Ex vivo models of HIV sexual transmission and microbicide development

Here, we review the armamentarium on in vitro/ex vivo models of HIV sexual transmission and discuss how these models can be applied to study candidate microbicides.     

Clinical and Pathologic Impact of Select Chromatin-modulating Tumor Suppressors in Clear Cell Renal Cell Carcinoma

Background

Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.

Objective

To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.

Design, setting, and participants

Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded.

Outcome measurements and statistical analysis

The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]).

Results and limitations

PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III–IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events.

Conclusions

Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.     

Ruling Out Myocardial Infarction with Troponin T and Creatine Kinase MB Mass: Diagnostic and Prognostic Aspects

Objective - To investigate the time window for ruling out myocardial infarction (MI) with troponin T (TnT) and creatine kinase isoenzyme MB mass (CK-MBm) and the prognosis of patients with ruled-out MI diagnosis. Design - The study was based on 397 patients admitted with a suspected acute coronary syndrome but with relief of symptoms within 24 h. Results - MI diagnosis was confirmed with elevated TnT (> 0.10 µg/l) in 108 patients, in 91% within 12-24 h from the onset of symptoms, and in 99% within 12 h from admission. In 94 of these patients CK-MBm became elevated (> 5.0 µg/l), in 95% within 10-12 h from the onset of symptoms, and in 99% within 6 h from admission. Among patients with ruled-out MI diagnosis, the 1-year incidence of recurrent coronary events was 29% in those with positive history of coronary heart disease (CHD) but only 7% in those without prior CHD ( p < 0.001). Conclusion - Using TnT or CK-MBm, MI can be ruled out within 12 h from admission in the majority of patients. Among patients with ruled-out MI diagnosis, positive history of CHD is an important determinant of prognosis.     

Awake craniotomy and electrophysiological mapping for eloquent area tumours

Objective

An awake craniotomy facilitates radical excision of eloquent area gliomas and ensures neural integrity during the excision. The study describes our experience with 67 consecutive awake craniotomies for the excision of such tumours.

Methods

Sixty-seven patients with gliomas in or adjacent to eloquent areas were included in this study. The patient was awake during the procedure and intraoperative cortical and white matter stimulation was performed to safely maximize the extent of surgical resection.

Results

Of the 883 patients who underwent craniotomies for supratentorial intraaxial tumours during the study period, 84 were chosen for an awake craniotomy. Sixty-seven with a histological diagnosis of glioma were included in this study. There were 55 men and 12 women with a median age of 34.6 years. Forty-two (62.6%) patients had positive localization on cortical stimulation. In 6 (8.9%) patients white matter stimulation was positive, five of whom had responses at the end of a radical excision. In 3 patients who developed a neurological deficit during tumour removal, white matter stimulation was negative and cessation of the surgery did not result in neurological improvement. Sixteen patients (24.6%) had intraoperative neurological deficits at the time of wound closure, 9 (13.4%) of whom had persistent mild neurological deficits at discharge, while the remaining 7 improved to normal. At a mean follow-up of 40.8 months, only 4 (5.9%) of these 9 patients had persistent neurological deficits.

Conclusion

Awake craniotomy for excision of eloquent area gliomas enable accurate mapping of motor and language areas as well as continuous neurological monitoring during tumour removal. Furthermore, positive responses on white matter stimulation indicate close proximity of eloquent cortex and projection fibres. This should alert the surgeon to the possibility of postoperative deficits to change the surgical strategy. Thus the surgeon can resect tumour safely, with the knowledge that he has not damaged neurological function up to that point in time thus maximizing the tumour resection and minimizing neurological deficits.     

Clinical Meaning of Hot Uptake on Bone Scan in Symptomatic Accessory Navicular Bones

Introduction

We analyzed clinical factors related to uptake on a Tc-99 m HDP bone scan of the accessory navicular (AN).

Materials and Methods

We retrospectively reviewed patients who had been examined by an orthopedic surgeon and underwent bone scan due to suspected symptomatic AN. A three-point grading system was used to evaluate uptake on bone scan. Relationships between grade, symptoms, age, gender, symptom duration, and bone size were analyzed.

Results

In total, 73 ANs (30 asymptomatic, 43 symptomatic) were enrolled. The majority of asymptomatic ANs had no uptake but some had grade 1 (n?=?8) or 2 (n?=?2) uptake. All asymptomatic ANs with uptake remained asymptomatic during follow-up. For the asymptomatic ANs, larger bones showed a higher grade. With a cut-off value of size ≤6.8 mm, there is no chance of uptake. All symptomatic ANs showed uptake on bone scan. For symptomatic ANs, larger size and shorter pain duration were related to a higher grade. Age, gender, and left-/right-sideness were not related to grade. Multiple regressions revealed that only uptake grade, not size or symptom duration, was the significant risk factor for a symptomatic AN. With a cut-off value of grade <1, a symptomatic AN could be ruled out with a negative predictive value of 100 %.

Conclusion

Bone scanning is useful for symptomatic ANs with a high negative predictive value. Higher grade is related to larger size and shorter pain duration. For asymptomatic ANs, grade was related to size but did not predict symptom development.

     

Second primary malignancies in renal cortical neoplasms: an updated evaluation from a single institution

Purpose

To examine the incidence of secondary primary malignancies in patients with renal cortical neoplasms.

Methods

Between January 1989 and July 2010, 3647 patients underwent surgery at our institution for a renal cortical neoplasm and were followed through 2012. Occurrence of other malignancies was classified as antecedent, synchronous, or subsequent. All patients with antecedent malignancies (n = 498) and a randomly selected half of those with synchronous malignancies (n = 83) were excluded. The expected number of second primaries was calculated by multiplying Surveillance, Epidemiology, and End Results Program incidence rates of renal cortical neoplasms by person-years at risk within categories of age, sex, and year of diagnosis. The standardized incidence ratio (SIR) was calculated as observed cancers divided by expected incidence of the cancer, with approximation to the exact Poisson test used to obtain confidence intervals (CI) and p values.

Results

Of 3066 patients with renal cortical neoplasms, 267 had a second primary cancer; the five most common in men were prostate, colorectal, bladder, lung, and non-Hodgkin’s lymphoma; the five most common in women were breast, colorectal, lung, endometrium, and thyroid. Men demonstrated higher than expected thyroid cancer rate (SIR 5.0; 95 % CI 1.83–10.88, p = 0.002), and women had higher than expected rates of stomach cancer (SIR 5.0; 95 % CI 1.61–11.67, p = 0.004) and thyroid cancer (SIR 4.62; 95 % CI 1.69–10.05, p = 0.003).

Conclusions

The incidence of certain types of second malignancies may be higher in patients after diagnosis of renal cortical neoplasms compared to the general population. These observations can inform clinical follow-up in kidney cancer survivorship and future research studies.