Automated Annotation of Epileptiform Burden and Its Association with Outcomes.

OBJECTIVE: This study was undertaken to determine the dose-response relation between epileptiform activity burden and outcomes in acutely ill patients. METHODS: A single center retrospective analysis was made of 1,967 neurologic, medical, and surgical patients who underwent >16 hours of continuous electroencephalography (EEG) between 2011 and 2017. We developed an artificial intelligence algorithm to annotate 11.02 terabytes of EEG and quantify epileptiform activity burden within 72 hours of recording. We evaluated burden (1) in the first 24 hours of recording, (2) in the 12-hours epoch with highest burden (peak burden), and (3) cumulatively through the first 72 hours of monitoring. Machine learning was applied to estimate the effect of epileptiform burden on outcome. Outcome measure was discharge modified Rankin Scale, dichotomized as good (0-4) versus poor (5-6). RESULTS: Peak epileptiform burden was independently associated with poor outcomes (p < 0.0001). Other independent associations included age, Acute Physiology and Chronic Health Evaluation II score, seizure on presentation, and diagnosis of hypoxic-ischemic encephalopathy. Model calibration error was calculated across 3 strata based on the time interval between last EEG measurement (up to 72 hours of monitoring) and discharge: (1) <5 days between last measurement and discharge, 0.0941 (95% confidence interval [CI] = 0.0706-0.1191); 5 to 10 days between last measurement and discharge, 0.0946 (95% CI = 0.0631-0.1290); >10 days between last measurement and discharge, 0.0998 (95% CI = 0.0698-0.1335). After adjusting for covariates, increase in peak epileptiform activity burden from 0 to 100% increased the probability of poor outcome by 35%. INTERPRETATION: Automated measurement of peak epileptiform activity burden affords a convenient, consistent, and quantifiable target for future multicenter randomized trials investigating whether suppressing epileptiform activity improves outcomes. ANN NEUROL 2021;90:300-311.

International Society of Urological Pathology (ISUP)-Grade Grouping in Prostatic Adenocarcinoma and its Prognostic Implications.

In this study, we evaluated the association of ISUP/WHO-grade groups with various pathological prognostic parameters and cancer-specific survival in patients with prostatic adenocarcinoma. We found 27 (15.7%) cases of grade group 1, 22 (12.8%) grade group 2, 30 (17.4%) grade group 3, 40 (23.3%) grade group 4 and 53 (30.8%) grade group 5 prostatic adenocarcinoma. We found that high-grade tumors (grade 3-5) had a higher frequency of perineural invasion and higher tumor volumes (>50%). Moreover, a significant association of tumor grade was noted with cancer-specific survival of patients, signifying prognostic significance of grade grouping in prostatic adenocarcinoma.

Pain phenotypes classified by machine learning using electroencephalography features.

Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive.

Burden of Epileptiform Activity Predicts Discharge Neurologic Outcomes in Severe Acute Ischemic Stroke.

BACKGROUND/OBJECTIVES: Clinical seizures following acute ischemic stroke (AIS) appear to contribute to worse neurologic outcomes. However, the effect of electrographic epileptiform abnormalities (EAs) more broadly is less clear. Here, we evaluate the impact of EAs, including electrographic seizures and periodic and rhythmic patterns, on outcomes in patients with AIS. METHODS: This is a retrospective study of all patients with AIS aged ≥ 18 years who underwent at least 18 h of continuous electroencephalogram (EEG) monitoring at a single center between 2012 and 2017. EAs were classified according to American Clinical Neurophysiology Society (ACNS) nomenclature and included seizures and periodic and rhythmic patterns. EA burden for each 24-h epoch was defined using the following cutoffs: EA presence, maximum daily burden < 10% versus > 10%, maximum daily burden < 50% versus > 50%, and maximum daily burden using categories from ACNS nomenclature ("rare" < 1%; "occasional" 1-9%; "frequent" 10-49%; "abundant" 50-89%; "continuous" > 90%). Maximum EA frequency for each epoch was dichotomized into ≥ 1.5 Hz versus < 1.5 Hz. Poor neurologic outcome was defined as a modified Rankin Scale score of 4-6 (vs. 0-3 as good outcome) at hospital discharge. RESULTS: One hundred and forty-three patients met study inclusion criteria. Sixty-seven patients (46.9%) had EAs. One hundred and twenty-four patients (86.7%) had poor outcome. On univariate analysis, the presence of EAs (OR 3.87 [1.27-11.71], p = 0.024) and maximum daily burden > 10% (OR 12.34 [2.34-210], p = 0.001) and > 50% (OR 8.26 [1.34-122], p = 0.035) were associated with worse outcomes. On multivariate analysis, after adjusting for clinical covariates (age, gender, NIHSS, APACHE II, stroke location, stroke treatment, hemorrhagic transformation, Charlson comorbidity index, history of epilepsy), EA presence (OR 5.78 [1.36-24.56], p = 0.017), maximum daily burden > 10% (OR 23.69 [2.43-230.7], p = 0.006), and maximum daily burden > 50% (OR 9.34 [1.01-86.72], p = 0.049) were associated with worse outcomes. After adjusting for covariates, we also found a dose-dependent association between increasing EA burden and increasing probability of poor outcomes (OR 1.89 [1.18-3.03] p = 0.009). We did not find an independent association between EA frequency and outcomes (OR: 4.43 [.98-20.03] p = 0.053). However, the combined effect of increasing EA burden and frequency ≥ 1.5 Hz (EA burden * frequency) was significantly associated with worse outcomes (OR 1.64 [1.03-2.63] p = 0.039). CONCLUSIONS: Electrographic seizures and periodic and rhythmic patterns in patients with AIS are associated with worse outcomes in a dose-dependent manner. Future studies are needed to assess whether treatment of this EEG activity can improve outcomes.

Burst Suppression: Causes and Effects on Mortality in Critical Illness.

BACKGROUND: Burst suppression in mechanically ventilated intensive care unit (ICU) patients is associated with increased mortality. However, the relative contributions of propofol use and critical illness itself to burst suppression; of burst suppression, propofol, and critical illness to mortality; and whether preventing burst suppression might reduce mortality, have not been quantified. METHODS: The dataset contains 471 adults from seven ICUs, after excluding anoxic encephalopathy due to cardiac arrest or intentional burst suppression for therapeutic reasons. We used multiple prediction and causal inference methods to estimate the effects connecting burst suppression, propofol, critical illness, and in-hospital mortality in an observational retrospective study. We also estimated the effects mediated by burst suppression. Sensitivity analysis was used to assess for unmeasured confounding. RESULTS: The expected outcomes in a "counterfactual" randomized controlled trial (cRCT) that assigned patients to mild versus severe illness are expected to show a difference in burst suppression burden of 39%, 95% CI [8-66]%, and in mortality of 35% [29-41]%. Assigning patients to maximal (100%) burst suppression burden is expected to increase mortality by 12% [7-17]% compared to 0% burden. Burst suppression mediates 10% [2-21]% of the effect of critical illness on mortality. A high cumulative propofol dose (1316 mg/kg) is expected to increase burst suppression burden by 6% [0.8-12]% compared to a low dose (284 mg/kg). Propofol exposure has no significant direct effect on mortality; its effect is entirely mediated through burst suppression. CONCLUSIONS: Our analysis clarifies how important factors contribute to mortality in ICU patients. Burst suppression appears to contribute to mortality but is primarily an effect of critical illness rather than iatrogenic use of propofol.

Prognostic significance of epidermal growth factor receptor (EGFR) over expression in urothelial carcinoma of urinary bladder.

BACKGROUND: Epidermal growth factor receptor (EGFR) has been shown to have abnormal expression in many human cancers and is considered as a marker of poor prognosis. Frequency of over expression in bladder cancer has not been studied in our population; therefore we aimed to evaluate the frequency and prognostic significance of EGFR immunohistochemical expression in locoregional population. METHODS: We performed EGFR immunohistochemistry on 126 cases of bladder cancer and association of EGFR expression with tumor grade, lamina propria invasion, deep muscle invasion and recurrence of disease was evaluated. RESULTS: High EGFR expression was noted in 26.2% (33 cases), 15.1% (19 cases) and 58.7% (74 cases) revealed low and no EGFR expression respectively. Significant association of EGFR expression was noted with tumor grade, lamina propria invasion, deep muscle invasion and recurrence status while no significant association was seen with age, gender and overall survival. Kaplan- Meier curves revealed significant association of EGFR expression with recurrence while no significant association was seen with overall survival. CONCLUSION: Significant association of EGFR overexpression with tumor grade, muscularis propria invasion and recurrence signifies its prognostic value; therefore EGFR can be used as a prognostic biomarker in Urothelial bladder carcinoma.

Prognostic significance of p16 & p53 immunohistochemical expression in triple negative breast cancer.

Background: p16 and p53 genes are frequently mutated in triple negative breast cancer & prognostic value of these mutations have been shown; however, their role as immunohistochemical overexpression has not been fully validated. Therefore we aimed to evaluate the association of p16 and p53 overexpression in triple negative breast cancer with various prognostic parameters. Methods: Total 150 cases of triple negative breast cancers were selected from records of pathology department archives that underwent surgeries at Liaquat National hospital, Karachi from January 2008 till December 2013. ER, PR and Her2neu immunohistochemistry were re-performed to confirm triple negative status. p16 & p53 immunohistochemistry was performed on all cases and association with various clinicopathologic parameters was determined. Results: Mean age of the patients involved in the study was 48.9 years. Most of the patients presented at stage T2 with a high mean ki67 index i.e. 46.9%. 42.7% of cases had nodal metastasis. Although 84% cases were of invasive ductal carcinoma; however a significant proportion of cases were of metaplastic histology (9.3%). Fifty-one percent (76 cases) of cases showed positive p53 expression while 49% (74 cases) were negative. Higher percentage of p53 expression was found to correlate with higher T stage, high ki67 index and higher nodal stage. On the other hand, strong intensity of p53 expression was positively correlated with higher tumor grade and ki67 index. Seventy-one percent (98 cases) of cases showed positive p16 expression, whereas 24.8% (34 cases) were negative and 3.6% (5 cases) showed focal positive p16 expression. However, no significant association was found between p16 expression and various clinical and pathologic parameters. Similarly, no significant association of either p16 or p53 over-expression was noted with recurrence status of patients. Conclusion: On the basis of significant association of p53 over-expression with worse prognostic factors in triple negative breast cancer, therefore we suggest that more large scale studies are needed to validate this finding in loco-regional population. Moreover, high expression of p16 in triple negative breast cancer suggests a potential role of this biomarker in triple negative breast cancer pathogenesis which should be investigated with molecular based research in our population.

Colorectal dysplasia and adenocarcinoma in patients with ulcerative colitis: an experience from a tertiary care hospital.

BACKGROUND: The rationale behind this study was to find out the frequency of dysplasia and colorectal cancer (CRC) in young patients with ulcerative colitis (UC) using histopathological examination. This facilitated early detection of dysplasia and CRC by regular endoscopic biopsies and also guided physicians on appropriate surveillance and management, thus improved outcome. METHODS: It was a prospective cross-sectional study conducted at the Department of Pathology, PIMS, Islamabad. Seventy-six biopsies of already diagnosed cases of UC of young patients aged between 15 and 40 years of either gender were included. Specimens were fixed in 10% buffer formalin, paraffin embedded followed by cutting, slide preparation, and staining with hematoxylin and eosin (H&E) stain, and examined under light microscope. Statistical package for social sciences (SPSS 21) was used for data compilation and analysis. Mean and standard deviation were calculated for quantitative variables. Frequency and percentage were calculated for qualitative variables. RESULTS: There were 13 (17.2%) patients who were diagnosed with colorectal dysplasia, 3 (4.0%) with indefinite for dysplasia, 8 (10.5%) with low-grade dysplasia, and 2 (2.6%) with high-grade dysplasia. There were three (3.9%) patients who were diagnosed for colorectal carcinoma, one (1.3%) with grade 1, one (1.3%) with grade 2, and one (1.3%) with grade 3 CRC. CONCLUSION: Routine biopsies can identify dysplastic epithelium, which is an established sign for synchronized carcinoma with ulcerative colitis, and give the rationale for surveillance of the patients.

Immunohistochemical expression of epidermal growth factor receptor (EGFR) in South Asian head and neck squamous cell carcinoma: association with various risk factors and clinico-pathologic and prognostic parameters.

BACKGROUND: In this study, we intend to determine the immunohistochemical expression of EGFR in cases of head and neck squamous cell carcinoma and its association with prognostic clinico-pathologic features. METHODS: A total of 115 cases of head and neck squamous cell carcinoma treated at Liaquat National Hospital, Karachi, Pakistan, were included in the study. Clinico-pathologic features, risk factors, and recurrence status of cases were evaluated, and EGFR immunohistochemistry was performed. RESULTS: In our study, 52 cases (45.2%) of head and neck SCC were positive and 10 cases (8.7%) were focal positive for EGFR expression, while 53 cases (46.1%) were negative for EGFR expression. High EGFR expression (> 70%) was noted in 6.1% (7 cases), while 12.2% (14 cases) and 26.1% (30 cases) revealed 51-70% and 11-50% EGFR expression respectively. On the basis of intensity, strong EGFR expression was noted in 13.9% (16 cases) while 16.5% (19 cases) and 23.5% (27 cases) revealed intermediate and weak EGFR expression respectively. Significant association of EGFR expression was noted with tumor stage and disease-free survival. CONCLUSION: We found a significant association of EGFR expression with tumor stage and disease-free survivals, which are the most important prognostic factors in head and neck squamous cell carcinoma; therefore, EGFR expression can help as a prognostic biomarker in head and neck squamous cell carcinoma. On the other hand, we suggest that molecular studies should be performed in squamous cell carcinoma of head and neck in our setup to identify patients that can avail response from anti-EGFR therapy.

Prognostic parameters of luminal A and luminal B intrinsic breast cancer subtypes of Pakistani patients.

BACKGROUND: Prognosis of breast cancer and success of therapeutic interventions largely rely on the clinico-pathologic and biological characteristics of the tumor and vary due to the heterogeneous nature of breast cancers. The aim of this study was to determine the frequency and prognostic parameters of luminal breast cancers in our population to devise targeted and personalized therapeutic regimens tailored to the needs of the loco-regional population. METHODS: A retrospective cross-sectional study including 1951 cases of primary breast cancer treated at Liaquat National Hospital Karachi was conducted during the year 2011-2016. The clinico-pathologic characteristics were observed and semiquantitative immunohistochemical analysis was performed to study the luminal subtypes A and B. The cross-tabulated statistics of the observed characteristics were performed between the two subtypes. The significance level of each characteristic was estimated utilizing the chi-square test. RESULTS: Luminal cancers comprised 62.7% of the total number of cases diagnosed with breast cancers in the study period. Out of these 1224 cases of luminal cancers, 845 cases (69%) were luminal B, while 379 (31%) cases were of luminal A. Luminal B cancers were significantly more common in younger age groups as compared to luminal A cancers. Comparison of the two subtypes of luminal breast cancers revealed significant differences. Luminal B cancers were associated with higher grade (26% grade III in luminal B compared to 8% in luminal A), micropapillary histology, and high frequency of nodal metastasis (54 vs. 43%). CONCLUSIONS: Luminal B comprised the most frequent subtype of breast cancer in our study and they were found more constantly in a younger age group. Moreover, they were associated with adverse clinico-histologic parameters like higher grade and nodal metastasis. Therefore, we suggest that, despite lack of widespread availability of molecular studies in our setup, IHC-based typing should be done in every case of breast cancer to individualize therapy.

Diagnostic accuracy of touch imprint cytology for head and neck malignancies: a useful intra-operative tool in resource limited countries.

BACKGROUND: Intraoperative consultation is an important tool for the evaluation of the upper aerodigestive tract (UAT) malignancies. Although frozen section analysis is a preferred method of intra-operative consultation, however in resource limited countries like Pakistan, this facility is not available in most institutes; therefore, we aimed to evaluate the diagnostic accuracy of touch imprint cytology for UAT malignancies using histopathology of the same tissue as gold standard. METHODS: The study involved 70 cases of UAT lesions operated during the study period. Intraoperatively, after obtaining the fresh biopsy specimen and prior to placing them in fixative, each specimen was imprinted on 4-6 glass slides, fixed immediately in 95% alcohol and stained with Hematoxylin and Eosin stain. After completion of the cytological procedure, the surgical biopsy specimen was processed. The slides of both touch Imprint cytology and histopathology were examined by two consultant histopathologists. RESULTS: The result of touch imprint cytology showed that touch imprint cytology was diagnostic in 68 cases (97.1%), 55 (78.6%) being malignant, 2 cases (2.9%) were suspicious for malignancy, 11 cases (15.7%) were negative for malignancy while 2 cases (2.9%) were false negative. Amongst the 70 cases, 55 cases (78.6%) were malignant showing squamous cell carcinoma in 49 cases (70%), adenoid cystic carcinoma in 2 cases (2.9%), non-Hodgkin lymphoma 2 cases (2.9%), Mucoepidermoid carcinoma 1 case (1.4%), spindle cell sarcoma in 1 case (1.4%). Two cases (2.9%) were suspicious of malignancy showing atypical squamoid cells on touch imprint cytology, while 13 cases (18.6%) were negative for malignancy, which also included 2 false negative cases. The overall diagnostic accuracy of touch imprint cytology came out to be 96.7% with a sensitivity and specificity of 96 and 100%, respectively while PPV and NPV of touch imprint cytology was found to be 100 and 84%, respectively. CONCLUSION: Our experience in this study has demonstrated that touch imprint cytology provides reliable specific diagnoses and can be used as an adjunct to histopathology, particularly in developing countries, where the facility of frozen section is often not available, since a rapid preliminary diagnosis may help in the surgical management planning.

Latent membrane protein 1 (LMP1) expression in Hodgkin lymphoma and its correlation with clinical and histologic parameters.

BACKGROUND: Hodgkin lymphoma is one of the most prevalent lymphoproliferative disorders in Pakistan; however, no risk factors for this disease have yet to be established in our population. Epstein-Barr virus (EBV) is a well-known risk factor for Hodgkin lymphoma in endemic regions of the world; however, frequency of its association in our population has not been widely studied. Latent membrane protein 1 (LMP1) expression by immunohistochemistry (IHC) is a surrogate marker of EBV in Hodgkin lymphoma. Therefore, we aimed to evaluate the frequency of expression of LMP1 in cases of Hodgkin lymphoma at our institute and its correlation with other clinical and histologic parameters. METHODS: The study included 66 cases of Hodgkin lymphoma diagnosed at Liaquat National Hospital over a duration of 2 years from January 2014 to December 2015. The slides and blocks of all cases were retrieved, and representative blocks were selected for LMP1 by IHC. LMP1 expression of >10% of cells was considered as positive expression and correlated with histologic subtypes and clinical parameters like age, gender, and site of involvement. RESULTS: The mean age of patients was 35.11 (+20.22). LMP1 expression was found in 68.1% (45/66) of cases of Hodgkin lymphoma. Mean age of the patients with LMP1 expression was 32.04 (+21.02). LMP1 expression was found in 40% cases of lymphocyte-rich, 66.7% of lymphocyte-depleted, 73.9% of mixed cellularity, 66.7% of nodular sclerosis, and 73.7% of classic Hodgkin lymphoma, NOS. No significant correlation of LMP1 expression with any clinical or histological parameter could be established in our studied patient population. CONCLUSIONS: A high frequency of expression of LMP1 is seen in cases of Hodgkin lymphoma at our setup comparable to endemic regions of the world; therefore, preventive and treatment protocols should be designed accordingly.

Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters.

BACKGROUND: Microsatellite instability (MSI) operates as the second major pathway in the colorectal carcinogenesis. Although genetic testing remains the gold standard for the detection of MSI, the College of American Pathologists (CAP) recommends an initial immunohistochemical workup with a four-antibody panel (MLH1, PMS2, MSH2, and MSH6) to screen for a defective mismatch repair system. An increased trend towards young age colorectal carcinoma (CRC) has been noticed in our population over recent years; however, neither screening for MSI by immunohistochemistry (IHC)/genetic testing was done nor were its morphological features studied. We aimed to determine the frequency of mismatch repair deficiency (dMMR) by loss of IHC expression of the aforementioned enzymes in CRC patients and its correlatation with clinicopathologic parameters. METHODS: This was a retrospective study conducted at Liaquat National Hospital, Karachi, between 2012 and 2015. A total of 100 cases of CRC were included in the study that underwent surgical resection. IHC stains using antibodies MLH1, PMS2, MSH2, and MSH6 were performed by DAKO EnVision method on representative tissue blocks. The results were interpreted by senior histopathologists and correlated with clinico-pathological parameters. RESULTS: A total of 100 cases of CRC were studied that included 51 males and 49 females. Thirty-four percent (n = 34) of the patients showed loss of IHC staining for MMR markers. Combined loss of expression for MLH1/PMS2 were observed in 16% (n = 16) of the cases. Loss of MSH2/MSH6 were seen in 6% (n = 6) of the cases. Loss of expression for all markers were noted in 7% (n = 7) of the cases. There were 5% (n = 5) of the cases that showed isolated loss of MLH1 only. The tumors with dMMR status were significantly associated with right-sided location (p = 0.013), exhibited intra-tumoral lymphocytosis (p = 0.007), and lymphovascular invasion (p = 0.043). No significant association was seen with gender, age, tumor stage, grade, or other morphological features. CONCLUSION: The frequency of mismatch repair deficiency in CRC patients was found to be 34% in Pakistani population which warrants further genetic testing to exclude Lynch syndrome. Moreover, right-sided location and intra-tumoral lymphocyte count may be used to identify patients who may need further workup.

Accuracy of intraoperative frozen section for the evaluation of ovarian neoplasms: an institutional experience.

BACKGROUND: Ovarian neoplasms are a heterogeneous group of tumors including surface epithelial, germ cell and sex cord stromal tumors with a subset having low malignant potential (borderline tumors). While the surgical management plan differs in different categories of tumors, preoperative diagnosis is seldom available. In these circumstances, the role of frozen section becomes invaluable. In the current study, we aimed to evaluate the accuracy of the frozen section of ovarian tumors in our setup. METHODS: It was a retrospective study involving 141 cases of ovarian tumors undergoing surgical resection with frozen section evaluation from January 2009 to December 2014. After gross examination, one to five blocks were prepared on the frozen section depending upon the size of the specimen. After frozen section reporting, specimens were processed routinely for final paraffin section evaluation. Results of frozen and paraffin sections were categorized in benign, borderline, and malignant, and accuracy of frozen section was determined. RESULTS: Out of 141 cases, 107 were diagnosed as benign on final (paraffin) examination, while 6 were borderline and 28 were malignant. Out of 107 benign cases, 45 were non-neoplastic cystic lesions of the ovary including endometriotic, follicular, and corpus luteal cysts. The most common benign neoplastic tumor was mature cystic teratoma (20 cases) followed by mucinous cystadenoma (19 cases), serous cystadenoma (14 cases), sex cord stromal tumors (8 cases), and Brenner tumor (1 case). Among borderline cases, four cases were serous and two of mucinous neoplasms. The most common malignant neoplasm was serous carcinoma (11 cases) followed by mucinous carcinoma (6 cases). The overall accuracy of frozen section diagnosis is above 99 %. The sensitivity and specificity for benign tumors were found to be 100 and 97 %, respectively. The sensitivity and specificity for borderline tumors was 83 and 99 %, respectively, while for malignant tumors, it was 96 and 100 %, respectively. CONCLUSIONS: We found a high sensitivity and specificity of frozen section for the diagnosis of ovarian tumors and to determine its malignant potential. Therefore, it should always be used when the preoperative diagnosis is not definite to govern extent of surgical resection. However, under-diagnosis can occur in tumors of borderline category which can be minimized by increased sampling on the frozen section.

Role of peritoneal washing cytology in ovarian malignancies: correlation with histopathological parameters.

BACKGROUND: Peritoneal dissemination of ovarian tumors is a major prognostic parameter in ovarian malignancies. Analysis of peritoneal washing cytology serves as a useful predictor of ovarian surface involvement and peritoneal metastasis even in the absence of clinical omental spread. The aim of the current study is to correlate peritoneal cytology with various histologic features of ovarian cancers in our setup. METHODS: A total of 60 cases of ovarian tumors were included in the study that underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and omental and lymph node sampling during 2009 till 2014 at the Liaquat National Hospital, Karachi. Any free abdominal fluid was aspirated at the time of surgery. In the absence of free fluid, peritoneal washing was done with 50-100 ml of normal saline. Four cytospin preparations were done along with a cell block preparation. Correlation of peritoneal cytology with various histologic parameters was performed. RESULTS: Out of the 60 cases of ovarian tumors involved in the study, 56 were surface epithelial tumors, 2 germ cell tumors, and 2 metastatic carcinomas. The mean tumor size was 9.6 cm. Capsular invasion was seen in 61 % of the cases, and omental metastasis in 51 % of the cases. Serous carcinoma was found to have a significantly higher frequency of positive peritoneal cytology (76.9 %) compared to endometrioid and mucinous carcinomas (44 and 25 %, respectively). A significant positive correlation was seen between positive peritoneal cytology and capsular invasion and omental metastasis with a p value of <0.001. CONCLUSIONS: Positive peritoneal washing cytology has been implemented in ovarian cancer guidelines because of its prognostic significance in ovarian tumors. In addition to being an indicator of peritoneal metastasis, positive cytology also correlates with capsular invasion and histologic type in ovarian tumors. Therefore, it should always be used as an adjunctive tool in the surgical management of ovarian tumors.

Clinical pattern and spectrum of endometrial pathologies in patients with abnormal uterine bleeding in Pakistan: need to adopt a more conservative approach to treatment.

BACKGROUND: Abnormal uterine bleeding (AUB) is one of the most common debilitating menstrual problems and has remained one of the most frequent indications for hysterectomy in developing countries. Approximately in 40% of hysterectomy specimens, no definite organic pathology could be established. The problem is common worldwide but causes may vary from one region to another. This study may help gynecologists in our population to improve their therapeutic strategies by promoting minimally invasive uterus sparing modalities such as endometrial ablation and hysteroscopic resection of early proliferative lesions. METHODS: It was a prospective, cross-sectional study conducted at Liaquat National Hospital from 15(th) January 2010 till 14(th) July 2011 over a period of 18 months. Women who underwent dilatation and curettage for endometrial sampling with complaints of AUB were included in the study and histopathologic spectrum was determined. RESULTS: Polymenorrhea was the most common presenting pattern (30%, 72/241) with reproductive age women being the most susceptible (49.3%,119/241). The commonest histopathological spectrum was normal menstrual pattern (34%, 82/241) and the commonest pathology was hormonal imbalance (27%, 65/241), followed by endometrial polyp (14%, 34/241), chronic endometritis (12%, 28/241), atrophic endometrium (6%, 15/241), endometrial hyperplasia (5%, 12/241), and endometrial carcinoma (2%, 5/241). Chronic endometritis was commonly seen in reproductive age (18%, 21/119); hormonal imbalance (45%, 35/77) and endometrial hyperplasia (6.5%, 5/77) in perimenopausal age; endometrial polyp (35.5%, 16/45) and endometrial carcinoma (9%, 4/45) in postmenopausal age. CONCLUSION: Frequency of benign endometrial pathology is quite high in AUB, 236 participants (98%, 236/241). Histopathological spectrum in patients with AUB is quite variable with respect to age. The most common pattern of AUB was polymenorrhea. The most common pathology was hormonal imbalance. It is suggested that age was associated with more progressive lesions found in peri and postmenopausal age group such as endometrial hyperplasia and endometrial carcinoma. Yet endometrial polyp was the most common pathology found in postmenopausal women. Therefore, the management strategy should be individualized, as in most cases a restrictive approach is appropriate in order to avoid unnecessary hysterectomies.

Molecular subtypes of breast cancer in South Asian population by immunohistochemical profile and Her2neu gene amplification by FISH technique: association with other clinicopathologic parameters.

Molecular breast cancer subtypes were defined by gene expression prolife; however, immunohistochemical (IHC) expression can categorize breast cancers analogous to gene expression profiling. We aimed to evaluate distribution of these molecular breast cancer subtypes in our population and their association with clinocopathologic parameters. We retrospectively analyzed 1,104 cases of primary breast cancers over 3 years duration. ER, PR, Her2neu IHC staining, and subsequent fluorescent in situ hybridization studies (Her2neu gene amplification in cases with 2+ IHC staining) were performed to categorize breast cancer subtypes. Luminal A breast cancers were most frequent (45.8%) followed by triple negative (18.6%), luminal B (17.8%) and Her2neu (17.8%) subtypes. We found a strong association of breast cancer subtypes with tumor grade and Ki67 proliferation index with triple negative cancers being associated with higher grade and proliferation index. Significant association was seen with age groups, luminal A subtype occurring at a slightly older age, whereas triple negative and Her2neu cancers were more frequent in younger age group. We found a higher proportion of triple negative cancers in our set up, and they were found to have high-tumor grade and proliferation index along with presentation at younger age. As these cancers are associated with BRCA 1 mutations and abnormal BRCA 1 pathways, we suggest that large scale studies should be done to evaluate BRCA 1 mutations and abnormal BRCA 1 pathways in our population to establish risk factors for this highly aggressive tumor subtype.

SARS-CoV-2 alters neural synchronies in the brain with more severe effects in younger individuals.

Coronavirus disease secondary to infection by SARS-CoV-2 (COVID19 or C19) causes respiratory illness, as well as severe neurological symptoms that have not been fully characterized. In a previous study, we developed a computational pipeline for the automated, rapid, high-throughput and objective analysis of electroencephalography (EEG) rhythms. In this retrospective study, we used this pipeline to define the quantitative EEG changes in patients with a PCR-positive diagnosis of C19 (n = 31) in the intensive care unit (ICU) of Cleveland Clinic, compared to a group of age-matched PCR-negative (n = 38) control patients in the same ICU setting. Qualitative assessment of EEG by two independent teams of electroencephalographers confirmed prior reports with regards to the high prevalence of diffuse encephalopathy in C19 patients, although the diagnosis of encephalopathy was inconsistent between teams. Quantitative analysis of EEG showed distinct slowing of brain rhythms in C19 patients compared to control (enhanced delta power and attenuated alpha-beta power). Surprisingly, these C19-related changes in EEG power were more prominent in patients below age 70. Moreover, machine learning algorithms showed consistently higher accuracy in the binary classification of patients as C19 versus control using EEG power for subjects below age 70 compared to older ones, providing further evidence for the more severe impact of SARS-CoV-2 on brain rhythms in younger individuals irrespective of PCR diagnosis or symptomatology, and raising concerns over potential long-term effects of C19 on brain physiology in the adult population and the utility of EEG monitoring in C19 patients.

Clinicopathological Features of Primary Neuroendocrine Tumors of Gastrointestinal/Pancreatobiliary Tract With Emphasis on High-Grade (Grade 3) Well-Differentiated Neuroendocrine Tumors.

Introduction The two broad subcategories of neuroendocrine neoplasms (NENs) are well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs), based on tumor architecture and cytology. Grade 3 WDNETs are a subset of WDNETs that not only are high grade by mitotic activity or proliferative index but exhibit a well-differentiated histology. In this study, we evaluated the clinicopathological features of primary neuroendocrine tumors of the gastrointestinal (GI)/pancreatobiliary tract with emphasis on high-grade WDNETs, as it is a newly defined entity. Methods We conducted a retrospective observational study, including a total number of 122 cases of primary GI and pancreatobiliary tract NENs. Slides and blocks of all cases were retrieved from the departmental archives. Immunohistochemical stains including Ki67 were applied to selected tissue blocks of all cases. Tumors were then evaluated for their histological differentiation and tumor grade. Results Our results showed that the mean age of patients was 46.8 ± 17.1 years. Majority of the NENs were GI tract origin (86.9%). The most common site of tumor in gastroenteropancreatic tract was the small bowel (31.1%), followed by the stomach (26.2%). Ninety five percent of the tumors were WDNETs, of which the most common grade was G2. The mean Ki67 index was 15.8 ± 23.8. Grade 3 WDNETs were noted to have an older mean age than grades 1 and 2 WDNETs. Ten out of 102 (9.8%) WDNETs of GI tract were grade 3, compared with four out of 14 (28.6%) of pancreatobiliary tract.  Conclusion In this study, we found that high-grade (grade 3) WDNETs were more frequent in pancreatobiliary tract than GI tract. Moreover, high-grade WDNETs were associated with a higher mean age than low-grade (grade 1-2) WDNETs. It is extremely important to recognize this subset (high grade) of WDNETs and to distinguish it from PDNECs, as the latter are known to be associated with a worse overall survival. Despite high mitotic rate/proliferative index, high-grade WDNETs are characterized by organoid architecture and monomorphic cell population.

CD30-Positive Anaplastic Variant of Diffuse Large B-cell Lymphoma: Frequency and Association With Clinicopathological Parameters.

Introduction Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma and is the most common type of non-Hodgkin's lymphoma (NHL) worldwide. The World Health Organization (WHO) classification of hematopoietic tumors has recognized three morphological variants of DLBCL: centroblastic, immunoblastic, and anaplastic. Some studies have shown that the anaplastic variant of DLBCL is associated with aggressive clinicopathological features. Anaplastic DLBCL is rare, and the clinicopathological characteristics of this subtype of DLBCL are not widely studied in our population. Therefore, in this study, we evaluated the frequency of the anaplastic variant of DLBCL and its association with other clinicopathological parameters. Methods A retrospective study was conducted in the Department of Histopathology at the Liaquat National Hospital and Medical College over a period of six years, from January 2015 to December 2020. All cases diagnosed as DLBCL based on morphology and immunohistochemical (IHC) profile were included in the study. The diagnosis of anaplastic DLBCL was rendered based on morphology (large bizarre pleomorphic cells in a cohesive or sheet-like growth pattern), combined with CD30 IHC expression. Results The mean age of the patients was 52.90 ±16.42 years, and the mean Ki67 index was 73.18 ±16.52%. Of the 220 cases of DLBCL, 47.3% cases were germinal center B-cell (GCB) subtype, and 59.1% cases were nodal. BCL-2, BCL-6, MUM1, c-MYC, and CD10 positivity were noted in 60%, 45.5%, 40.9%, 44.1, and 38.6% cases, respectively. Only 14 cases (6.4%) were recognized as anaplastic variants of DLBCL according to the previously defined criterion. The only significant association of anaplastic-variant DLBCL was noted with a lack of BCL-2 expression. No significant association of anaplastic-variant DLBCL was noted with age, gender, Ki67 index, DLBCL subtype, or any other IHC marker expression. Conclusion We found a low frequency of the anaplastic variant of DLBCL in our study. No significant association of this DLBCL variant was noted with any of the clinicopathological parameters, except for the lack of BCL-2 expression. Alternatively, from a pathological perspective, it is important to recognize this variant of DLBCL as it often mimics other CD30-positive lymphoma and undifferentiated carcinoma.