The clinical efficacy of PSMA PET/MRI in biochemically recurrent prostate cancer compared with standard of care imaging modalities and confirmatory histopathology: results of a single-centre, prospective clinical trial.

Prospective evidence for the clinical role and efficacy of prostate specific membrane antigen (PSMA) positron emission tomography (PET)/magnetic resonance imaging (MRI) combining MRI characterization and localization of lesions with PET avidity in comparison to conventional imaging is limited. In a prospective clinical trial, we aimed to evaluate the diagnostic yield and therapeutic impact of PSMA PET/MRI in men with biochemical recurrence (BCR) following curative therapy. A single-centre, prospective clinical trial at the Princess Alexandra Hospital recruited 30 patients with BCR. Patients underwent PSMA PET/MRI and concurrent conventional CT chest, abdomen, pelvis and whole-body bone scan. Biopsy was performed when safety possible for histological correlation of identified lesions. Clinical efficacy and impact of PSMA PET findings were evaluated. 30 patients with BCR were recruited (median PSA 0.69 ng/ml). PSMA avid lesions were present in 21 patients (70%). 23 patients were previously treated with definitive surgery, 6 patients received external beam radiotherapy and 1 patient had low dose rate brachytherapy. A total of 8 of 9 lesions biopsied were positive (88.9% histological correlation). PSMA PET/MRI detected local recurrence (p = 0.005) and pelvic lesions (p = 0.06) more accurately than conventional imaging. PSMA PET/MRI may be useful in staging men with biochemical recurrence, especially when PSA is low. Our data demonstrates a high detection rate, especially for locally recurrent disease, and highlights the role of this modality when PSA is low. This modality has the potential to significantly improve prostate cancer detection and may have implications for earlier salvage treatment, avoidance of futile local therapy and change patient management to lead to improved outcomes.

Initial Experience With Hand-Assisted Laparoscopic Living Donor Nephrectomy: Training and Clinical Practice as a General Surgeon.

BACKGROUND: To analyze our initial results of hand-assisted laparoscopic living donor nephrectomy, executed by a skilled gastrointestinal surgeon. METHODS: A total of 22 consecutive patients underwent the hand-assisted laparoscopic living donor nephrectomy between December 2014 and January 2017. We retrospectively analyze the patient's perioperative clinical data, which were collected prospectively. RESULTS: The right kidney was harvested in 12 patients. The mean operative time and intraoperative blood loss was 241.0 ± 43.4 minutes (range, 140-310 min) and 293.2 ± 203.1 mL (range, 50-700 mL), respectively. The mean warm ischemic time was 288.4 ± 103.4 seconds (range, 179-610 s). Postoperative complications included chyle leakage in 2 patients who were left kidney donors and oliguria in 1 patient who was a right kidney donor. All patients recovered with conservative care, and the mean hospital stay was 7.5 ± 1.7 days. The mean creatinine level was 0.7 ± 0.2 mg/dL before surgery, 1.1 ± 0.3 mg/dL at postoperative day (POD) 1, and 1.0 ± 0.2 mg/dL after discharge. The mean glomerular filtration rate was 97.9 ± 18.2 mL/min/1.73 m2 before surgery, 60.7 ± 10.4 at POD 1, and 67.3 ± 11.1 after discharge. Operation time was not associated with patient body mass index and case number. No significant differences, other than postoperative complications, were found in the perioperative data for the side of kidney donation. CONCLUSION: A skilled surgeon with experience in laparoscopic abdominal surgery (such as gastrectomy or colectomy) might safely perform hand-assisted donor nephrectomy. However, we could not identify a clear case number to complete the learning curve.

Importance of Timed and Detailed Evaluation of Kidney Transplantation Candidates.

Kidney transplant recipients are at increased risk of cardiovascular morbidity and malignant neoplasm, and meticulous evaluation of potential recipients is needed to minimize risks of complications after transplantation. The purpose of this study was to analyze the results of preoperative assessments and document the importance of timed and detailed examinations. METHODS: Medical records of patients evaluated as kidney transplant candidates from January 2015 to September 2017 were retrospectively collected and analyzed. RESULTS: Of the 216 patients evaluated during the study period, 135 (62.5%) were male, 112 (51.9%) had diabetes mellitus, 163 (75.5%) had hypertension, 31 (14.4%) had a cardiovascular event history, and 7 (3.2%) had previous history of malignant neoplasms. Mean (SD) patient age was 50.7 (10.8) years. All 216 recipient candidates underwent echocardiography. Mean (SD) ejection fraction was 57.8% (5.9%), and 48 candidates (22.2%) showed regional wall motional abnormality. Coronary angiography was performed on 81 candidates, and in 57 (70.4%) of these, coronary artery disease was detected. Malignant neoplasms were detected in 10 (4.6%) candidates. Kidney transplantation was performed on 55 candidates. One recipient died of Pneumocystis jirovecii pneumonia at 15 months after kidney transplant, but there was no death-censored graft failure, newly detected malignant neoplasm, or cardiovascular event over a mean (SD) follow-up duration of 15.5 (8.6) months. CONCLUSION: Evaluation of kidney transplant candidates resulted in diagnoses of malignant neoplasms in 4.6% of patients and coronary artery disease in 26.4% of patients. The results of this study demonstrate candidates for kidney transplant should undergo detailed preoperative evaluation.

Case Report: Spontaneous Hemorrhage of a Rare Renal Tumor in the Native Kidney of a Renal Transplant Recipient.

Renal cancers are some of the most common solid organ malignancies found during follow-up of patients who have undergone renal transplantation (RT). In this case report, we describe a life-threatening spontaneous hemorrhage of a rare subtype of renal cell carcinoma in the native kidney of a 27-year-old man, 4 years after RT. After fluid resuscitation and stabilization, the patient underwent emergent open radical nephrectomy with the final histopathology reporting T1bN0Mx mucinous tubular and spindle cell (MTSC) carcinoma. This case report highlights the need to consider an underlying malignancy in patients who presents with spontaneous hemorrhage of native kidneys after RT.

Regular sun exposure benefits health.

Since it was discovered that UV radiation was the main environmental cause of skin cancer, primary prevention programs have been started. These programs advise to avoid exposure to sunlight. However, the question arises whether sun-shunning behaviour might have an effect on general health. During the last decades new favourable associations between sunlight and disease have been discovered. There is growing observational and experimental evidence that regular exposure to sunlight contributes to the prevention of colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis, hypertension and diabetes. Initially, these beneficial effects were ascribed to vitamin D. Recently it became evident that immunomodulation, the formation of nitric oxide, melatonin, serotonin, and the effect of (sun)light on circadian clocks, are involved as well. In Europe (above 50 degrees north latitude), the risk of skin cancer (particularly melanoma) is mainly caused by an intermittent pattern of exposure, while regular exposure confers a relatively low risk. The available data on the negative and positive effects of sun exposure are discussed. Considering these data we hypothesize that regular sun exposure benefits health.

Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer.

PURPOSE: Positron emission tomography using ligands targeting prostate specific membrane antigen has recently been introduced. Positron emission tomography imaging with (68)Ga-PSMA-HBED-CC has been shown to detect metastatic prostate cancer lesions at a high rate. In this study we compare multiparametric magnetic resonance imaging and prostate specific membrane antigen positron emission tomography of the prostate with whole mount ex vivo prostate histopathology to determine the true sensitivity and specificity of these imaging modalities for detecting and locating tumor foci within the prostate. MATERIALS AND METHODS: In a prospective clinical trial setting 20 patients with localized prostate cancer and a planned radical prostatectomy were recruited. All patients underwent multiparametric magnetic resonance imaging and positron emission tomography before surgery, and whole mount histopathology slides were directly compared to the images. European Society of Urogenital Radiology guidelines for reporting magnetic resonance imaging were used as a template for regional units of analysis. The uropathologist and radiologists were blinded to individual components of the study, and the final correlation was performed by visual and deformable registration analysis. RESULTS: A total of 50 clinically significant lesions were identified from the whole mount histopathological analysis. Based on regional analysis the sensitivity, specificity, positive predictive value and negative predictive value for multiparametric magnetic resonance imaging were 44%, 94%, 81% and 76%, respectively. With prostate specific membrane antigen positron emission tomography the sensitivity, specificity, positive predictive value and negative predictive value were 49%, 95%, 85% and 88%, respectively. Prostate specific membrane antigen positron emission tomography yielded a higher specificity and positive predictive value. CONCLUSIONS: A significant proportion of cancers are potentially missed and underestimated by both imaging modalities. Prostate specific membrane antigen positron emission tomography may be used in addition to multiparametric magnetic resonance imaging to help improve local staging in those patients undergoing retropubic radical prostatectomy.

Interaction of hepatitis B virus X protein with PARP1 results in inhibition of DNA repair in hepatocellular carcinoma.

Hepatitis B virus X protein (HBx) contributes to the development of hepatocellular carcinoma (HCC), probably by regulating activities of many host or viral proteins through protein-protein interactions. In this study, we identified poly(ADP-ribose) polymerase (PARP1), a crucial factor in DNA repair, as an HBx-interacting protein using a proteomics approach. Coimmunoprecipitation and proximity ligation assays confirmed the binding and colocalization of HBx and PARP1 in the nucleus. The carboxyl-terminus of HBx protein bound to the catalytic domain of PARP1, and this binding reduced the enzymatic activity of PARP1 in both in vitro and in vivo assays. HBx interrupted the binding of PARP1 to Sirt6, which catalyzes the mono-ADP-ribosylation required for DNA repair. Consistently, overexpression of HBx inhibited the clearance of γH2AX DNA repair foci generated under oxidative stress in Chang liver cells. Recruitment of the DNA repair complex to the site-specific double-strand breaks was inhibited in the presence of HBx, when measured by laser microirradiation assay and damage-specific chromatin immunoprecipitation assays. Consequently, HBx increased signs of DNA damage such as accumulation of 8-hydroxy-2'-deoxyguanosine and comet formation, which were reversed by overexpression of PARP1 and/or Sirt6. Finally, the interaction between PARP1 and Sirt6 was markedly lower in the livers of HBx-transgenic mice and specimens obtained from HCC patients to compare with the corresponding control. Our data suggest that the physical interaction of HBx and PARP1 accelerates DNA damage by inhibiting recruitment of the DNA repair complex to the damaged DNA sites, which may lead to the onset of hepatocarcinogenesis.

Differentiation of early hepatocellular carcinoma from benign hepatocellular nodules on gadoxetic acid-enhanced MRI.

OBJECTIVE: To test new diagnostic criteria for the discrimination of early hepatocellular carcinoma (HCC) from benign hepatocellular nodules on gadoxetic acid-enhanced MRI (Gd-EOB-MRI). METHODS: We retrospectively analysed 34 patients with 29 surgically diagnosed early HCCs and 31 surgically diagnosed benign hepatocellular nodules. Two radiologists reviewed Gd-EOB-MRI, including diffusion-weighted imaging (DWI), and the signal intensity at each sequence, presence of arterial enhancement and washout were recorded. We composed new diagnostic criteria based on the lesion size and MRI findings, and then the diagnostic performance was compared with that of conventional imaging criteria with logistic regression and a generalised estimating equation method. RESULTS: A size cut-off value (≥1.5 cm diameter) and MRI findings of T(1) hypointensity, T(2) hyperintensity, DWI hyperintensity on both low and high b-value images (b=50 and 800 s mm(-2), respectively), arterial enhancement, late washout and hepatobiliary hypointensity were selected as the diagnostic criteria. When lesions were considered malignant if they satisfied three or more of the above criteria, the sensitivity was significantly higher than when making a diagnosis based on arterial enhancement and washout alone (58.6% vs 13.8%, respectively; p=0.0002), while the specificity was 100.0% for both criteria. CONCLUSION: Our new diagnostic criteria on Gd-EOB-MRI may help to improve the discrimination of early HCC from benign hepatocellular nodules.

Comparison of an intraoperative infusion of dexmedetomidine or remifentanil on perioperative haemodynamics, hypnosis and sedation, and postoperative pain control.

This prospective, randomized, double-blind study compared the effects of dexmedetomidine and remifentanil on haemodynamic stability, sedation and postoperative pain control in the postanaesthetic care unit (PACU). Fifty consecutive patients scheduled for total laparoscopic hysterectomy were randomly assigned to receive infusions of either dexmedetomidine (1 µg/kg) i.v. over 10 min followed by 0.2 - 0.7 µg/kg per h continuous i.v. infusion or remifentanil (0.8 - 1.2 µg/kg) i.v. over 1 min followed by 0.05 - 0.1 µg/kg i.v. per min, starting at the end of surgery to the time in the PACU. Modified observer's assessment of alertness scores were significantly lower in the dexmedetomidine group than in the remifentanil group at 0, 5 and 10 min after arrival in the PACU. Blood pressure and heart rate in the dexmedetomidine group were significantly lower than that recorded in the remifentanil group in the PACU. Dexmedetomidine, at the doses used in this study, had a significant advantage over remifentanil in terms of postoperative haemodynamic stability.

Identification of stathmin 1 expression induced by Epstein-Barr virus in human B lymphocytes.

INTRODUCTION: The Epstein-Barr virus transforms resting B cells into proliferating lymphoblastoid cells, the origin of cell lines. METHOD AND RESULTS: Our cDNA microarray analyses led to the identification of 232 up-regulated and 112 down-regulated genes with more than a 3-fold difference in lymphoblastoid cell lines compared to resting B cells. The functional classification of these genes exhibited the distinct expression signature for cell proliferation, cell cycle and an immune response. Among them, we verified the differential expression of several oncogenes such as stathmin 1 (STMN1), RAB27A, RAB9A, BACH1 and BACH2 using quantitative real-time reverse transcriptase-polymerase chain reactions or Western blot analysis. Expression of STMN1 (which is involved in regulation of the microtubule filament system, cell growth and S-phase of cell cycle) was increased in lymphoblastoid cell line as well as in 7-day post-Epstein-Barr virus infection B cells, compared to resting B cells. CONCLUSION: Thus, this study suggests that Epstein-Barr virus infection induces STMN1 expression, which play a role in cell cycle progression and proliferation in the human B lymphocyte.

[Favourable and unfavourable effects of exposure to sunlight]. / Gunstige en ongunstige effecten van zonlichtexpositie.

The negative effects of sunlight include the more frequent or earlier development of skin cancer and degenerative changes in the skin, and the occurrence ofphotodermatoses. - However, sunlight also has a favourable effects; specifically, it may inhibit the development and progression of diseases of the bones, muscles and skin, ofvarious malignancies (carcinoma of the prostate, breast, colon and ovary, non-Hodgkin lymphoma), and may prevent certain autoimmune diseases, particularly multiple sclerosis. - This protective effect is ascribed to an increased synthesis of vitamin D, which is important for bone metabolism and is also able to regulate cell proliferation and differentiation, apoptosis, tumour invasion and angiogenesis. - The possible consequence of this new information is that public information regarding exposure to sunlight must continue to include a warning against excessive exposure to the sun, while at the same time stimulating regular although limited sunbathing.

Does sunlight prevent cancer? A systematic review.

Accumulating evidence for beneficial effects of sunlight on several types of cancer with a high mortality rate makes it necessary to reconsider the health recommendations on sun exposure, which are now mainly based on the increased risks for skin cancer. We reviewed all published studies concerning sun exposure and cancer, excluding skin cancer. All selected studies on prostate (3 ecologic, 3 case-control and 2 cohort), breast (4 ecologic, 1 case-control and 2 cohort) and ovary cancer (2 ecologic and 1 case-control) showed a significantly inverse correlation between sunlight and mortality or incidence. Two ecologic, 1 case-control and 2 prospective studies showed an inverse relation between sunlight and colon cancer mortality; 1 case-control study found no such association. Ecologic studies on non-Hodgkin lymphoma (NHL) mortality and sunlight gave conflicting results: early studies showing mostly positive and later studies showing mostly negative correlations. Three case-control studies and 1 cohort study found a significant inverse association between the incidence of NHL and sunlight. The question of how to apply these findings to (public) health recommendations is discussed.

[Trends, causes, approach and consequences related to the skin-cancer epidemic in the Netherlands and Europe]. / Trends, oorzaken, aanpak en gevolgen van de huidkankerepidemie in Nederland en Europa.

The annual incidence of the three main forms of skin cancer has increased rapidly over the past few decades by 2.4% in men and 3.9% in women for basal-cell carcinoma, 3.9% in men and 3.1% in women for melanoma and 1.2% in men and 3.4% in women for squamous-cell carcinoma. The mortality rate has increased less rapidly. There has been an increase of 1.8% per year in rates of melanoma and a decrease of 1.9% in squamous cell carcinoma. The mortality rate for melanoma in younger people appears to have stabilized, however the death rate in older men continues to increase. Possible causes of the increase include excessive exposure to ultraviolet rays, immunosuppression and viruses. Early detection continues to offer the best chance of a cure. Screening older men for melanoma should be considered. Rising incidence and improved survival rates mean that there are likely to be more new patients with skin cancer in the future. Problems in balancing the availability of preventative and curative care may be offset by the timely planning of available manpower, by optimizing medical policy and by implementing new technological developments such as dermatoscopy.

Fatty acids, inhibitors for the DNA binding of c-Myc/Max dimer, suppress proliferation and induce apoptosis of differentiated HL-60 human leukemia cell.

c-Myc is instrumental in the progression of Burkitt's lymphoma including HL-60 human leukemia cells. We tested fatty acids for their inhibitory effect on the DNA binding of c-Myc/Max dimeric proteins of human origin, prepared as recombinant proteins encompassing DNA binding (basic) and dimerization (HLHZip) domain, and found that those suppress proliferation and induce apoptosis of DMSO-differentiated HL-60 cells. The analyzed IC50 values of myristic acid, stearic acid, gamma-linolenic acid, linoleic acid, linolenic acid and arachidonic acid by EMSA were 97(+/-3), 2.2(+/-1.2), 55(+/-5), 32(+/-2), 62(+/-12), 22(+/-2)microM for DNA binding of recombinant c-Myc/Max, respectively. According to the results shown by XTT assay, their influence on proliferation was quite different from the rank order of IC50. Whereas the degree of influence of the unsaturated fatty acids on the proliferation of DMSO-differentiated HL-60 cells was similar, the influence of saturated fatty acids, stearic acid in particular, was very weak at same concentrations. In addition, we confirmed that these fatty acids have no influence on the expression of c-Myc in DMSO-differentiated HL-60 cells. Our experiments demonstrated that the inhibitors for the DNA binding of c-Myc/Max contribute to the downregulation of Myc-dependent proliferation and to the inducement of apoptosis, and serve as an exploration of potent new inhibitors.

[Guideline 'Melanoma' (3rd revision)]. / Richtlijn 'Melanoom' (3e herziening).

The guidelines 'Melanoma' (3rd revision) are evidence-based in nature. A number of outcomes are summarised in this article. Dermatoscopy deserves a standard role in the clinical diagnosis of pigmented skin abnormalities. Pathological findings from a diagnostic excision should be recorded meticulously to include anatomical localisation, type of intervention used, excision margin, diagnosis, Breslow thickness, and the completeness of the removal. The sentinel node procedure should be reserved for patients who want to be as informed as possible about their prognosis. The procedure is not considered a part of standard diagnosis. Sentinel node assessment should include stains for specific markers and should be conducted in multiple sections. The following margins of non-affected skin are recommended for therapeutic re-excision of melanoma: in situ melanoma, 0.5 cm; Breslow thickness < or = 2 mm, 1 cm; Breslow thickness > 2 mm, 2 cm. Pathological assessment of a re-excised specimen depends on the completeness of the first excision. Systematic adjuvant treatment of patients with melanoma is not recommended outside the context of a clinical study. Patients with metastatic melanoma are preferably treated within a clinical study. Outside of a clinical study, these patients should be treated with dacarbazine. There is no evidence to suggest that survival is improved by frequent follow-up. However, follow-up can be a useful way to meet the information needs of patients and care requirements for physicians.

Risk factors of back pain frequency in schoolchildren: a search for explanations to a public health problem.

UNLABELLED: This study examined physical, behavioral and social factors associated with schoolchildren's back pain. Factors associated with back pain were also identified using a stepwise regression method. The study was based on a self-administered questionnaire survey of a random national sample of 2173 Icelandic 11-12 and 15-16-y-old schoolchildren. It found that older subjects tended to report back pain more frequently than younger children. Back pain showed significant associations with different aspects of physical condition such as chronic health conditions, tiredness and physical fitness. A number of behavioral factors including participation in sports, television viewing, eating habits and smoking also had a relationship with back pain. Finally, children with lower social support were more likely to experience back pain. CONCLUSION: Overall, four major factors (age, morning tiredness, eating habits and parental support) emerged as factors associated with back pain in the study subjects. These results highlighted the roles of lifestyle and social factors in the experience of back pain in schoolchildren.

Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a three-dimensional rotating-wall vessel.

A three-dimensional (3D) integrated rotating-wall vessel cell-culture system was used to evaluate the interaction between a human prostate cancer cell line, LNCaP, and microcarrier beads alone, or microcarrier beads previously seeded with either prostate or bone stromal cells. Upon coculture of LNCaP cells with microcarrier beads either in the presence or in the absence of prostate or bone stromal cells, 3D prostate organoids were formed with the expected hormonal responsiveness to androgen, increased cell growth, and prostate-specific antigen production. In this communication, we define permanent phenotypic and genotypic changes of LNCaP cells upon coculture with microcarrier beads alone, or with microcarrier beads previously seeded with either prostate or bone stromal cells. Most notably, we observed selective genetic changes, i.e., chromosomal losses or gains, as evaluated by both conventional cytogenetic and comparative genomic hybridization, in LNCaP sublines derived from the prostate organoids. Moreover, the derivative LNCaP cells appear to have altered growth profiles, and exhibit permanent and stable changes in response to androgen, estrogen, and growth factors. The derivative LNCaP sublines showed increased anchorage-independent growth rate, and enhanced tumorigenicity and metastatic potential when inoculated orthotopically in castrated athymic mice. Our results support the hypothesis that further nonrandom genetic and phenotypic changes in prostate cancer epithelial cells can occur through an event that resembles "adaptive mutation" such as has been described in bacteria subjected to nutritional starvation. The occurrence of such permanent changes may be highly contact dependent, and appears to be driven by specific microenvironmental factors surrounding the tumor cell epithelium grown as 3D prostate organoids.

Synthesis and biological properties of C-2, C-8, N-9 substituted 6-(3-chloroanilino)purine derivatives as cyclin-dependent kinase inhibitors. Part II.

In this study, C-2, C-8, N-9 substituted 6-(3-chloroanilino)purine derivatives were synthesized and their inhibitory effects on cyclin-dependent kinases (CDK2, 4) as well as their cytotoxicities were evaluated. The effects of substituents at the C-2, C-8, and N-9 positions of the substituted purine were investigated. Among the compounds tested, [6-(3-chloroanilino)-2-(2-hydroxymethyl-4-hydroxypyrrolidyl)-9- isopropylpurine] (4h) was the most active inhibitor of CDK2 with IC50 of 0.3 microM, i.e. a two-fold increased inhibitory activity as compared to roscovitine. Results from structure-activity relationship studies should allow the design of more potent and selective CDK2 inhibitors, which may provide an effective therapy for cancer or other CDK-dependant diseases.

[Interferon for adjuvant therapy in melanoma; although approved, not indicated]. / Interferon als adjuvante therapie bij het melanoom: wel geregistreerd, niet geïndiceerd.

The Dutch melanoma group reconsidered their 1997 consensus statement on treatment of melanoma because new studies on adjuvant treatment with interferon(IFN)-alpha have been published. These have resulted in its registration for stage IIa; for stage IIb/III IFN-alpha was already registered. Overall survival should be the main endpoint of adjuvant clinical studies, especially when treatment is associated with toxicity. Since a benefit has not been unequivocally demonstrated in melanoma with Breslow thickness > 1.5 mm and/or regional lymph node metastases, there is no need to change the Dutch consensus statement. Drug registration authorities and medical professionals should cooperate more closely.

A facile synthesis of cis-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine and its derivative.

The synthesis of carbocyclic nucleosides, cis-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (3) and cis-2-amino-6-cyclopropylamino-9-[4-(1,2-dihydroxyethyl)- cyclopent-2- enyl]purine (4), was achieved from cyclopentadiene (5) in five and six steps, respectively. This route involves a hetero Diels-Alder reaction and a Pd(0)-catalyzed coupling reaction.