Patient-derived, three-dimensional spheroid cultures provide a versatile translational model for the study of organ-confined prostate cancer.

PURPOSE: To generate and characterize 3D spheroid suspension cultures from radical prostatectomy (RP) specimens as a versatile model system for organ-confined prostate cancer (PCa). METHODS: Cancerous tissue samples from RP specimens were excised by a uropathologist. Preparation of 3D spheroids was done by mechanical disintegration and limited enzymatic digestion followed by serial filtration through 100 µm- and 40 µm-cell strainers. Thereafter, spheroids were cultured in a modified stem cell medium and characterized by a live/dead assay, whole-spheroid immunohistochemistry (IHC; CK5, CK8, AMACR, PSA, Ki67, AR, αSMA, Vimentin, E-Cadherin) and PSA-measurements in culture medium. Furthermore, their response to pharmaceutical treatment with docetaxel, bicalutamide, enzalutamide and abiraterone was tested. RESULTS: 173 RP cases were included. The median preoperative PSA-level was 16.12 ng/ml [range 0.99;345], the median Gleason score was 7b [6;10]. 64 cases were excluded due to low tumor content in frozen sections (43) or to insufficient spheroid formation (21). In the remaining 109 cases, spheroids formed successfully and stayed viable for up to several months. IHC analysis revealed AR-, CK8-, and AMACR-positivity in nearly all cases, while CK5-positive cells were detectable only occasionally as were α-SMA and Vimentin. E-Cadherin was positive in most cases. Furthermore, spheroids proved to be amenable to cryopreservation. While abiraterone had no effect and docetaxel only a moderate effect, spheroid viability was markedly reduced upon bicalutamide and enzalutamide treatment. CONCLUSIONS: Multicellular 3D spheroids can be generated from patient-derived RP tissue samples and serve as an innovative in vitro model of organ-confined PCa.

Human Papillomavirus-Associated Invasive Condylomas in a Man with Immunosuppressive Comorbidities.

Human papilloma virus (HPV) infections are one of the most common sexually transmitted diseases. We present the case of a 77-year-old Caucasian male with enormous genital warts of the penis, scrotum, groins and anus. Lesions were excised by electrosurgery. The histological examination revealed Condylomata gigantea as well as an invasive perianal squamous cell carcinoma. Mucosal "low-risk" HPV type 6 was detected. The patient had a history of an immunosuppressing disease. During the 4-year follow-up, multiple relapses occurred. Thus, particularly in immunosuppressed patients, early prophylactic HPV vaccination seems to be indicated for use in the prevention of HPV-associated mutilating and life-threatening disease. Vaccination should also protect from "low-risk" HPV.

Large Paraesophageal Schwannoma With Intense Prostate-Specific Membrane Antigen Expression on 68Ga-PSMA-PET/CT Mimicking Lymph Node Metastasis in a Patient With Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-PET/CT as an emerging modality in molecular imaging will lead to earlier detection and localization of relapse in prostate cancer but will undoubtedly also lead to false-positive findings, as it becomes clear that this new tracer is not as specific as its name would suggest. In this context, we present a case of a large PSMA-expressing schwannoma, a rare nerve sheath tumor mimicking paraesophageal lymph node metastasis in a patient with a history of prostate cancer and biochemical recurrence.

Oral etoposide for metastatic choriocarcinoma: a case report and review of guidelines.

BACKGROUND AND PURPOSE: Choriocarcinoma (CCA) is a rare form of malignant trophoblastic disease. Systemic polychemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO) is the mainstay of treatment for metastatic disease. Due to the rarity of the condition, however, the evidence basis for this management is small and other chemotherapy regimens may also be effective. The reported case presents anecdotal evidence of an effective etoposide monotherapy treatment. METHOD: CASE PRESENTATION: We report the case of a patient with gestational choriocarcinoma and pulmonary metastases initially treated with methotrexate. Due to local disease progression, she underwent hysterectomy and continued treatment with methotrexate. After pulmonary progression, she was switched to oral etoposide. RESULTS: After four cycles of etoposide monotherapy at a oral dosage of 100 mg d1-7, q28, the patient had no evidence of disease according to human chorionic gonadotropin serum levels and imaging studies. The treatment was well tolerated with World Health Organization (WHO) grade 2 alopecia and hot flushes as the most prominent side effects. The patient has achieved a sustained complete remission with a follow-up of 6 years. CONCLUSION: Oral etoposide may be an effective treatment alternative to EMA/CO in selected patients with oligometastatic CCA.

Two Years of Gynecomastia Caused by Leydig Cell Tumor.

Gynecomastia is a common incidental finding in males that can be caused by various benign or malignant diseases. In rare cases, it results from Leydig cell tumors, a rare entity accounting for 3% of all testicular neoplasms. Some of them are hormonally active but seldom cause symptomatic endocrine disturbance. Here we report on a 32-year-old male presenting with gynecomastia which he had already been suffering from for two years. Although he had been seen by three other specialists, including a urologist, none of them found the small mass in the upper pole of his right testis. We decided to perform testis-sparing surgery which confirmed the diagnosis of a hormonally active Leydig cell tumor. During follow-up, hormonal status normalized, and gynecomastia began to resolve.

A novel mouse model of human prostate cancer to study intraprostatic tumor growth and the development of lymph node metastases.

BACKGROUND: In this study, we aimed to establish a versatile in vivo model of prostate cancer, which adequately mimics intraprostatic tumor growth, and the natural routes of metastatic spread. In addition, we analyzed the capability of high-resolution ultrasonography (hrUS), in vivo micro-CT (µCT), and 9.4T MRI to monitor tumor growth and the development of lymph node metastases. METHODS: A total of 5 × 105 VCaP cells or 5 × 105 cells of LuCaP136- or LuCaP147 spheroids were injected into the prostate of male CB17-SCID mice (n = 8 for each cell type). During 12 weeks of follow-up, orthotopic tumor growth, and metastatic spread were monitored by repetitive serum-PSA measurements and imaging studies including hrUS, µCT, and 9.4T MRI. At autopsy, primary tumors and metastases were harvested and examined by histology and immunohistochemistry (CK5, CK8, AMACR, AR, Ki67, ERG, and PSA). From imaging results and PSA-measurements, tumor volume doubling time, tumor-specific growth rate, and PSA-density were calculated. RESULTS: All 24 mice developed orthotopic tumors. The tumor growth could be reliably monitored by a combination of hrUS, µCT, MRI, and serum-PSA measurements. In most animals, lymph node metastases could be detected after 12 weeks, which could also be well visualized by hrUS, and MRI. Immunohistochemistry showed positive signals for CK8, AMACR, and AR in all xenograft types. CK5 was negative in VCaP- and focally positive in LuCaP136- and LuCaP147-xenografts. ERG was positive in VCaP- and negative in LuCaP136- and LuCaP147-xenografts. Tumor volume doubling times and tumor-specific growth rates were 21.2 days and 3.9 %/day for VCaP-, 27.6 days and 3.1 %/day for LuCaP136- and 16.2 days and 4.5 %/day for LuCaP147-xenografts, respectively. PSA-densities were 433.9 ng/mL per milliliter tumor for VCaP-, 6.5 ng/mL per milliliter tumor for LuCaP136-, and 11.2 ng/mL per milliliter tumor for LuCaP147-xenografts. CONCLUSIONS: By using different monolayer and 3D spheroid cell cultures in an orthotopic xenograft model, we established an innovative, versatile in vivo model of prostate cancer, which enables the study of both intraprostatic tumor growth as well as metastatic spread to regional lymph nodes. HrUS and MRI are feasible tools to monitor tumor growth and the development of lymph node metastases while these cannot be visualized by µCT.

In Silico Oncology: Quantification of the In Vivo Antitumor Efficacy of Cisplatin-Based Doublet Therapy in Non-Small Cell Lung Cancer (NSCLC) through a Multiscale Mechanistic Model.

The 5-year survival of non-small cell lung cancer patients can be as low as 1% in advanced stages. For patients with resectable disease, the successful choice of preoperative chemotherapy is critical to eliminate micrometastasis and improve operability. In silico experimentations can suggest the optimal treatment protocol for each patient based on their own multiscale data. A determinant for reliable predictions is the a priori estimation of the drugs' cytotoxic efficacy on cancer cells for a given treatment. In the present work a mechanistic model of cancer response to treatment is applied for the estimation of a plausible value range of the cell killing efficacy of various cisplatin-based doublet regimens. Among others, the model incorporates the cancer related mechanism of uncontrolled proliferation, population heterogeneity, hypoxia and treatment resistance. The methodology is based on the provision of tumor volumetric data at two time points, before and after or during treatment. It takes into account the effect of tumor microenvironment and cell repopulation on treatment outcome. A thorough sensitivity analysis based on one-factor-at-a-time and latin hypercube sampling/partial rank correlation coefficient approaches has established the volume growth rate and the growth fraction at diagnosis as key features for more accurate estimates. The methodology is applied on the retrospective data of thirteen patients with non-small cell lung cancer who received cisplatin in combination with gemcitabine, vinorelbine or docetaxel in the neoadjuvant context. The selection of model input values has been guided by a comprehensive literature survey on cancer-specific proliferation kinetics. The latin hypercube sampling has been recruited to compensate for patient-specific uncertainties. Concluding, the present work provides a quantitative framework for the estimation of the in-vivo cell-killing ability of various chemotherapies. Correlation studies of such estimates with the molecular profile of patients could serve as a basis for reliable personalized predictions.

In silico oncology: exploiting clinical studies to clinically adapt and validate multiscale oncosimulators.

This paper presents a brief outline of the notion and the system of oncosimulator in conjunction with a high level description of the basics of its core multiscale model simulating clinical tumor response to treatment. The exemplary case of lung cancer preoperatively treated with a combination of chemotherapeutic agents is considered. The core oncosimulator model is based on a primarily top-down, discrete entity - discrete event multiscale simulation approach. The critical process of clinical adaptation of the model by exploiting sets of multiscale data originating from clinical studies/trials is also outlined. Concrete clinical adaptation results are presented. The adaptation process also conveys important aspects of the planned clinical validation procedure since the same type of multiscale data - although not the same data itself- is to be used for clinical validation. By having exploited actual clinical data in conjunction with plausible literature-based values of certain model parameters, a realistic tumor dynamics behavior has been demonstrated. The latter supports the potential of the specific oncosimulator to serve as a personalized treatment optimizer following an eventually successful completion of the clinical adaptation and validation process.

Simulation of intra-aneurysmal blood flow by different numerical methods.

The occlusional performance of sole endoluminal stenting of intracranial aneurysms is controversially discussed in the literature. Simulation of blood flow has been studied to shed light on possible causal attributions. The outcome, however, largely depends on the numerical method and various free parameters. The present study is therefore conducted to find ways to define parameters and efficiently explore the huge parameter space with finite element methods (FEMs) and lattice Boltzmann methods (LBMs). The goal is to identify both the impact of different parameters on the results of computational fluid dynamics (CFD) and their advantages and disadvantages. CFD is applied to assess flow and aneurysmal vorticity in 2D and 3D models. To assess and compare initial simulation results, simplified 2D and 3D models based on key features of real geometries and medical expert knowledge were used. A result obtained from this analysis indicates that a combined use of the different numerical methods, LBM for fast exploration and FEM for a more in-depth look, may result in a better understanding of blood flow and may also lead to more accurate information about factors that influence conditions for stenting of intracranial aneurysms.

Histology and function: analyzing the uvular muscle.

OBJECTIVE: Virtual surgery and virtual patients necessitate quantitative data on the area of interest. The study was conducted to exactly describe the embryonic and fetal uvular muscle (MU), relevant for clinical as well as virtual surgery and virtual patient generation. METHOD: Serially sectioned viscerocrania of 10 aborted embryos and fetuses underwent three-dimensional reconstruction to obtain detailed anatomic data and perform finite element analyses. RESULTS: The MU was paired in 80% of cases, while 20% allowed no clear-cut distinction. The MU merged with the levator muscle beneath the palatal aponeurosis without a hard palate insertion. Superior longitudinal central fibers ran below the nasal mucosa, and few circular peripheral fibers crossed in the central third to the contralateral side. This was seen in 30% of the paired muscles and in all cases when no differentiation was possible; about 40% to 80% MU fibers crossed to the ipsilateral and contralateral palatopharyngeus muscle behind the levator loop. MU fibers inserted 60% nasal and 40% oral to the basal membrane at the middle third of the macroscopic uvula, made of loose connective tissue and salivary glands. The results of the finite element simulation of the uvula showed no distinct patterns or distributions of local stress. CONCLUSIONS: Detailed anatomical study supported the concept of mediocranial MU repositioning during corrective surgery, although the impact is minor to the levator muscle's action. Future mathematical models describing effects of such a maneuver should integrate surrounding structures.

[Serous-papillary adenocarcinoma with Müllerian neoplasia after prophylactic ovariectomy]. / Auftreten eines serös-papillären Adenokarzinoms mit Müllerscher Neoplasie nach prophylaktischer Ovarektomie.

The so-called prophylactic ovariectomy, i.e. the removal of macroscopically nonpathological ovaries during laparotomy or vaginal hysterectomy, does not always prevent ovarian cancer. A case of a 76-year-old woman with a Müllerian tumor is reported, and the literature will be discussed.