[Systemic treatment of locally advanced or metastatic penile cancer]. / Traitement systémique du cancer du pénis localement avancé ou métastatique.

Penile cancers are rare, the vast majority is represented by squamous cell carcinoma, with HPV virus being found in 30 to 40% of cases. At a locally advanced or metastatic stage, first-line treatment relies on platinum and taxane based polychemotherapy. The prognosis for advanced or metastatic penile cancer remains poor, with overall survival ranging from 13.9 to 17.1 months. After the first line, guidelines recommend various chemotherapy treatments or targeted anti-EGFR therapies whose results as well as the level of evidence are limited. A better understanding of the oncogenic pathways involved in penile cancer and a frequent expression of PD-L1 are the rationale for the elaboration of new strategies. This review article presents the data, guidelines and ongoing studies in locally advanced or metastatic penile cancer.

Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial).

BACKGROUND: Microwave (MWA) and radiofrequency ablation are the commonly used local ablation for hepatocellular carcinoma (HCC). Studies comparing both techniques are scarce. The aim of this study was to compare the efficacy of MWA versus RFA as a treatment for HCC. METHODS: Patients with HCC who were suitable for local ablation were randomized into MWA or RFA. All patients were followed up regularly with contrast-enhanced computed tomography (CT) performed at 1, 3, 6 and 12 months after ablation. Both patients and the radiologists who interpreted the post-procedure CT scans were blinded to the treatment allocation. Treatment-related morbidity, overall and disease-free survivals were analyzed. RESULTS: A total of 93 patients were recruited. Among them, 47 and 46 patients were randomized to MWA and RFA respectively. Patients in two groups were comparable in baseline demographics and tumor characteristics. With a median follow-up of around 30 months, there were no significant difference in the treatment-related morbidity, overall and disease-free survivals. MWA had a significantly shorter overall ablation time when compared with RFA (12 min vs 24 min, p < 0.001). CONCLUSIONS: MWA is no different to RFA with respect to completeness of ablation and survivals. It is, however, as safe and effective as RFA in treating small HCC.

[Radiotherapy of oligometastases: Sequences and interactions with systemic therapies, example of kidney cancer]. / Radiothérapie des oligométastases : interactions/séquences avec thérapies systémiques, exemple du cancer du rein.

This article is a review of the literature that aims to clarify the place of systemic and locoregional treatments, with a focus on radiotherapy and surgery in the management of patients with oligometastatic kidney cancer. We have selected articles of interest published in Medline indexed journals. We have also analysed the related guidelines: National Comprehensive Cancer Network (NCCN) 2019, European Association of Urology (EAU) 2019, European Society of Medical Oncology (ESMO) 2019, Association française d'urologie (Afu) 2018 as well as some abstracts of international congresses. The main treatments evaluated were surgery and radiotherapy. We defined the different scenarios conventionally encountered in clinical practice. The evolution of systemic therapies (increased overall survival and response rate) is likely to increase the number of patients potentially accessible to locoregional treatments. The complete analysis of the literature underlines the place of locoregional treatments whatever the scenarios mentioned. Data on stereotactic radiotherapy found a local control rate consistently above 70% in all studies with a maintained response and positive impact on overall survival and progression-free survival. The improvement of overall survival by sequential use of the various therapeutic classes confirms the need for optimization of locoregional treatments in the model of oligometastatic kidney cancer. The dogma of radioresistance must definitely be set aside with current irradiation techniques.

Impact of everolimus blood concentration on its anti-cancer activity in patients with metastatic renal cell carcinoma.

PURPOSE: Everolimus has demonstrated its efficacy in metastatic renal cell carcinoma (mRCC). Preliminary studies have shown high variability of everolimus blood concentrations (EBC). In other settings, its activity was correlated with EBC. We therefore decided to monitor EBC in patients treated with mRCC to assess its influence on oncologic outcomes. PATIENTS AND METHODS: Our study analyzed first 3 months' trough EBC levels in 42 patients treated in 4 French oncologic centers between March 2010 and August 2013. Patients presented a histologically confirmed diagnosis of mRCC and have failed prior anti-angiogenic (AA) therapies. RESULTS: Median follow-up was 25.9 months. A total of 113 EBC were analyzed. The median trough concentration was 14.1 µg/L (range 2.6-91.5). Fourteen patients (67 %) versus 8 (38 %) patients with median EBC above or below 14.1 µg/L were free from progression at 6 months (p = 0.06). Median progression-free survival was 13.3 versus 3.9 months (HR 0.66 95 % CI 0.33-1.31; p = 0.23), and the median overall survival was 26.2 versus 9.9 months (HR 0.62 95 % CI 0.28-1.37; p = 0.24), for patients above or below the median value of trough concentrations, respectively. CONCLUSION: Impact of drug exposure for AA tyrosine kinase inhibitors activity has been demonstrated in mRCC setting. Interpatients EBC variability was confirmed in the present study, and the results suggest a relationship between initial EBC within the first 3 months and the drug activity. It underlines the need to prospectively include EBC monitoring in future clinical trials to determine the need of its implementation in routine use.

Comparison of the influence of cataract and pupil size on retinal nerve fibre layer thickness measurements with time-domain and spectral-domain optical coherence tomography.

BACKGROUND: To investigate and compare the effect of cataract and pupil size on retinal nerve fibre layer (RNFL) thickness measurements using spectral-domain optical coherence tomography (Cirrus OCT) and time-domain OCT (Stratus OCT). DESIGN: Prospective, hospital-based study. PARTICIPANTS: Twenty-five eyes from 25 normal subjects undergoing cataract surgery. METHODS: Three retinal nerve fibre layer (RNFL) thickness measurements were taken before and after dilation, preoperatively and postoperatively, using Cirrus 200×200 Optic Disc Scan and Stratus Fast RNFL Scan. MAIN OUTCOME MEASURES: Linear regression, intraclass correlation coefficient (ICC) and coefficient of variation analysis. RESULTS: Cataract removal caused significant increase in RNFL measurements in both modalities (Cirrus P<0.02; Stratus P<0.001). There was no significant difference in the increase in measurements between the two machines. Pupil dilation had variable and non-statistically significant effect in both (P>0.05). ICC showed excellent reproducibility with Cirrus OCT after mydriasis, preoperatively (ICC=0.78-0.90) and postoperatively (ICC=0.90-0.97), but poor reproducibility before mydriasis (P<0.75). Stratus OCT achieved excellent reproducibility after cataract removal both before (ICC=0.86-0.96) and after mydriasis (ICC=0.92-0.95), but poor reproducibility before cataract surgery (P<0.75). CONCLUSIONS: Cataracts, not pupil size, cause significant underestimation of RNFL measurements in both Cirrus and Stratus OCT. The extent of influence exerted does not appear different between the two instruments. Reproducibility of each machine appears to be affected differently. Mydriasis is required to achieve excellent reproducibility with Cirrus OCT, and media clarity is required with Stratus OCT.

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.

BACKGROUND: We investigated the temporal progression of the clinical, radiological, and virological changes in a community outbreak of severe acute respiratory syndrome (SARS). METHODS: We followed up 75 patients for 3 weeks managed with a standard treatment protocol of ribavirin and corticosteroids, and assessed the pattern of clinical disease, viral load, risk factors for poor clinical outcome, and the usefulness of virological diagnostic methods. FINDINGS: Fever and pneumonia initially improved but 64 (85%) patients developed recurrent fever after a mean of 8.9 (SD 3.1) days, 55 (73%) had watery diarrhoea after 7.5 (2.3) days, 60 (80%) had radiological worsening after 7.4 (2.2) days, and respiratory symptoms worsened in 34 (45%) after 8.6 (3.0) days. In 34 (45%) patients, improvement of initial pulmonary lesions was associated with appearance of new radiological lesions at other sites. Nine (12%) patients developed spontaneous pneumomediastinum and 15 (20%) developed acute respiratory distress syndrome (ARDS) in week 3. Quantitative reverse-transcriptase (RT) PCR of nasopharyngeal aspirates in 14 patients (four with ARDS) showed peak viral load at day 10, and at day 15 a load lower than at admission. Age and chronic hepatitis B virus infection treated with lamivudine were independent significant risk factors for progression to ARDS (p=0.001). SARS-associated coronavirus in faeces was seen on RT-PCR in 65 (97%) of 67 patients at day 14. The mean time to seroconversion was 20 days. INTERPRETATION: The consistent clinical progression, shifting radiological infiltrates, and an inverted V viral-load profile suggest that worsening in week 2 is unrelated to uncontrolled viral replication but may be related to immunopathological damage.

The Hsp70-Ydj1 molecular chaperone represses the activity of the heme activator protein Hap1 in the absence of heme.

In Saccharomyces cerevisiae, heme directly mediates the effects of oxygen on transcription through the heme activator protein Hap1. In the absence of heme, Hap1 is bound by at least four cellular proteins, including Hsp90 and Ydj1, forming a higher-order complex, termed HMC, and its activity is repressed. Here we purified the HMC and showed by mass spectrometry that two previously unidentified major components of the HMC are the Ssa-type Hsp70 molecular chaperone and Sro9 proteins. In vivo functional analysis, combined with biochemical analysis, strongly suggests that Ssa proteins are critical for Hap1 repression in the absence of heme. Ssa may repress the activities of both Hap1 DNA-binding and activation domains. The Ssa cochaperones Ydj1 and Sro9 appear to assist Ssa in Hap1 repression, and only Ydj1 residues 1 to 172 containing the J domain are required for Hap1 repression. Our results suggest that Ssa-Ydj1 and Sro9 act together to mediate Hap1 repression in the absence of heme and that molecular chaperones promote heme regulation of Hap1 by a mechanism distinct from the mechanism of steroid signaling.

Functional analysis of heme regulatory elements of the transcriptional activator Hap1.

Heme regulation of the activity of diverse proteins was thought to be mediated by heme-responsive motifs (HRMs). The yeast transcriptional activator Hap1 contains seven HRMs: HRM1-7. Three copies of a 17-amino-acid repeat are also located in the region encompassing HRM1 to -6. We examined the effects of these HRMs and repeats on heme regulation of Hap1 activity by deletion analysis and by Ala substitutions of key residues. We found that the effect of mutation or deletion of one HRM or 17-amino-acid repeat on Hap1 heme responsiveness is different from the effect of mutation or deletion of another HRM or repeat. Our data suggest that HRM7 plays a dominant role in mediating heme activation of Hap1 in heme-sufficient cells while HRM1-6 may scavenge heme and cause a low level of Hap1 activation in heme-deficient cells. These results may help in understanding the roles of HRMs in other hemoproteins.

The coiled coil dimerization element of the yeast transcriptional activator Hap1, a Gal4 family member, is dispensable for DNA binding but differentially affects transcriptional activation.

The heme activator protein Hap1 is a member of the yeast Gal4 family, which consists of transcription factors with a conserved Zn(2)Cys(6) cluster that recognizes a CGG triplet. Many members of the Gal4 family contain a coiled coil dimerization element and bind symmetrically to DNA as homodimers. However, Hap1 possesses two unique properties. First, Hap1 binds asymmetrically to a direct repeat of two CGG triplets. Second, Hap1 binds to two classes of DNA elements, UAS1/CYC1 and UAS/CYC7, and permits differential transcriptional activation at these sites. Here we determined the residues of the Hap1 dimerization domain critical for DNA binding and differential transcriptional activation. We found that the Hap1 dimerization domain is composed of functionally redundant elements that can substitute each other in DNA binding and transcriptional activation. Remarkably, deletion of the coiled coil dimerization element did not severely diminish DNA binding and transcriptional activation at UAS1/CYC1 but completely abolished transcriptional activation at UAS/CYC7. Furthermore, Ala substitutions in the dimerization element selectively diminished transcriptional activation at UAS/CYC7. These results strongly suggest that the coiled coil dimerization element is responsible for differential transcriptional activation at UAS1/CYC1 and UAS/CYC7 and for making contacts with a putative coactivator or part of the transcription machinery.

The yeast heme-responsive transcriptional activator Hap1 is a preexisting dimer in the absence of heme.

In the absence of heme, Hap1 is associated with molecular chaperones such as Hsp90 and Ydj1 and forms a higher order complex termed HMC. Heme disrupts this complex and permits Hap1 to bind to DNA with high affinity, thereby activating transcription. Heme regulation of Hap1 activity is analogous to the regulation of steroid receptors by steroids, which involves molecular chaperones. Steroid receptors often exist as monomers when associated with molecular chaperones in the absence of ligand but as dimers when activated by steroids. Furthermore, previous studies indicate that dimerization might be important for heme activation of Hap1. We therefore determined whether Hap1 is a monomer or oligomer in the absence of heme. By coeluting two Hap1 size variants and by comparing DNA binding properties of the HMC and Hap1 dimer, we show that Hap1 is a preexisting dimer in the HMC. Further, increasing overexpression of Hap1 caused progressive increases in Hap1 DNA binding and transcriptional activities. Our data suggest that in the absence of heme, Hap1 exists as a dimer, and the two subunits act cooperatively in DNA binding. Hap1 repression is caused, at least in part, by inhibition of the DNA binding activity of the preexisting dimer.

Neurodevelopmental outcome of very low birth weight babies admitted to a Malaysian nursery.

OBJECTIVE: To examine the prevalence and pattern of neurodevelopmental handicap at 2 years of age in very low birth weight infants (VLBW) admitted in 1993 to a level 3 Malaysian nursery. METHODS: All VLBW babies born in the hospital or referred for neonatal care during 1993 were enrolled prospectively in the study. At 2 years of age development was assessed using the Griffiths mental scales. Neurological, hearing and visual assessments were graded into five groups according to functional handicap. Control infants were randomly selected during attendance at a primary health care clinic. RESULTS: One hundred and fifty VLBW infants were admitted and 82 (54.6%) survived to 2 years, of whom 77 (93.9%) were assessed. The mean General Quotient (GQ) on the Griffiths Scales was 94 (15.7) for the study group and 104 (8.3) for the 60 controls. For GQ, 21 (27.3%) of the study population were 1 or more SD below the mean (18 between 1 and 2 SD and 3 > 2 SD) compared with 1 (1.6%) of the controls who was 1-2 SD below the mean. Visual impairment occurred in 2 study infants and none of the controls. There was no hearing impairment in either group. Cerebral palsy occurred in 3 (1 mild and 2 moderate-severe) of the study group and none of the controls. Functionally 18 (23.3%) of the study group had mild handicap, 1 (1.3%) moderate, 2 (2.5%) severe, 2 (2.5%) multiply severe and 54 (70.2%) were normal. CONCLUSION: Although survival was low, overall rates of functional handicap were similar to those reported in developed countries but the proportion with moderate or severe handicap was low.

PIP: This paper examines the prevalence and pattern of neurodevelopmental handicap at 2 years of age in very-low-birth-weight (VLBW) infants admitted during 1993 to a level 3 nursery in Malaysia. The study included all VLBW babies born in the hospital or referred for neonatal care. Control infants were randomly selected during attendance at a primary health care clinic. A total of 82 (54.6%) out of the 150 VLBW infants admitted survived for 2 years, 77 (93.9%) of which were evaluated. The mean General Quotient (GQ) on the Griffiths Scales was 94 (15.7) for the study group and 104 (8.3) for the 60 controls. For GQ, 21 infants (27.3%) of the study population were 1 or more standard deviations (SD) below the mean, as compared with 1 infant (1.6%) of the control group who was 1-2 SD below the mean. Visual impairment occurred in 2 study infants and none of the controls. There was no hearing impairment in either group. In conclusion, mortality was higher than reported in developing countries but the rate of handicap was not different. Neonatal intensive care should continue to be upgraded in developing countries but at a rate compatible with the availability of resources.

A new class of repression modules is critical for heme regulation of the yeast transcriptional activator Hap1.

Heme plays key regulatory roles in numerous molecular and cellular processes for systems that sense or use oxygen. In the yeast Saccharomyces cerevisiae, oxygen sensing and heme signaling are mediated by heme activator protein 1 (Hap1). Hap1 contains seven heme-responsive motifs (HRMs): six are clustered in the heme domain, and a seventh is near the activation domain. To determine the functional role of HRMs and to define which parts of Hap1 mediate heme regulation, we carried out a systematic analysis of Hap1 mutants with various regions deleted or mutated. Strikingly, the data show that HRM1 to -6, located in the previously designated Hap1 heme domain, have little impact on heme regulation. All seven HRMs are dispensable for Hap1 repression in the absence of heme, but HRM7 is required for Hap1 activation by heme. More importantly, we show that a novel class of repression modules-RPM1, encompassing residues 245 to 278; RPM2, encompassing residues 1061 to 1185; and RPM3, encompassing residues 203 to 244-is critical for Hap1 repression in the absence of heme. Biochemical analysis indicates that RPMs mediate Hap1 repression, at least partly, by the formation of a previously identified higher-order complex termed the high-molecular-weight complex (HMC), while HRMs mediate heme activation by permitting heme binding and the disassembly of the HMC. These findings provide significant new insights into the molecular interactions critical for Hap1 repression in the absence of heme and Hap1 activation by heme.

Heme initiates changes in the expression of a wide array of genes during the early erythroid differentiation stage.

Heme is central to oxygen sensing and utilization in all living organisms. It directly regulates numerous molecular and cellular processes for systems that sense or use oxygen. In mammals, heme plays an indispensable role in erythroid cell differentiation. To investigate heme regulatory functions, we identified, by differential display, and confirmed, by quantitative RT-PCR and Northern blotting analysis, the genes whose expression is altered by heme during the early stage of K562 cell differentiation. These include genes encoding a GAP-associated p62 protein, histone H2A.Z, a subunit of the small nuclear ribonucleoprotein complex, and the chaperonin Tcp20, and a cellular immediate-early-response gene. The results suggest that heme initiates changes in key factors that control a wide array of processes ranging from cell cycle and Ras signaling to chromatin structure, splicing and protein folding. These key factors might act together to mediate heme action, which is critical for erythroid cell differentiation.

Colonic diverticulosis in Hong Kong: distribution pattern and clinical significance.

This is a retrospective study on the prevalence of diverticulosis in Hong Kong Chinese adults. Eight-hundred and fifty-eight consecutive barium enema examinations over a period of 18 months (January 1995-June 1996) were analysed. Results show that the prevalence of diverticulosis in our community is 25.1% with no significant difference between male and female adults. The prevalence is lower than Western countries but higher than in Asia. Moreover, the peak prevalence is at the 50-79 years age group with lower prevalence in the older age groups. This may be explained by the rapid rise in prevalence in the younger age groups so that the age-related increase in prevalence become obscured. We postulate that this may be due to Western cultural influence in our diet and lifestyle. There is no significant difference in the symptomatology of patients with and without diverticulosis, supporting the idea that diverticulosis alone is usually asymptomatic. There is predominance of right hemicolon involvement in our subjects, in contrast to the left hemicolon predominance in the Caucasian population. Of patients with diverticulosis, 55.3% have only right-sided involvement and 32.6% have bilateral involvement. Only 12.1% of patients with diverticulosis have exclusively left hemicolon involvement. Caecal and ascending colon diverticula are found in 6.4% and 17.6% of all the adults under study, respectively. Clinicians caring for patients from our community should take note of this high frequency of caecal and ascending colon diverticulosis as caecal and ascending colon diverticulitis is notoriously difficult to diagnose clinically.

Torsion of the wandering spleen.

A case of torsion of the wandering spleen with splenic infarction is reported. The medical imaging studies performed with typical findings are described. Case reports have been reviewed. Although rare, torsion of the spleen remains an important differential diagnosis in patients presenting with acute abdominal pain. Early intervention is necessary to reduce the risk of splenic infarction and other complications, and an increased awareness of the condition together with the use of appropriate medical imaging can lead to the correct diagnosis more readily.

Traumatic dental injuries at the Accident and Emergency Department of Singapore General Hospital.

The purpose of this retrospective study was to determine the occurrence and the type of after office-hours traumatic dental injuries managed by the Dental Unit of the Accident and Emergency Department at the Singapore General Hospital. During a 2-year period (from August 1990 to July 1992), 461 trauma patients (314 males, 147 females) sustained injuries to 968 teeth. The distribution in different races of Chinese: Malay: Indian: others was 7.3: 1.3: 0.9: 0.5. The predominant age groups were 2-3 years, 3-4 years and 17-18 years; 71.3% of the teeth sustained luxation type injuries, the remaining 28.7% had fractures, 45.3% of the cohort had concomitant soft tissues injuries, while 13.7% had associated facial bone fractures. Teenager traumas were more common during school vacations. It is concluded that thorough standardized documentation is imperative to obtain baseline information on dental trauma. This could facilitate future preventive measures, education and research.

A field evaluation of baits for delivering oral rabies vaccines to raccoons (Procyon lotor).

Eight field trials were conducted in 1989 and 1990 in Georgia (USA) and Maryland (USA) to evaluate baits and baiting strategies for delivering oral rabies vaccines to raccoons (Procyon lotor). Bait packets consisting of corn meal and egg batter-based baits enclosed in plastic bags were placed at 1.0-m diameter, raked tracking stations and checked daily. Packets were well accepted by raccoons; they visited 31 to 44% of the tracking stations where they removed 69 to 90% of the packets within 4 to 5 days. All or nearly all baits were removed from plastic bags and less than 1% of the baits were found only partially eaten. No rejection of water-filled paraffin ampules in baits was observed. The use of an odor attractant on bait packets did not appear to enhance bait discovery when packets were placed on raccoon travel routes. An attractant did enhance discovery when baits were placed off-road in a simulated aerial baiting test. Nontarget species comprised 31 to 53% of all visits to the stations; they took 28 to 55% of the baits but did not appear to adversely affect bait availability for raccoons. A total of 2,300 baits, each containing a wax ampule holding 10 mg of a physiological marker (iophenoxic acid), were distributed at a rate of 82 baits/km2 on 2,800 ha of Sapelo Island, Georgia. Thirty-five (65%) of 54 raccoons collected following bait placement had eaten one or more baits as indicated by elevated levels of iodine in the blood serum.

Restoration of gamma camera-based nuclear medicine images.

Experiments were conducted using a Siemens Rota camera to study the applicability of two linear shift-invariant (LSI) filters, namely, the Wiener and power spectrum equalization filters, for restoration of planar projections and single-photon-emission computed tomography (SPECT) images. In the restoration scheme, the system transfer function, computed from a line source image, is modeled by a 2-D Gaussian function. The noise power spectrum is modeled as a constant for planar images and as a ramp for SPECT images. The filters have been applied to restore computer-simulated 1-D and 2-D projections and SPECT images of two simple phantoms, 2-D projections of two phantoms obtained from the Siemens Rota camera, and SPECT images of a cardiac phantom obtained from the Siemens Rota camera. The filters are shown to perform partial restoration. Considerable noise suppression and detail enhancement have been observed in the restored images. quantitative measurements such as root-mean-squared error and contrast ratio have been used for objective analysis of the results, which are encouraging.