Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes.

AIM: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. METHODS: Twenty-five insulin-treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks. Dual-energy X-ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre-/posttreatment (a ratio <1 represents fatty liver). RESULTS: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 ± 0.3 to 7.2 ± 0.3% and 7.6 ± 0.3 to 7.1 ± 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 ± 4.5 kg) versus insulin therapy alone (1.7 ± 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 ± 48.5 to 443.2 ± 56.7 cm(2) , p < 0.01) compared to a non-significant increase with insulin therapy alone (412.9 ± 42.5 to 420.8 ± 43.8 cm(2) ). VAT decreased non-significantly in both groups (240.3 ± 41.7 to 223.8 ± 38.1 cm(2) with insulin + pioglitazone and 266.6 ± 27.4 to 250.5 ± 22.2 cm(2) with insulin therapy). LBM increased significantly by 1.92 ± 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 ± 0.1 to 1.04 ± 0.1 (p = ns) and increased from 1.00 ± 0.1 to 1.08 ± 0.05 (p = 0.06) in the pioglitazone + insulin group. CONCLUSIONS: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain.

Effects of intensive insulin therapy alone and with added pioglitazone on renal salt/water balance and fluid compartment shifts in type 2 diabetes.

OBJECTIVE: To evaluate the effects of intensive insulin therapy alone or with added pioglitazone on renal salt/water balance and body fluid compartment shifts in type 2 diabetes. METHODS: A total of 25 insulin-treated, obese patients with type 2 diabetes were randomized to pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks to achieve equivalent glycaemic control. We measured total body water (TBW) and extracellular/intracellular fluid by bioimpedance analysis; plasma/RBC volume with I(131)albumin; sodium handling by fractional excretion of sodium/lithium (FeNa/FeLi) and other renal/hormonal parameters. RESULTS: Intensification of insulin therapy and the addition of pioglitazone significantly improved glycaemia (HbA1C 7.8-7.2% and 7.6-7.1%) and increased body weight (1.7 and 4.9 kg) respectively. TBW increased 1.7 l with insulin alone (65% intracellular) and 1.6 l with added pioglitazone (75% extracellular) (p = 0.06 and 0.09 respectively). Plasma volume increased 0.2 +/- 0.1 l with insulin alone (p = 0.05) and 0.4 +/- 0.1 l with added pioglitazone (p < 0.05). Extravascular, extracellular (interstitial) fluid increased significantly and more with added pioglitazone (0.8 +/- 0.2 l, p < 0.01) than with insulin alone (0.4 +/- 0.2 l, p = ns). At steady-state, FeLi (marker of proximal-tubular sodium delivery to the distal nephron) increased significantly with added pioglitazone (12.4 +/- 1.3 to 18.0 +/- 3.2%) vs. no significant change with insulin alone (15.4 +/- 1.2 to 14.5 +/- 2.3%). There were no significant changes in the other parameters. CONCLUSION: In intensively insulin-treated obese type 2 diabetic patients, at equivalent glycaemic control, the addition of pioglitazone causes greater weight gain, but a similar increase in body water that is mainly extracellular and interstitial compared with intracellular increase with insulin therapy alone. Pioglitazone also increases the filtered load of sodium reabsorbed at the distal nephron with no net change in FeNa.

Survey of current practices from an international task force for gynecological stereotactic ablative radiotherapy.

BACKGROUND: Stereotactic Ablative Radiotherapy (SABR) is an effective treatment that improves local control for many tumours. However, the role of SABR in gynecological cancers (GYN) has not been well-established. We hypothesize that there exists considerable variation in GYN-SABR practice and technique. The goal of this study is to describe clinical and technical factors in utilization of GYN-SABR among 11 experienced radiation oncologists. MATERIALS AND METHODS: A 63 question survey on GYN-SABR was sent to 11 radiation oncologists (5 countries) who have published original research, conducted trials or have an established program at their institutions. Responses were combined and analyzed at a central institution. RESULTS: Most respondents indicated that salvage therapy (non-irradiated or re-irradiated field) for nodal (81%) and primary recurrent disease (91%) could be considered standard options for SABR in the setting of inability to administer brachytherapy. All other indications should be considered on clinical trials. Most would not offer SABR as a boost in primary treatment off-trial without absolute contraindications to brachytherapy. Multi-modality imaging is often (91%) used for planning including PET, CT contrast and MRI. There is a wide variation for OAR tolerances however small bowel is considered the dose-limiting structure for most experts (91%). Fractionation schedules range from 3 to 6 fractions for nodal/primary definitive and boost SABR. CONCLUSIONS: Although SABR has become increasingly standard in other oncology disease sites, there remains a wide variation in both clinical and technical factors when treating GYN cancers. Nodal and recurrent disease is considered a potential indication for SABR whereas other indications should be offered on clinical trials. This study summarizes SABR practices among GYN radiation oncologists while further studies are needed to establish consensus guidelines for GYN-SABR treatment.

Comparative validation of c-kit exon 11 mutation analysis on cytology samples and corresponding surgical resections of gastrointestinal stromal tumours.

OBJECTIVE: Studies have shown that c-kit mutation analysis of gastrointestinal stromal tumours (GISTs) obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) can be routinely performed. We validated c-kit exon 11 mutational analysis on cell block material obtained from fine needle aspiration cytology (FNAC) for diagnostic purposes and compared it with the same analysis in formalin-fixed paraffin-embedded full sections of the corresponding resection specimens. METHODS: c-kit mutation analysis was done on cell block material obtained from ten cases encountered in our department from 1999 to 2008 on which FNAC was attempted pre-operatively. The findings were compared with analysis on full paraffin section of the corresponding resected tumours in seven cases where patients opted for resection. c-kit exon 11 was examined via bidirectional nucleic acid sequencing. RESULTS: Our results showed 100% concordance for the presence and type of exon 11 mutation in the resected and aspirated tumours in all seven cases. These mutations had diagnostic value when compared with other neoplasms that are part of the cytomorphological differential diagnosis, such as leiomyosarcoma or gastric adenocarcinomas. CONCLUSION: Molecular cytopathology is a powerful tool that can complement morphology and immunohistochemical assessment of cytological material in routine practice for the diagnosis and prognostication of GISTs. We briefly discuss the advantages and limitations of the fine needle method of obtaining tissue for the diagnosis and prognostication of GISTs, and its current therapeutic strategies.

Rapid diagnosis of Penicillium marneffei infection by fine needle aspiration cytology.

This report describes the use of fine needle aspiration (FNA) cytology to make a rapid diagnosis of Penicillium marneffei infection in an HIV positive patient. P marneffei is a thermally dimorphic fungus that is a mould at 25 degrees C and a yeast at 37 degrees C. It multiplies by fission. It can be easily mistaken for various other infections that are characterised by the presence of histiocytes with phagocytosed yeast cells. In smears the demonstration of yeast cells with a distinctive central septum confirms the diagnosis.

Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors.

Current evidence suggests that epigenetic changes play an important role in the evolution of human cancers. In this study, we evaluated whether hypermethylation of CpG islands at the gene promotor regions of several tumor-related genes is involved in the carcinogenesis of oligodendroglial tumors. We examined the methylation status of 11 genes in a series of 43 oligodendroglial tumors (19 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 9 oligoastrocytomas, and 2 anaplastic oligoastrocytomas) by methylation-specific polymerase chain reaction. Our results showed that hypermethylation of CpG islands was detectable in 8 of 11 genes studied and 74% of tumors were hypermethylated in at least 1 gene. Promotor hypermethylations were detected in O6-methylguanine-DNA methyltransferase (MGMT), RB1, estrogen receptor, p73, p16INK4a, death-associated protein kinase, p15INK4b, and p14ARF at 60%, 34%, 30%, 16%, 12%, 10%, 7%, and 2%, respectively. No hypermethylation was detected in the promotors of glutathione-S-transferase P1, von Hippel-Lindau or the DNA mismatch repair (hMLH1) genes. Statistical analysis revealed that concordant hypermethylation of at least 2 genes, p16INK4a and p15INK4b were significantly associated with anaplastic oligodendroglial tumors, and hypermethylation of MGMT was significantly associated with loss of chromosome 19q and with combined loss of chromosomes 1p and 19q. More importantly, several candidate tumor suppressor genes such as p16INK4a, p15INK4b, and p73 that were previously reported as unmutated in oligodendroglial tumors were found to be hypermethylated in their CpG islands. Taken together, we conclude that hypermethylation of CpG islands is a common epigenetic event that is associated with the development of oligodendroglial tumors.

Intrathyroidal lymphoepithelial (branchial) cyst: sonographic features of a rare lesion.

Intrathyroidal lymphoepithelial cysts are rare, and only 15 such cases have been reported. Although sonography has been performed in some cases, the findings have not been discussed previously. Despite its rarity, the sonographic appearances of this lesion are similar to those of other commonly encountered congenital cystic lesions in the head and neck, such as thyroglossal duct cysts and second branchial cleft cysts, and this may provide a clue to its diagnosis. We describe the sonographic appearances of intrathyroidal lymphoepithelial cysts.

Identification of novel regions of allelic loss in ependymomas by high-resolution allelotyping with 384 microsatellite markers.

OBJECT: Ependymomas are rare glial neoplasms; little is known about the molecular pathogenesis of this tumor entity. In a previous study the authors found multiple genomic imbalances in ependymomas resected in 20 adults and eight children, including loss of chromosomes 1p, 6, 16, 17, 19q, 20q, and 22q, as well as gain of chromosomes 4q, 5q, 7q, 9q, and 12q on comparative genomic hybridization. The aim of this study was to map in more detail the commonly affected regions in ependymomas. METHODS: A comprehensive allelotype analysis of 16 ependymomas was conducted using 384 microsatellite markers that span the 22 autosomes. Based on this high-resolution loss of heterozygosity analysis, multiple overlapping deletion regions were identified as follows: 6q25.2-27, 16p12-13.1, 16q22.3-24.1, 17q22-24, 19q12-13.2, 20q13.2-13.3, and 22q13.1-13.3. CONCLUSIONS: These data confirmed previous reports that loss of chromosomes 17 and 22 were common in ependymomas. Moreover, the authors were able to identify loss of chromosomes 13, 16, 19, and 20 as novel findings in ependymomas. It is believed that potential tumor suppressor genes that reside in these commonly deleted regions may contribute to the molecular tumorigenesis of ependymomas.

Assessment of proliferating cell nuclear antigen in nasopharyngeal carcinoma tissue and its relation to clinical findings.

47 newly diagnosed patients with nasopharyngeal carcinoma (NPC) were studied using the proliferating cell nuclear antigen (PCNA) immunostaining technique. The results were reproducible as shown by assessment of three separate sections performed for each patient. No statistical correlation was found between PCNA labelling index (LI) and Ho's clinical staging or time required to achieve complete remission of the local disease. A higher PCNA LI was associated with a poorer disease-free survival. The literature on the use of PCNA in human tumours is reviewed.

Test and teach. Number twenty-one. Diagnosis: practolol induced sclerosing peritonitis.

A relatively uncommon but unique and life threatening iatrogenic condition is described. There are few aids to diagnosis but once it is known that the patient has been on practolol the surgical and pathological findings are pathognomonic. Other practolol related side effects are usually present in the patient. The conditions may develop months or possibly years after cessation of intake of the drug and further cases may occur, although practolol has been withdrawn from use. Awareness of the condition is therefore of continuing importance.

The histopathology of biopsies taken from women attending a New Zealand colposcopy clinic.

Analysis of the histopathology of biopsies taken from 1371 women attending the Dunedin Hospital Colposcopy Clinic during the period 1982-1988 showed that CIN3, either alone or in conjunction with human papillomavirus (HPV) infection, was the most commonly encountered abnormality. Women under the age of 29 years accounted for 58.3% of the CIN3 lesions. There was also a dramatic increase in the number of women with evidence of HPV infection. Several cases of invasive carcinoma were encountered, 3 in very young women. However, there was no obvious age predilection for the various grades of CIN and for HPV lesions. This raises the question of whether or not HPVs in cervical cancer are chance associations rather than being actively involved in lesion information.

Rapid induction of gastric ulceration in guinea pigs by sequential exposure to a barrier breaker and indomethacin.

In short term experiments under halothane anesthesia, guinea pig total gastric pouches were initially and terminally exposed to 0.1 M HCl for 30 min. During an intervening 50-min test period, the gastric mucosa was exposed at pH 7.3, either to a barrier breaker (lysolecithin or diluted bile or sodium taurocholate) or to phosphate buffered saline (PBS) for half of the period, followed by exposure to indomethacin or further PBS for the second half of the test period. Scoring of mucosal damage was assessed from coded photographs and histological slides and by measurement of the transmucosal potential difference. In comparison with controls exposed only to PBS in the test period, indomethacin did produce minor but significant mucosal damage, whereas over this short time interval, the barrier breaking agents did not. Sequential exposure of pouches to lysolecithin and indomethacin caused a highly significant increase in ulceration, compared to controls or to indomethacin or lysolecithin exposure separately.

The cervical smear test in the next millennium.

This paper traces the cervical Papanicolaou smear test from the seminal work of George Papanicolaou undertaken more than 70 years ago, to the present use of computer technology to examine cervical smears. However, to successfully detect cervical cancer and precursor lesions, the standard of the specimens, as well as that of the screening laboratory, must be of the highest order so that false negative results are eliminated. Newer sampling devices, techniques for improving specimen quality, computerised laboratory technology, and the need for laboratory accreditation are also discussed. The Papanicolaou test is the most successful test invented for cancer prevention but despite this, up to two thirds of Hong Kong women have not had a test. There is a need for more public health education directed at women so that there is a greater awareness of the importance of disease prevention, with an emphasis on cancer prevention. The implementation of a cervical screening programme in the new millennium will ensure that women receive all the benefits that the Papanicolaou smear test can confer.

An analysis of abnormal cervical smears at Dunedin Hospital 1963-82.

Analysis of the abnormal cervical smears seen in the Dunedin Hospital during the 20 year period 1963-82 showed a significant increase in abnormal smears in patients 34 years of age and younger during 1978-82. There were also a number of abnormal smears seen in teenagers; indicating early onset of sexual activity. The increase in abnormal smears is expected to continue; especially in the younger subjects and a one yearly screening programme for all sexually active females is advocated. The possible role of the human papilloma virus in cervical neoplasia is discussed.

The pivotal role of the pathology laboratory in the context of a Singapore cervical cancer screening programme.

Singapore is poised to implement a national cervical screening programme and pathology laboratories have a pivotal role to play. This review describes the laboratory examination of Pap smears and the importance of providing a first class service. This will require sufficient experienced cyto-technologists and pathologists. There also needs to be a mechanism in place to monitor all stages of the Pap smear, from the time it is taken until it is reported. The Bethesda System for reporting Pap smears, new smear collection devices, liquid-based specimens, use of computer screening and other measures to enhance laboratory standards, are also discussed.