum deprivation or addition of 3-nitropropionic acid. In sum, the neuroprotective properties in combination with promotion of neuronal differentiation suggest that creatine has potential as a therapeutic drug in the treatment of neurodegenerative diseases, like HD.

Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue.

Parkinson's disease is a disabling neurodegenerative disorder of unknown etiology characterized by a predominant and progressive loss of dopaminergic neurons in the substantia nigra. Recent findings suggest that impaired energy metabolism plays an important role in the pathogenesis of this disorder. The endogenously occurring guanidino compound creatine is a substrate for mitochondrial and cytosolic creatine kinases. Creatine supplementation improves the function of the creatine kinase/phosphocreatine system by increasing cellular creatine and phosphocreatine levels and the rate of ATP resynthesis. In addition, mitochondrial creatine kinase together with high cytoplasmic creatine levels inhibit mitochondrial permeability transition, a major step in early apoptosis. In the present study, we analyzed the effects of externally added creatine on the survival and morphology of dopaminergic neurons and also addressed its neuroprotective properties in primary cultures of E14 rat ventral mesencephalon. Chronic administration of creatine [5 mM] for 7 days significantly increased survival (by 1.32-fold) and soma size (by 1.12-fold) of dopaminergic neurons, while having no effect on other investigated morphological parameters. Most importantly, concurrent creatine exerted significant neuroprotection for dopaminergic neurons against neurotoxic insults induced by serum and glucose deprivation (P < 0.01), 1-methyl-4-phenyl pyridinium ion (MPP+) [15 microM] and 6-hydroxydopamine (6-OHDA) [90 microM] exposure (P < 0.01). In addition, creatine treatment significantly protected dopaminergic cells facing MPP+-induced deterioration of neuronal morphology including overall process length/neuron (by 60%), number of branching points/neuron (by 80%) and area of influence per individual neuron (by 60%). Less pronounced effects on overall process length/neuron and number of branching points/neuron were also found after 6-OHDA exposure (P < 0.05) and serum/glucose deprivation (P < 0.05). In conclusion, our findings identify creatine as a rather potent natural survival- and neuroprotective factor for developing nigral dopaminergic neurons, which is of relevance for therapeutic approaches in Parkinson's disease and for the improvement of cell replacement strategies.