Comparative predictive value of three prognostic markers--S-phase fraction, PCNA and mitotic count on axillary lymph node metastasis in carcinoma breast

Background: Axillary lymph node metastasis is the single most important prognostic factor in carcinoma of the breast. Therefore, prognostic markers that may reliably predict probability of lymph node (LN) metastases are of great value. This study was conducted to compare the predictive value of two novel prognostic / proliferative markers i.e. S-phase fraction (SPF) and proliferating cell nuclear antigen (PCNA) in parallel with mitotic index. Methods: Data of consecutive cases of infiltrating ductal carcinoma (IDC) breast diagnosed from July 2003 to July 2004 at the section of the Histopathology, The Aga Khan University Hospital, Karachi, were reviewed. A total of 112 cases of infiltrating ductal carcinoma (IDC) of the breast with axillary LN sampling were selected. SPF was calculated by flow cytometry while PCNA staining was done by immunohistochemistry. Mitotic count was calculated according to modified Bloom and Richardson’s grading guidelines. Result: It was observed that the number of axillary LN metastases was increased with higher SPF (p value: 0.008). However no significant difference was found between the results of various categories of PCNA on axillary LN metastases (p value: 0.182) and mitotic count with axillary lymph node metastases (p value: 0.324). Conclusion: It was concluded that mitotic count and / PCNA alone cannot be used in predicting axillary LN metastases. SPF was found to be a more reliable marker compared to PCNA reactivity and conventional mitotic count in predicting axillary LN metastases

Looks can be deceiving: adrenal Teratoma causing diagnostic difficulty

Teratomas are unusual tumours that derived from totipotent cells with their origin from more than one or usually all three germ cells. Here authors are presenting a case of primary retroperitoneal tumour that is a rare clinical entity. A 19-year-old male presented with right lumbar pain and was found to have complex cyst with large calcification in right adrenal gland on imaging. Intraoperatively, he was found to have a solid mass with areas of soft consistency, which was excised en bloc. On gross examination, the cyst contained pieces of bone, few teeth, and hairs entangled in mucinous material. On histological evaluation, it was confirmed to be mature teratoma arising from the right adrenal gland. He made uneventful recovery and was kept well on annual follow-up

Retinoblastoma tells the story of our health care system

Objective: To review cases of retinoblastoma. Setting: Department of Pathology Aga Khan University Hospital Karachi. Method: Twenty three specimens from cases of retinoblastoma received over a period of eight years were routinely processes and stained with haematoxylin and Eosin stain Other stains were used for tuberculosis and melanin. Immunochemistry was resorted to in undifferentiated tumors. Results: Over 60% cases of retinoblastoma were diagnosed after 5 years and nine cases showed involvement of opti-nerve. Conclusion: Late diagnosis of retinoblastoma effects the stage of the tumors and the prognisis

Comparison of Various Clinical Risk Assessment Tools in Predicting Major Adverse Cardiac Events in Patients Presenting in Emergency Department with Undifferentiated Cardiac Chest Pain

Objective: To compare the “HEART (History, ECG, Age, Risk factors, Troponin), GRACE (Global Registry of Acute Coronary Events), and TIMI (Thrombolysis in Myocardial Infarction)” scores in predicting major adverse cardiac events (MACE) in patients reporting with undifferentiated cardiac chest pain to the Emergency Department (ED). Study Design: Cross-sectional validation study Duration and place of Study: Emergency Department, Combined Military Hospital, Rawalpindi Pakistan, from Jan to Jun 2021. Methodology: Two hundred and thirty-seven adult patients with atraumatic cardiac-like chest pain and non-diagnostic electrocardiogram (ECG) reporting to the ED were included in the study. HEART, GRACE and TIMI scores were calculated from the data. The number of patients with low risk was identified by each score and compared at a fixed safety level of minimum 95% sensitivity. The potential occurrence of MACE was confirmed using a telephonic follow-up six weeks after the presentation. Results: At an absolute safety level of minimum 95% sensitivity, the HEART score determined 101 patients as “low-risk” with 1.98% MACE missed. The GRACE score identified 49 “low-risk” patients with 4.08% MACE missed, and the TIMI score identified 66 “low-risk” patients with 3.03% MACE missed. Conclusion: Among the three scores under comparison, the HEART score performed better than the GRACE and TIMI scores at the same safety level and surpassed them in differentiating between those with MACE and without MACE

The accuracy of protein structure alignment servers

Background: Protein structural alignment is one of the most fundamental and crucial areas of research in the domain of computational structural biology. Comparison of a protein structure with known structures helps to classify it as a new or belonging to a known group of proteins. This, in turn, is useful to determine the function of protein, its evolutionary relationship with other protein molecules and grasping principles underlying protein architecture and folding. Results: A large number of protein structure alignment methods are available. Each protein structure alignment tool has its own strengths andweaknesses that need to be highlighted.We compared and presented results of six most popular and publically available servers for protein structure comparison. These web-based servers were compared with the respect to functionality (features provided by these servers) and accuracy (how well the structural comparison is performed). The CATH was used as a reference. The results showed that overall CE was top performer. DALI and PhyreStorm showed similar results whereas PDBeFold showed the lowest performance. In case of few secondary structural elements, CE, DALI and PhyreStorm gave 100% success rate. Conclusion: Overall none of the structural alignment servers showed 100% success rate. Studies of overall performance, effect of mainly alpha and effect of mainly beta showed consistent performance. CE, DALI, FatCat and PhyreStorm showed more than 90% success rate

Adolopment of adult diabetes mellitus management guidelines for a Pakistani context: Methodology and challenges

IntroductionPakistan has the highest national prevalence of type 2 diabetes mellitus (T2DM) in the world. Most high-quality T2DM clinical practice guidelines (CPGs) used internationally originate from high-income countries in the West. Local T2DM CPGs in Pakistan are not backed by transparent methodologies. We aimed to produce comprehensive, high-quality CPGs for the management of adult DM in Pakistan.MethodsWe employed the GRADE-ADOLOPMENT approach utilizing the T2DM CPG of the American Diabetes Association (ADA) Standards of Medical Care in Diabetes – 2021 as the source CPG. Recommendations from the source guideline were either adopted as is, excluded, or adapted according to our local context.ResultsThe source document contained 243 recommendations, 219 of which were adopted without change, 5 with minor changes, and 18 of which were excluded in the newly created Pakistani guidelines. One recommendation was adapted: the recommended age to begin screening all individuals for T2DM/pre-diabetes was lowered from 45 to 30 years, due to the higher prevalence of T2DM in younger Pakistanis. Exclusion of recommendations were primarily due to differences in the healthcare systems of Pakistan and the US, or the unavailability of certain drugs in Pakistan.ConclusionA CPG for the management of T2DM in Pakistan was created. Our newly developed guideline recommends earlier screening for T2DM in Pakistan, primarily due to the higher prevalence of T2DM amongst younger individuals in Pakistan. Moreover, the systematic methodology used is a significant improvement on pre-existing T2DM CPGs in Pakistan. Once these evidence based CGPs are officially published, their nationwide uptake should be top priority. Our findings also highlight the need for rigorous expanded research exploring the effectiveness of earlier screening for T2DM in Pakistan

Analysis of health related quality of life (HRQoL) of patients with clinically localized prostate cancer, one year after treatment with external beam radiotherapy (EBRT) alone versus EBRT and high dose rate brachytherapy (HDRBT)

<p>Abstract</p> <p>Purpose</p> <p>Prostate cancer is the leading form of cancer diagnosed among North American men. Most patients present with localized disease, which can be effectively treated with a variety of different modalities. These are associated with widely different acute and late effects, which can be both physical and psychological in nature. HRQoL concerns are therefore important for these patients for selecting between the different treatment options.</p> <p>Materials and methods</p> <p>One year after receiving radiotherapy for localised prostate cancer 117 patients with localized prostate cancer were invited to participate in a quality of life (QoL) self reported survey. 111 patients consented and participated in the survey, one year after completion of their treatment. 88 patients received EBRT and 23 received EBRT and HDRBT. QoL was compared in the two groups by using a modified version of Functional Assessment of Cancer Therapy-Prostate (FACT-P) survey instrument.</p> <p>Results</p> <p>One year after completion of treatment, there was no significant difference in overall QoL scores between the two groups of patients. For each component of the modified FACT-P survey, i.e. physical, social/family, emotional, and functional well-being; there were no statistically significant differences in the mean scores between the two groups.</p> <p>Conclusion</p> <p>In prostate cancer patients treated with EBRT alone versus combined EBRT and HDRBT, there was no significant difference in the QoL scores at one year post-treatment.</p

Planning target volume margins for prostate radiotherapy using daily electronic portal imaging and implanted fiducial markers

<p>Abstract</p> <p>Background</p> <p>Fiducial markers and daily electronic portal imaging (EPI) can reduce the risk of geographic miss in prostate cancer radiotherapy. The purpose of this study was to estimate CTV to PTV margin requirements, without and with the use of this image guidance strategy.</p> <p>Methods</p> <p>46 patients underwent placement of 3 radio-opaque fiducial markers prior to prostate RT. Daily pre-treatment EPIs were taken, and isocenter placement errors were corrected if they were ≥ 3 mm along the left-right or superior-inferior axes, and/or ≥ 2 mm along the anterior-posterior axis. During-treatment EPIs were then obtained to estimate intra-fraction motion.</p> <p>Results</p> <p>Without image guidance, margins of 0.57 cm, 0.79 cm and 0.77 cm, along the left-right, superior-inferior and anterior-posterior axes respectively, are required to give 95% probability of complete CTV coverage each day. With the above image guidance strategy, these margins can be reduced to 0.36 cm, 0.37 cm and 0.37 cm respectively. Correction of all isocenter placement errors, regardless of size, would permit minimal additional reduction in margins.</p> <p>Conclusions</p> <p>Image guidance, using implanted fiducial markers and daily EPI, permits the use of narrower PTV margins without compromising coverage of the target, in the radiotherapy of prostate cancer.</p

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society