Real-World Challenges of Managing Diffuse Large B-Cell Lymphoma in a Developing Country.

PURPOSE: To highlight challenges and cancer care disparities in patients of diffuse large B-cell lymphoma management in resource-constrained settings. MATERIALS AND METHODS: This multicenter retrospective study included 738 patients from 12 public and private sector hematology-oncology centers across Pakistan. Patients were divided into limited-resource and enhanced-resource settings as per national diffuse large B-cell lymphoma (DLBCL) guidelines. RESULTS: The median age at diagnosis was 47 years (range, 14-89). Male:female ratio was 2.5:1. Majority of the patients (69.3%) were treated in limited-resource settings. Computed tomography was used as a staging modality in 442 (60%) patients. Limited-stage DLBCL was present in 13.5% of patients, while 86.3% had advanced-stage disease at diagnosis. First-line regimens included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in 56% and cyclophosphamide, doxorubicin, vincristine, prednisone in 34% of patients, while 10% of patients received palliative regimens upfront. Of evaluable data, complete remission was documented in 299 (74.4%) patients, 39 (9.8%) had partial response and 63 (13.5%) had progressive disease. Disease-free survival (DFS) and overall survival (OS) status were not available for 345 (46.8%) patients at the time of data collection. Overall study cohort had a median follow-up of 2.2 years with a median OS of 3.6 years (95% CI, 3.1 to 4.1), median DFS of 3.1 years (95% CI, 2.6 to 3.6), and a 5-year OS of 40% and DFS of 36%. CONCLUSION: Patients from low- and middle-income countries present at an earlier age and have more advanced disease. Patients were frequently lost to follow-up, and record keeping was inadequate more so in patients treated in limited-resource settings. There is a need to establish a national lymphoma registry, improve record keeping, and standardize treatments to ensure improvement in treatment outcomes.

Radiation Oncology Research in Asia: Current Status and a Peep Into the Future From the Federation of Asian Organizations for Radiation Oncology.

PURPOSE: This survey was conducted to assess the current research practices among the 14 members of the Federation of Asian Organizations for Radiation Oncology (FARO) committee, to inform measures for research capacity building in these nations. MATERIALS AND METHODS: A 19-item electronic survey was sent to two research committee members from the 14 representative national radiation oncology organizations (N = 28) that are a part of FARO. RESULTS: Thirteen of the 14 member organizations (93%) and 20 of 28 members (71.5%) responded to the questionnaire. Only 50% of the members stated that an active research environment existed in their country. Retrospective audits (80%) and observational studies (75%) were the most common type of research conducted in these centers. Lack of time (80%), lack of funding (75%), and limited training in research methodology (40%) were cited as the most common hindrances in conducting research. To promote research initiatives in the collaborative setting, 95% of the members agreed to the creation of site-specific groups, with head and neck (45%) and gynecological cancers (25%) being the most preferred disease sites. Projects focused on advanced external beam radiotherapy implementation (40%), and cost-effectiveness studies (35%) were cited as some of the potential areas for future collaboration. On the basis of the survey results, after result discussion and the FARO officers meeting, an action plan for the research committee has been created. CONCLUSION: The results from the survey and the initial policy structure may allow facilitation of radiation oncology research in the collaborative setting. Centralization of research activities, funding support, and research-directed training are underway to help foster a successful research environment in the FARO region.

Prevalence of HPV types in HIV-positive and negative females with normal cervical cytology or dysplasia.

The burden of HPV varies by country and HIV status. The study aimed to evaluate HPV types prevalent in HIV-positive females compared with HIV-negative females in the local population of the federal capital territory in Pakistan. METHOD: The selected female population consisted of 65 already diagnosed HIV-positive females and 135 HIV-negative females. Cervical scrap was collected and analyzed for HPV and cytology. RESULTS: The prevalence of HPV in HIV-positive patients was 36.9%, higher than HIV-negative patients (4.4%). 12.30% had cervical cytology interpreted as "LSIL" and 87.69% had cytology interpreted as "NIL." The high-risk type was detected in 15.39% while 21.54% showed low-risk HPV types. Among the high-risk types, HPV18 (6.15%), HPV16 (4.62%), HPV45 (3.07%), HPV33 (1.53%), HPV58 (3.07%), and HPV68 (1.53%) were found. In patients with LSIL, high-risk HPV accounts for 62.5%. Risk factors, such as age, marital status, educational status, residence, parity, other STDs, and contraceptives, were analyzed to find the correlation with HPV infection Age ≤35 years (OR 1.21, 95% CI, 0.44-3.34), illiterate and incomplete secondary education (OR 1.08, 95% CI, 0.37-3.15), and those reported not to use contraceptives (OR: 1.90; 95% CI: 0.67-5.42) have an association for increased risk of HPV infection. CONCLUSION: HPV18, HPV16, HPV58, HPV45, HPV68, and HPV33 were identified among high-risk HPV types. High-risk HPV was detected in 62.5% of low-grade squamous intraepithelial lesions. The data is useful for health policymakers to develop a strategy for HPV screening and prophylactic vaccination to prevent cervical cancer.

Antibody Response to SARS-CoV-2 in Relation to the Contributing Factors in COVID-19 Patients.

Human health has always been challenged by variety of viral infections, but severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has surpassed all previous viral diseases and emerged as a major health challenge around the globe. Real-time polymerase chain reaction (PCR) is the gold standard for the diagnosis of SARS-CoV-2 and serological assay provides a compliment to diagnosis after second week of infection. The aim of the study is the characterization of antibody response to SARS-CoV-2 in the blood sample of diagnosed coronavirus disease 2019 (COVID-19) patients, and its potential association with factors such as age, gender, time, and symptoms. Serum from 248 confirmed SARS-CoV-2 patients was investigated for antibodies. Elecsys anti-SARS chemiluminescent immune assay was performed for the detection of nucleocapsid-specific antibodies. Association of antibody response with gender, age, and time after onset of symptoms was analyzed. Among 248 PCR positive SARS-CoV-2 patients, 214 (86.3%) have virus-specific antibody signals. Antibodies positivity rate was higher in male patient patients as compared with female patients (90.8% vs. 79.2%, p = 0.009). Patients aged 30-40 years had the highest antibody positivity rate as compared with other groups (89.10%, p = 0.04). Patients age group >60 years had a lower positivity rate (75%, p = 0.04). The increasing trend in the antibodies detection with time was observed, maximum positive antibodies response rate observed at 8 weeks. Patients were categorized on the basis of clinical symptoms into asymptomatic, mild, and moderate; 17.7% were asymptomatic, 60.5% showed mild symptoms, and 21.8% showed moderate symptoms of the disease. Males were seen to be more asymptomatic as compared with females (i.e., 59.1% to 40.9%). The serological test for SARS-CoV-2 has a high sensitivity at >2 weeks after the positive PCR result or onset of illness. In addition, the serological response differs among patients based on gender, age, as well as time between the onset of symptoms or PCR confirmation and sample collection for the study of antibody response.

Diagnosis and Management of Diffuse Large B-Cell Lymphoma: Society of Medical Oncology, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology Joint Clinical Practice Guideline.

Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma encountered by hematopathologists and oncologists. Management guidelines for DLBCL are developed and published by countries with high income and do not cater for practical challenges faced in resource-constrained settings. This report by a multidisciplinary panel of experts from Pakistan is on behalf of three major national cancer societies: Society of Medical Oncology Pakistan, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology. The aim is to develop a practical and standardized guideline for managing DLBCL in Pakistan, keeping in view local challenges, which are similar across most of the low- and middle-income countries across the globe. Modified Delphi methodology was used to develop consensus guidelines. Guidelines questions were drafted, and meetings were convened by a steering committee to develop initial recommendations on the basis of local challenges and review of the literature. A consensus panel reviewed the initial draft recommendations and rated the guidelines on a five-point Likert scale; recommendations achieving more than 75% consensus were accepted. Resource grouping initially suggested by Breast Health Global Initiative was applied for resource stratification into basic, limited, and enhanced resource settings. The panel generated consensus ratings for 35 questions of interest and concluded that diagnosis and treatment recommendations in resource-constrained settings need to be based on available resources and management expertise.

Identification of CDKN2A variants in breast cancer patients in Pakistan.

The role of cyclin-dependent kinase inhibitor 2A gene (CDKN2A) variants in breast cancer is not well understood, here we investigated their possible effects on breast cancer in Pakistani women attending the NORI Hospital, Islamabad. Direct DNA sequencing of CDKN2A identified an already known polymorphism in the 3' UTR, c.*29G>C (rs11515), in 5.88% patients and two novel variants. One, a deep intronic substitution (c.458-554T>G) in 1.96% patients, is also detected as a compound heterozygous form along with c.*29G>C in 1.96% patients (c.[458-554T>G; *29G>C]). The other is a novel deletion (c.458-82delG) occurring as a compound variant with two other identified variants c.[458-554T>G; 458-82delG; *29G>C] in 1.96% patients. In silico pathogenicity prediction analyses did not predict pathogenic effects on breast cancer for these individual variants. We conclude that variations in CDKN2A are not the major genetic cause of breast cancer in the enrolled Pakistani patients.

Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome.

Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor.

Human papillomavirus infection in females with normal cervical cytology: Genotyping and phylogenetic analysis among women in Punjab, Pakistan.

BACKGROUND: Globally, cervical cancer is the fourth most common cancer in women and the seventh most common cancer overall, accounting for an estimated 300 000 annual deaths. Human papillomavirus (HPV) is the second most common cause of cervical cancer worldwide. HPV screening is not a common practice in Pakistan. The aim of this study was to determine the prevalence of HPV and HPV types in women with a normal cytology of the cervix living in the upper and lower regions of Punjab, Pakistan, and to analyze the risk factors for HPV in this region. METHODS: PCR analysis was performed for 1011 female patients with a normal cytology of the cervix from various districts of Punjab Province, Pakistan. Risk factors for the acquisition of HPV were studied. High-risk HPV types (HPV16 and HPV18) were detected using the Abbott Real Time HR HPV test. To determine the genotype, partial L1 region sequences of HPV-positive samples were subjected to sequencing using MY/09/MY11 primers, and a phylogenetic tree was constructed using CLC software. RESULTS: The study found a 4.74% prevalence of HPV, with the most frequent HPV type found being the low-risk HPV6 (in 25% of infected individuals), followed by HPV55 (22.9%), HPV11 (20.8%), and high-risk types HPV45 (12.5%), HPV33 (8.33%), HPV18 (6.25%), and HPV16 (4.16%). Phylogenetic analysis of all HPV types in this study showed 80-99% nucleotide identity with types related to the same species. The sequences were clustered with China, India, Mexico, Iran, Slovenia, and Germany, showing the diversity in origin of the various genotypes prevalent in Pakistan. CONCLUSIONS: In this population with a normal cervical cytology, the prevalence of high-risk HPV types was very low. The major prevalent HPV genotype in Punjab Province of Pakistan was the low-risk HPV type 6, followed by HPV type 55. Sequencing of the partial L1 region suggested that the region was highly conserved in all reported sequences. This study highlights the need to conduct robust epidemiological studies in the region and to develop regular HPV screening so that the situation does not reach an alarming stage resulting in cervical cancer.

Mammary Analogue Secretory Carcinoma of Parotid Gland in a Teenage Boy.

Mammary analogue secretory carcinoma (MASC) is a rare salivary gland malignancy that exhibits resemblance with secretory carcinoma of the breast (SC) due to the presence of ETV6-NTRK3 gene fusion, formerly classified as acinic cell carcinoma. It is a slowly growing painless tumor that exhibits wide range of clinical behavior. This tumor typically affects middle aged people. Less than 100 such cases have been reported in the literature so far with only 8 case reports of patients less than 19 years of age. Very little is known about the clinical management of such cases. We hereby report a case of 15-year boy who had been managed for MASC of left parotid gland with exision.

Metastatic hepatoid carcinoma of ovarian origin - a case report from northern Pakistan.

•Hepatoid carcinoma of the ovary is rapidly progressing rare epithelial ovarian tumor.•The term 'hepatoid' refers to the morphological resemblance with hepatocellular carcinoma.•Final diagnosis is made via positive staining for alpha fetoprotein along with immunohistochemistry•Combination chemotherapy can be considered superior over the targeted agents while treating this tumor.

Optical Screening of Female Breast Cancer from Whole Blood Using Raman Spectroscopy.

This study is intended to develop a screening method for female breast cancer (BRC) from whole blood using Raman spectroscopy. A multivariate partial least squares (PLS) regression model is developed which is based upon Raman spectra of BRC-positive and healthy participants. It yields coefficients of regression at the corresponding Raman shifts. These coefficients represent the changes in molecular structures which are associated with the progress of disease. The present study pointed out some specific molecules which differentiated BRC-positive and healthy groups. In the BRC-positive group, a rising trend of calcium oxalate, calcium hydroxyapatite, phosphatidylserine and qunoid ring, and a lowering trend of tryptophan, tyrosine, and proline were observed in PLS-based coefficients of regression. The R-square value of the model was found to be 0.987, which is accepted clinically. The model was tested for the prediction of 50 randomly collected samples at a cutoff value of 0.5 with the gray region defined in the range of 0.4-0.6. Goodness of fit was estimated using accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curve, and area under ROC curve. All of these parameters were found to be very promising.

Corrigendum to "Metastatic hepatoid carcinoma of ovarian origin - A case report from Northern Pakistan" [Gynecol. Oncol. Rep. 21 (2017) 24-27].

[This corrects the article DOI: 10.1016/j.gore.2017.05.007.].

Type 2 Diabetes Mellitus as a Risk Factor for Female Breast Cancer in the Population of Northern Pakistan.

BACKGROUND: There has been much research work in the past to ascertain the association between type 2 diabetes mellitus and breast cancer, but definitive evidence has been scanty. The present study was carried out to determine the association of type 2 diabetes mellitus with breast cancer in the female population of Northern Pakistan. MATERIALS AND METHODS: This casecontrol study was carried out in the Oncology Department of NORI Hospital. A total of 400 patients were included. Data were entered into PSPP 0.8.1. Twotailed significance tests were used and a pvalue of 0.05 was considered significant. RESULTS: There were a higher percentage of postmenopausal women in the diabetic breast cancer patients' group as compared to the nondiabetic subset. The odds ratio for the association between diabetes and risk of developing breast cancer was elevated with statistical significance (OR = 2.96; 95 % CI =1.36.3; pvalue=0.004). The results of our study showed that diabetes is associated with a risk of developing breast cancer, especially in postmenopausal women (OR = 4.928; 95 % CI = 2.111.3; pvalue=0.001). The association was particularly marked in obese subjects (OR = 31.49; 95 % CI = 1.8 536; p value=0.01), as compared to nonobese subjects (OR = 0.642; 95 % CI = 0.21.7). CONCLUSIONS: Diabetes is strongly associated with obesity and it tends to increase the risk of breast Cancer, especially in postmenopausal women. A highrisk subset for breast cancer comprised postmenopausal, diabetic and overweight women.

Impact of age, tumor size, lymph node metastasis, stage, receptor status and menopausal status on overall survival of breast cancer patients in Pakistan.

BACKGROUND: Survival of breast cancer patients depends on a number of factors which are not only prognostic but are also predictive. A number of studies have been carried out worldwide to find out prognostic and predictive significance of different clinicopathological and molecular variables in breast cancer. This study was carried out at Nuclear Medicine, Oncology and Radiotherapy Institute (NORI), Islamabad, to find out the impact of different factors on overall survival of breast cancer patients coming from Northern Pakistan. MATERIALS AND METHODS: This observational retrospective study was carried out in the Oncology Department of NORI Hospital. A total of 2,666 patients were included. Data were entered into SPSS 20. Multinomial logistic regression analysis was performed to determine associations of different variables with overall survival. P values <0.05 were considered significant. RESULTS: The mean age of the patients was 47.6 years, 49.5% being postmenopausal. Some 1,708 were ER positive and 1,615 were PR positive, while Her 2 neu oncogene positivity was found in 683. A total of 1,237 presented with skin involvement and 426 had chest wall involvement. Some 1,663 had > 5cm tumors. Lymph node involvement was detected in 2,131. Overall survival was less than 5 years in 669 patients, only 324 surviving for more than 10 years, and in the remainder overall survival was in the range of 5-10 years. CONCLUSIONS: Tumor size, lymph node metastases, receptor status, her 2 neu positivity, skin involvement, and chest wall involvement have significant effects whereas age and menopausal status have no significant effect on overall survival of breast cancer patients in Pakistan.

Epithelioid trophoblastic tumor: an unusual malignancy of ovary.

Epithelioid Trophoblastic Tumor (ETT) is a distinct but rare variety of gestational trophoblastic tumors. Misdiagnosis delays effective treatment and affects the survival. The case being reported here involved a 43 years old lady presented with 4 months history of intermenstrual per vaginal bleeding and 6 weeks amenorrhea. Workup has revealed pelvic mass. The patient underwent laparotomy with transabdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathology turned out to be clear cell carcinoma of the ovary. Patient was put on chemotherapy but there was progression of disease. Review of histopathology and immunohistochemistry revealed it as Epithelioid Trophoblastic Tumor; serum b-hCG was also raised. The case was really challenging for histopathologist. By the time final diagnosis was made, patient developed extensive metastases in lungs and liver and expired. Such an uncommon yet distinct trophoblastic tumor should be kept in mind by pathologists and treating physicians.

Transitional cell carcinoma of urinary bladder in a breast cancer survivor.

There is a propensity for the development of second malignancy in breast cancer patients either simultaneously with the first primary malignancy or after the control of the primary disease. The commonest sites to be involved with second malignancy in breast cancer patients are ovary, colon and endometrium. Other malignancies can also develop rarely either as a complication of treatment or de Novo. Here, a rare case is presented who developed transitional cell carcinoma of the urinary bladder 10 years after the treatment for breast cancer.

Adenocarcinoma of rectum as second primary cancer after treatment of endometrium cancer.

Colorectal cancer is the second leading cause of death from cancer in women in the United States. Previous epidemiologic studies have identified a 1.5 - 3 fold increased risk of colorectal cancer in women after ovarian and endometrial cancer. In Pakistan, neither such a study showing relationship of colorectal cancer with gynaecological cancer has been done nor any case has been reported. Here, a case is being reported who developed adenocarcinoma of rectum as the second primary about nine years after completion of treatment for adenocarcinoma of endometrium.

Carcinosarcoma of the breast.

Carcinosarcoma of the breast is an extremely rare and aggressive tumour with two distinct cell lines comprising epithelial and mesenchymal components, with few cases reported in the literature. The prognosis of carcinosarcoma breast is less favourable compared to more common types of breast cancers such as infiltrating ductal or lobular carcinomas. These tumours form a diagnostic and therapeutic challenge. A case of carcinosarcoma breast in a 36 years old woman is presented here.

Estrogen receptor, progesterone receptor, and Her 2 Neu positivity and its association with tumour characteristics and menopausal status in a breast cancer cohort from northern Pakistan.

OBJECTIVES: To measure the frequency of estrogen receptor (ER), progesterone receptor (PR), and Her 2 Neu positivity and to study their association with tumour characteristics and menopausal status in a breast cancer cohort from Northern Pakistan. METHODOLOGY: Patients attending NORI with histopathologically proven diagnosis of invasive ductal carcinoma of the breast were included after providing informed consent. Age, menopausal status, and tumour size were recorded. The presence or absence of nodal involvement (including site and number), distant metastases, sites of metastases, skin involvement, chest wall involvement, recurrent disease, and bilateral breast cancer were noted along with ER, PR, and Her 2 Neu status. Mean ± standard deviations were calculated for continuous variables like age. Frequency and percentage were calculated for categorical variables like ER, PR, and Her 2 Neu status. Association of ER, PR, and Her 2 Neu status with menopausal status and tumour-related characteristics were sought employing t test, x(2 )square test, and ANOVA wherever appropriate. P value >0.05 was considered significant. RESULTS: There were 1226 patients included in the study. Mean patient age was 48.04 ± 11.97 years, and 743 (60.6%) patients were premenopausal. ER, PR, and Her 2 Neu were found positive in 763 (62.2%), 738 (60.1%), and 478 (38.9%) patients, respectively. Significant association (P < 0.05) was found between ER, PR positivity, and Her 2 Neu over expression with menopausal status, tumour size, involvement of skin, chest wall and lymph nodes and the presence of distant metastases. However, no significant association was detected between ER, PR, Her 2 Neu and recurrent disease. CONCLUSIONS: The frequency of expression of hormonal receptors in breast cancer patients from Northern Pakistan is the same as reported in the literature although overexpression of Her 2 Neu is a little higher in our population. There is an inverse relationship between hormonal receptors expression and Her 2 Neu expression. Postmenopausal women have a higher incidence of ER and PR positivity and Her 2 Neu negativity. ER and PR negativity and Her 2 Neu positivity are associated with more advanced disease and poor outcome.

Long-term survivor of brain metastases from malignant melanoma.

Malignant melanoma is notorious for distant metastases. Median survival for stage IV melanoma is 6-10 months and 5 year survival is less than 5%. Median survival for melanoma with brain metastases is even lower i.e. 2 to 9 months. Here a case is reported who was treated for melanoma of sole of left foot with ipsilateral inguinal adenopathy and brain metastases in 2001 and is still surviving disease-free after a lapse of 8 years.