Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model.

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.

Treatment Response following Radioactive Iodine Therapy in Miliary versus Macronodular Pulmonary Metastases in Papillary Thyroid Carcinoma.

Background Pulmonary metastases in papillary thyroid carcinoma have two common presentations-micro/miliary (MM) and macronodular metastases (MN). The mainstay of treatment, posttotal thyroidectomy, is multiple radioactive iodine ablations (RAIA) every 6 to 12 months. Response assessment is determined by decline in stimulated serum thyroglobulin levels (sTg), disease regression on chest x-ray (CXR), computed tomography thorax, or whole body iodine scintigraphy (TWBS). Aim This study aims to assess the difference in response to RAIA based on the pattern of presentation. Methodology Retrospective analysis of patients from January 2008 to July 2017 was done. Patients with pulmonary metastases treated with RAIA (3700MBq per therapy as opposed to theAmerican Thyroid Association recommendation of 7400MBq per therapy) and a minimum follow-up of 8 months were included. The initial and the final sTg, TWBS, and CXR were analyzed for both groups. Final outcome in terms of complete response, disease regression, static disease, and disease progression was determined. Results Of the total of 1,793 patients, 71 were included. There were 43 females and 28 males. The median age was 39 years and the range was 14 to 79 years. Forty-five (63.3%) patients had MM and 26 (36.6%) patients had MN disease. The average number of therapies was three and maximum follow-up period was 15 years. Of the 45 MM patients, 1 had progression, 7 were static, 23 had regression, and 14 had complete response. Of the 26 MN patients, 22 had progression, 2 were static, 1 had regression, and 1 had complete response. Conclusion MM metastases, when compared with MN disease, respond to RAIA with a better outcome. In addition to achieving comparable response with a lower dose per therapy, there were no radiation-related long-term complications reported.

Mutations seen among patients with pheochromocytoma and paraganglioma at a referral center from India.

Determining the mutational status of susceptibility genes including RET, VHL, SDHx (SDHB, SDHC, SDHD) among patients with pheochromocytoma/paraganglioma (PCC/PGL) is gaining importance. These genes have not been systematically characterized among patients with PCC/PGL from India. The aim of the work was to screen the most frequently mutated genes among patients with PCC/PGL to determine the frequency and spectrum of mutations seen in this region. Fifty patients with PCC/PGL treated at our tertiary care hospital between January 2010 and June 2012 were screened for mutations in susceptibility genes using an algorithmic approach. Thirty-two percent (16/50) of patients were found to be positive for mutations including mutations among RET (n=4), VHL (n=6), SDHB (n=3), and SDHD (n=3) genes. None of these patients were positive for SDHC mutations. A significant association was found between young patients with bilateral tumors and VHL mutations (p=0.002). Two of the 3 patients with extra-adrenal SDHB associated tumors, had unique mutations, viz., c.436delT (exon 5) and c.788_857del (exon 8), one of which was malignant. High frequency of mutations seen among patients in this study emphasizes the need to consider mutational analysis among Indian patients with PCC/PGL.

In-hospital delay in the diagnosis of breast cancer.

BACKGROUND: There is evidence that delay in the diagnosis of breast cancer may prejudice survival. The aim of this study was to determine the incidence, time trends and causes of delay in a dedicated breast clinic. METHODS: The interval between first breast clinic visit and a definitive diagnosis was recorded in all patients with invasive breast cancer between 1988 and 1997. In all patients with a delay of 3 months or more, the case notes were reviewed for evidence of a triple assessment (clinical examination, imaging and needle biopsy). The principal cause of delay was identified. RESULTS: Of 1004 patients with invasive breast cancer, there was a delay in diagnosis of 3 months or more in 42 patients between 1988 and 1997, an incidence of 4.2 per cent. The median delay was 6 months and the median age at diagnosis was 53 (range 27-89) years. Triple assessment was undertaken in 30 patients; ten did not have a needle biopsy performed and three patients had no mammography. The principal cause of delay was: false-negative or inadequate fine-needle aspiration cytology (FNAC) in 19 patients, failure of follow-up in eight, clinical signs did not impress in five, FNAC not carried out in four, false-negative mammogram in three, failure of needle localization in two and one patient did not accept clinical advice. The annual incidence of delay in diagnosis did not change significantly over the 10-year interval. CONCLUSION: Triple assessment is not sufficiently sensitive to detect every breast cancer and a small incidence of diagnostic delay is therefore inevitable with current techniques.

Evaluation of radioiodination of meta-iodobenzylguanidine (MIBG) catalysed by in situ generated Cu(I) and directly added Cu(II).

A reliable method of labelling MIBG with 131I is reported. Radioiodination involved nucleophilic exchange reaction (160 degrees C, 30 min) catalysed by directly added Cu(II) or by Cu(I) generated in situ by addition of Na2S2O5 to CuSO4. An additional step of purification of the radiolabelled MIBG by anion exchange chromatography is recommended. The radiochemical (RC) yield was over 90%, while the typical RC purity of 131I-MIBG was not less than 98%. Higher labelling yield was achieved with Cu(I) than when using Cu(II), and with 125I (commercial product) than with 131I obtained by wet radiochemical processing method in-house. The purity and stability of MIBG-131I was confirmed by biodistribution studies in monkeys with 0.03% and 0.8% uptake in adrenals and myocardium, respectively. It is concluded that Cu(I) or Cu(II) catalysed radioiodination method is well suited for production of MIBG-131I.

Predictive value of serum thyroglobulin in treated patients with differentiated thyroid carcinoma.

An in-house radioimmuno assay for serum thyroglobulin was developed in our laboratory and compared its relative sensitivity with that of whole body scan in the detection of residual tumour or metastases and evaluated the predictive value of serum thyroglobulin in the clinical course of the disease. Ninety six patients after thyroidectomy were followed up for a maximum period of five years in this study.The sensitivity and specificity of serum thyroglobulin were found to be close to that of whole body scan (85% and 94% respectively). According to this study, a serum thyroglobulin >40 ng/ml can differentiate between patients with metastases and those in remission. Serum thyroglobulin can replace whole body scan during the subsequent follow-up if the patient had concordant whole body scan and serum thyroglobulin during initial assessment.

Evaluation of 40 x 22 mm coverslip area in cervical cancer screening.

Nine hundred and twenty-three smears covered by 40 x 22 mm size coverslips were examined inside and outside the coverslip area to determine whether this coverslip size could be responsible for missed dyskaryotic cells in conventional cervical cancer screening. There was no instance when abnormal cells seen outside the coverslip were not also present within the coverslipped area.

Treatment of progressive renal failure and nephrotic syndrome with azathioprine and prednisolone.

Four patients with idiopathic membranous glomerulonephritis, heavy proteinuria and progressive renal failure received azathioprine and prednisolone. Renal function improved in all four and proteinuria declined sharply in three. We suggest that treatment with azathioprine and prednisolone may be of benefit in this form of idiopathic membranous glomerulonephritis.

Renal functional reserve in kidney donors assessed in different settings using scintigraphy.

Glomerular filtration rate (GFR) was measured in 9 voluntary male kidney donors by scintigraphy. In the basal state, the mean GFR was 96.1 +/- 22 ml/min/1.73 m2. Four weeks after donor nephrectomy, the GFR of the remaining kidney had increased by 22.8 +/- 20.7% (p < 0.05). A protein meal given at this time failed to significantly augment the GFR. The GFR of the grafted kidney increased by 59.7 +/- 24.4% after 6 months (p < 0.01). Renal functional reserve was thus demonstrated in the remaining kidney and the allograft, though a further reserve could not be elicited in the remaining kidney.

Association of a bleeding Meckel's diverticulum with upper thoracic vertebral anomalies and tetralogy of Fallot.

A 14-month-old child presented with recurrent episodes of melaena, upper thoracic hemivertebrae, and tetralogy of Fallot. The presence of the upper thoracic hemivertebrae led to the suspicion of intestinal duplication. However, technetium (Tc99m) scintigraphy revealed a Meckel's diverticulum. Following laparotomy and excision of the diverticulum, the histopathological examination confirmed the diagnosis.

Clinical audit of a specialist symptomatic breast clinic.

The efficient delivery of health care requires vigilant quality assurance. We describe the audit of our symptomatic breast clinic, which includes the option of a one-stop diagnostic service. A total of 134 new and 386 follow-up patients attended over four consecutive clinics. The majority of new referrals (68%) were seen by a consultant surgeon. Urgent referrals were seen significantly sooner than routine referrals (P < 0.001, chi 2-test), and the mean wait from designated appointment to seeing the surgeon was 37.6 (range-68 to 171) min. One-stop investigations were offered to 50 patients; of these, 36 women (72%) had a total wait of less than 2 h. For those not investigated at the same clinic, the mean time until investigations was 6.1 (range 0-36) days and mean recall was 2.7 (range 1-8) weeks. Patients undergoing definitive surgery for cancer (n = 5) were operated on average 14.2 (range 7-27) days after the decision was made in outpatients, while the mean waiting time for non-cancer operations was 49.7 (range 15-98) days. Objective audit on outpatient services is possible and can lead to improvement of services.

One-stop diagnosis for symptomatic breast disease.

A consultant-led one-stop diagnostic service has been available at a busy symptomatic breast clinic each week at St Bartholomew's Hospital for 18 months. Women can be investigated appropriately using mammography, ultrasonography and cytology with immediate reporting. The aim is to achieve a diagnosis and management plan for each patient at the initial outpatient visit. A prospective audit of four consecutive clinics was undertaken to assess the impact of this service on clinical practice. Fifty patients out of 134 new and 386 follow-up clinic attenders had one-stop investigations. As a result of immediate reporting, 48 (96%) patients had a management decision made at the first outpatient visit, 9 (18%) were offered surgery, and 18 (36%) were discharged with a benign diagnosis and no dominant mass. Four symptomatic cancers were detected and evaluated on a one-stop basis, constituting 8% of the workload of this clinic. The mean wait from designated appointment until surgical consultation was 37.7 min (range -68-171 min) and that for investigation until subsequent clinical review was 56.9 min (range -4-191 min). Thirty-six (72%) one-stop patients had a total wait of less than 2 h and 95% were seen in under 3 h. It is felt that the one-stop clinic allows optimum patient management, minimises anxiety associated with symptomatic breast disease, and maximises utilisation of hospital outpatient resources.

Scintigraphic diagnosis of thyroid cancer. Correlation of thyroid scintigraphy and histopathology.

Scintigraphy is part of the routine examination of thyroid disease, yet there are few published reports on its utility and pitfalls. Out of 2025 consecutive thyroid examinations after excluding 230 cases of proven thyroid malignancies, 403 patients who underwent surgery were studied for histopathologic correlation. There were 232 with cold nodules, 143 with multinodular goiters (MNG) and 28 with uniformly increased uptake suggestive of toxic goiter. Malignancy was reported in 72 of the 232 cold nodules (31%). In solitary nodules, the examination was useful in selecting cases for surgery and, in cold lesions, for planning of surgery. In the majority of patients with MNG or thyrotoxicosis who were operated on, scintigraphy provided no additional information. MNG requires scintigraphy only in selected cases where there is strong suspicion of malignancy. Contrary to reports in the literature, papillary carcinoma was found to be associated with MNG in our patients.

Correlation of serum prostate specific antigen levels and bone scintigraphy in carcinoma prostate.

Serum prostate specific antigen (PSA) has been suggested as an accurate means of monitoring prostate cancer. An analysis of PSA levels and bone scan findings was carried out in a heterogeneous group of patients with a view to determine whether PSA can accurately predict bone metastases in carcinoma prostate. Of the 48 patients studied, all 10 untreated cases had elevated PSA levels, eight having bone metastases. In 29 cases on follow-up after treatment of the primary, 10 out of 11 cases with normal PSA had a negative bone scan. In the nine who received hormonal therapy, the PSA levels were generally lower than others in the study group. Two out of four with normal PSA had bone metastases. In 26 cases with positive bone scans, 23 had elevated PSA levels (mean 109.9 ng ml-1). Among 22 patients who had normal bone scans, all 10 with high PSA were found to have soft tissue disease which could explain the elevated PSA. In those with normal PSA, 12 out of 15 patients had negative scans. PSA has fairly high sensitivity (86.5%) and negative predictive value (80%). But it suffers from low specificity (54.5%) and low positive predictive value (69.7%) for bone metastases. In an untreated patient with elevated PSA, a bone scan may be required to exclude bone metastases, whereas during follow-up after treatment, a normal PSA level may obviate a "routine" bone scan.

A state-wide campaign for the early detection of cancer in Sabah.

The Medical Department of Sabah, in collaboration with various governmental and non-governmental agencies and 'Surgeons International' conducted a state-wide campaign for the 'Early Detection of Cancer' over a period of 3 months from July 1992. The purpose of the campaign was to educate the population about the early signs and symptoms of common cancers, to remove the myth that cancer was incurable and to impress on the public the need to detect cancer early for a possible cure and a better prognosis.

Left ventricular diastolic function--pulsed Doppler echocardiography versus radionuclide angiography.

Fifty five consecutive patients diagnosed to have coronary artery disease by coronary angiography had their left ventricular (LV) diastolic functions evaluated by pulsed doppler (PD) methods and radionuclide angiography (RNA). Using PD, the peak velocities of the early filling wave 'E' and the late filling wave 'A' of mitral inflow were measured. LV diastolic dysfunction, defined as E/A ratio less than 1.0, was present in 31 of 38 patients with low RNA peak filling rates (PFR) of 2.3 EDV/sec or less (sensitivity 81.6%). Normal E/A ratios (> 1.0) were seen in 13 of 17 patients with normal RNA PFR of > 2.3 EDV/sec (specificity 76.5%). Both methods were in agreement in 44 of 55 patients (accuracy 80%). There was good direct correlation between RNA PFR and PD E/A ratio (correlation coefficient r = 0.51, P < 0.01). It is concluded that PD echocardiography is a simple and reliable method of identifying diastolic dysfunction in patients with ischaemic heart disease.