Predominance of MGMT promoter methylation among Pakistani glioblastoma patients.

BACKGROUND: Glioblastoma multiforme (GBM), the most prevalent subgroup of neuroepithelial tumors, is characterized by dismal overall survival (OS). Several studies have linked O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation to OS in GBM patients. However, MGMT methylation frequencies vary geographically and across ethnicities, with limited data for South Asian populations, including Pakistan. This study aimed to analyze MGMT promoter methylation in Pakistani GBM patients. METHODS: Consecutive primary GBM patients diagnosed ≥ 18 years-of-age, with no prior chemotherapy or radiotherapy history, were retrospectively selected. DNA was isolated from formalin-fixed-paraffin-embedded tissues. MGMT promoter methylation was analyzed using methylation-specific PCR. Clinical, pathological, and treatment data were assessed using Fisher's exact/Chi-squared tests. OS was calculated using Kaplan-Meier analysis in SPSS 27.0.1. RESULTS: The study included 48 GBM patients, comprising 38 (79.2%) males and 10 (20.8%) females. The median diagnosis age was 49.5 years (range 18-70). MGMT methylation was observed in 87.5% (42/48) of all cases. Patients with MGMT methylation undergoing radiotherapy or radiotherapy plus chemotherapy exhibited significantly improved median OS of 7.2 months (95% CI, 3.7-10.7; P < 0.001) and 16.9 months (95% CI, 15.9-17.9; P < 0.001), respectively, compared to those undergoing surgical resection only (OS: 2.2 months, 95% CI, 0.8-3.6). CONCLUSION: This is the first comprehensive study highlighting a predominance of MGMT methylation in Pakistani GBM patients. Furthermore, our findings underscore the association of MGMT methylation with improved OS across diverse treatment modalities. Larger studies are imperative to validate our findings for better management of Pakistani GBM patients.

MALIGNANT OVARIAN GERM CELL TUMORS AT A TERTIARY CARE SETTING IN PAKISTAN.

BACKGROUND: Malignant Ovarian Germ Cell Tumours (MOGCT) are rare neoplasms and their behavior is unknown in South-East Asian population. METHODS: Case records of 66 patients from 1994-2007 with MOGCT were reviewed. Histology was based on WHO classification. Tumours were staged according to International Federation of Gynecology and Obstetrics (FIGO) system. Data was collected on age, histopathology, stage, alpha-feto protein (AFP) and B-human chorionic gonadotropins (B-hCG) levels, treatment, time to recurrence (TTR) and overall survival (OS). OS was the interval in months between date of diagnosis and last encounter while TTR was between the date of diagnosis and recurrence. OS was determined by Kaplan-Meier method. RESULTS: Median age of our patients was 18 years. Ninteen patients were in stage I, eight in II, twenty-one in III and eighteen in stage IV. Histologically, dysgerminoma was the most common diagnosis (22 patients) followed by teratoma in 16, yolk sac tumor in 15, mixed germ cell tumor in 12 while embryonal carcinoma was identified in only one patient. Median followup was 48 months (0.2-183). All patients underwent initial surgery. Fertility sparing procedures were performed in 75% patients. Thirty-four patients (57.62%) achieved complete remission while 16 (27.11%) had progressive disease. Seven (10.60%) patients relapsed, all within first 3 years. TTR was 11.2-32.5 months. OS for study population was 60 months. Sixteen (88%) of stage I while only 4 (26.6%) of stage IV patients were alive at median follow-up. CONCLUSIONS: MOGCT has good prognosis with conservative surgery and platinum chemotherapy. Fertility sparing surgery has become a standard in MOGCTs, so awareness should be raised amongst professionals for early referral to cancer care facility.

Piperacillin-tazobactam as a cost effective monotherapy in febrile neutropenia.

BACKGROUND: Fever in neutropenic patient is a medical emergency. Timely intervention with antibiotics has been demonstrated to be effective. We assessed Piperacillin-Tazobactem as a cost effective mono-therapy in solid malignancy patients in our institution in relation to dual antibiotic therapy and other monotherapies. METHODS: This study was conducted to determine the efficacy, and cost effectiveness of Piperacillin-Tazobactem as monotherapy in febrile neutropenia. Total 150 patients with chemotherapy induced febrile neutropenia were selected. Piperacillin-Tazobactem was given intravenously 4500 mg every 6 hour. Outcome was assessed as success and failure. Success was defined as afebrile for four consecutive days, clearance of signs of infection, no new cultures, and no recurrence of primary infection after completion of therapy. Failure was defined as modification or addition of antibiotic due to clinical deterioration, cultured organism resistant to Piperacillin-Tazobactem and Death. RESULTS: The mean age was 43 years, 31% males and 69% were females. Out of total 150 patients, 73 patients were of breast carcinoma. There were 143 patients with negative blood cultures, and 7 patients with positive blood cultures, out of which 3 patients were resistant to Piperacillin-Tazobactem. Success was achieved in 83.3% of total patients. Daily cost of Piperacillin-Tazobactem was much less in relation to other monotherapies and dual antibiotic therapy including Gentamicin. None of the patient had adverse effects of Piperacillin-Tazobactem. CONCLUSION: We concluded that Piperacillin-Tazobactem is a safe, well tolerated as well as cost effective monotherapy in patient with febrile neutropenia with solid cancers. Only two percent organisms were resistant to Pipercillin-Tazobactam.

Clinicopathological Features and Outcomes of Granulosa Cell Tumor of the Ovaries - A Retrospective Study.

Background Granulosa cell tumor (GCT) is rare among all ovarian cancers. Its overall prognosis is favorable; however, the presence of extra-ovarian disease is associated with worse clinical outcomes. We report a retrospective analysis of granulosa cell tumors to evaluate the clinicopathological features and their outcomes.  Methods This retrospective study included 54 adult patients aged 13 years and older. After data extraction and scrutiny, only those patients who were treated and followed up later at our institute were included in this study. Results Fifty-four patients were evaluated in this study, with a median age of 38.5 years. Most of the patients had dysfunctional uterine bleeding and abdominal pain (40.7%, n=22). The majority (n=26, 48%) underwent completion surgery as per ovarian protocol; however, 16.7% (n=09) patients underwent simple total abdominal hysterectomy with a bilateral salpingo-oophorectomy (TAH+BSO), debulking surgery in 3.7% (n=2), unilateral salpingo-oophorectomy in 20.4% (n=11) and fertility-sparing surgery in 11.1% (n=06) of the patients. Pathological stage I-A was found in 59.3%(n=32), I-C in 25.9% (n=14), II-A in 1.9% (n=1), III-A in 1.9% (n=1), III-C in 9.3% (n=5) and IV-B in 1.9% (n=1) of the population. Eleven (20.3%) patients relapsed during their course of treatment. Out of these 11 patients, three went into remission, two still have active disease, and six patients died. Conclusion Post-menopausal patients, more advanced disease at presentation, capsular rupture, presence of ascites, omental involvement, peritoneal spread, and residual disease after surgical resection were the main contributing factors towards poorer outcomes affecting disease-free survival. Overall median disease-free survival was 60 months for all the stage groups, while the overall survival was 62 months.

Acute Tubulointerstitial Nephritis and Secondary Renal Amyloidosis: A Rare Complication of Atezolizumab.

Lung cancer is the second most common malignancy in both genders and the most common cause of cancer-related deaths worldwide. Broadly, lung cancer is divided into two types: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Non-small cell lung cancer accounts for 85% of the diagnoses of lung cancer. It is necessary to check for any targetable mutations, which can help in deciding the treatment plan for the patients. The patient we are reporting is a 70-year-old male with multiple co-morbidities diagnosed with non-small cell carcinoma, favoring adenocarcinoma on histopathology. He was started on Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel (ABCP). He was switched to maintenance Atezolizumab/Bevacizumab after four cycles due to poor tolerance to carboplatin and paclitaxel. The patient presented with neutropenic colitis and acute kidney injury (AKI), requiring admission. workup revealed nephrotic range proteinuria with a high urinary albumin-to-creatinine ratio. He underwent a renal biopsy to ascertain the cause of his proteinuria, which showed marked acute and chronic tubulo-interstitial nephritis (TIN), amyloidosis, and global glomerulosclerosis. Secondary (AA) amyloidosis is characterized by the extracellular deposition of misfolded proteins. Although interstitial nephritis is a reported side effect of immune checkpoint inhibitors, AA amyloidosis is a rarer side effect. So, to determine the exact cause and early therapeutic intervention in immune checkpoint inhibitor-related kidney injury, large retrospective or prospective studies should be done.

Radiotherapy and Limb-Sparing Surgery in the Management of Localized Soft Tissue Sarcomas: Tertiary Care Center Experience From Pakistan.

PURPOSE: When combined with radiotherapy, limb salvage surgery is an alternative to amputation. This study sought to determine the limb-sparing treatment outcomes in patients diagnosed with soft tissue extremity sarcomas treated at our institution. MATERIALS AND METHODS: All adult patients with extremity soft tissue sarcoma treated with the radical limb salvage strategy at Shaukat Khanum Memorial Cancer Hospital and Research Canter, Lahore, Pakistan, between January 2017 and December 2019 were retrospectively assessed. RESULTS: A total of 122 patients were included in the study. The mean age was 42 years (range 19-82), and 64 (52.5%) were males. The majority of patients, 65 (53.3%), were diagnosed with stage III and grade III disease according to American Joint Committee on Cancer TNM classification (Eighth edition). The most common surgical modality was wide local excision that was performed in 106 (86.9%) patients. Adjuvant radiation treatment was given in 111 (91%) patients, whereas 11 (9%) patients received neoadjuvant radiation treatment. The mean dose was 58 Gy (range: 46-66 Gy). Eighty-two (67.2%) of the patients were disease-free on post-treatment radiologic scans with disease recurrence observed in 40 (32.8%) patients. The median disease-free survival was 8 months (95% CI, 5.45 to 10.55). Local recurrence and distant metastases developed in 16 (13%) and 24 (20%) patients, respectively. CONCLUSION: About two thirds of patients with extremity soft tissue sarcoma were successfully treated with limb salvage strategy, surgery, and radiation therapy. However, high rate of relapse warrants further novel strategies in this patient population.

Baseline Characteristics, Prognostic Factors, and Treatment Outcomes for Adult Patients With Rhabdomyosarcoma (RMS).

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, while in adults it is one of the rarer tumors. Its prognosis is better in children with current treatment modalities; however, it carries poorer prognosis in adults. Recent data on adult RMS is scarce from our part of world. We report outcomes of adult patients with RMS, and with 40 patients; it is the first study to publish such a large data from Pakistan. METHODS: This was a retrospective study that included 64 adult patients aged 18 years and older. After data extraction and scrutiny, a total of 40 patients were segregated with diagnosis of RMS of various varieties who were treated and followed up subsequently. International Business Machines (IBM) Statistical Package for Social Sciences (SPSS), version 26 (IBM Corp., Armonk, NY) was used to evaluate all of the gathered data. RESULTS: Embryonal RMS (ERMS) was the most common subtype. Factors favoring better overall survival (OS) at 5 years were absence of nodal and distal metastases, treatment with surgery, margin negative resection, and absence of residual disease on postoperative imaging. Adjuvant radiation therapy (XRT) for positive resection margins as well as for residual disease on postoperative imaging also favored better OS at 5 years. Chemotherapy did impart a trend towards better OS; however, it was not significant. Histopathologic subtype and tumor size did not have any significant impact on outcomes. Median progression free survival (PFS) was 11 months and median OS was 15 months. CONCLUSIONS: Adult RMS is a rare disease entity with widely heterogeneous clinical picture and poorer outcomes as compared to the disease of childhood and adolescence. Further prospective studies with larger sample size are required to establish role of patient, disease, and treatment-related factors affecting outcomes in our population.

A phase 1b trial of selinexor, a first-in-class selective inhibitor of nuclear export (SINE), in combination with doxorubicin in patients with advanced soft tissue sarcomas (STS).

BACKGROUND: Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound with single-agent activity in soft tissue sarcoma (STS). The study's aim was to determine the safety and efficacy of selinexor in combination with doxorubicin in patients with locally advanced/metastatic STS. METHODS: This phase 1b study used a mTPI design. Patients received selinexor at either 60 or 80 mg weekly PO plus doxorubicin (75 mg/m2 IV q21 days). Patients with clinical benefit (defined as ≥stable disease via RECIST 1.1) after six cycles of combination treatment received maintenance selinexor until disease progression or unacceptable toxicity. Disease assessments were conducted every two cycles. Pharmacokinetic data were collected on the first three patients per dose level. RESULTS: Twenty-five patients were enrolled (20 female, ECOG 0/1: 13/12, median age 57 years [range 21-74]). Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumour (n = 3) and other sarcomas (n = 16). Three (12%) and 22 (88%) patients were treated at 60 mg and 80 mg of selinexor, respectively. The most common ≥G3 drug-related adverse events (AEs) were haematological, including neutropenia (56%), febrile neutropenia (28%) and anaemia (24%). There were four dose-limiting toxicities (febrile neutropenia (x2), vomiting, fatigue) all at the 80 mg dose level. There was one death secondary to heart failure. Of the 24 evaluable patients, 5 (21%) had a partial response and 15 (63%) had SD as best response. The estimated median progression-free survival (PFS) and overall survival (OS) were 5.5 (95% CI:4.1-5.7) and 10.5 (95% CI:7.5-14) months. CONCLUSION: In a heterogeneous group of patients with locally advanced/metastatic STS, the combination of selinexor and doxorubicin fulfilled the prespecified boundary for tolerability.

Clinical outcomes of non-osteogenic, non-Ewing soft-tissue sarcoma of bone--experience of the Toronto Sarcoma Program.

Non-osteogenic, non-Ewing soft-tissue sarcoma (NONE-STS) of bone is a rare presentation of primary bone cancers. Optimal treatments and outcomes for this heterogenous group are poorly described. We evaluated the factors associated with long-term outcomes in patients with this disease. Patients with localized NONE-STS of bone treated at the Toronto Sarcoma Program from 1987 to 2017 were identified. Clinical characteristics, treatment, and survival information were collected. Kaplan-Meier (log-rank) survival estimates from the time of definitive surgery, with uni-/multivariate analyses (Cox) of sarcoma-specific survival were performed. A total of 106 patients (60.4% male; median age 46 years) with NONE-STS of bone were identified. Common histologies included undifferentiated pleomorphic sarcoma [UPS]/malignant fibrous histiocytoma [MFH] (UPS/MFH, 41.5%), leiomyosarcoma (LMS, 20.8%), and fibrosarcoma (FS, 11.3%). Tumors were often high grade (59.4%) and involved the extremities (88.7%), with most receiving chemotherapy (67.9%) with cisplatin/doxorubicin-based regimens (73.6%). In the full cohort, 10-year DFS (45.7%, [95%CI: 35.7-55.8%]), OS (53.4%, [95%CI: 41.7-62.2%]), and SSS (63.9%, [95%CI: 53.9-72.5%]) were moderate. Histology specific, 10-year SSS was 70.7% [95%CI: 56.1-85.5%] for UPS/MFH, 51.8% [95%CI: 29.8-73.8%] for LMS, and 72.2% [95%CI: 45.1-99.2%] for FS. Only UPS/MFH (n = 4) showed sarcoma-related death >10 years. Multivariate analysis identified axial location (HR = 35.5, [95%CI: 3.4-369.6]), high grade (HR = 16.9, [95%CI: 1.6-185.1]), and disease relapse (HR = 485.1, [95%CI: 36.3-6482.6]) as risk factors for death (p < 0.05). Treatment with chemotherapy (HR = 0.1, [95%CI: 0.01-0.86]) and necrosis ≥85% (HR = 0.2, [95%CI: 0.04-0.99]) showed improved survival (p < 0.05). NONE-STS of bone has favorable long-term survival similar to osteosarcoma. Patients receiving chemotherapy derive benefit in retrospective analyses. UPS/MFH histologies show sarcoma-related death beyond 10 years. Further data on histologic subgroups are needed.

Epithelioid and spindle cell rhabdomyosarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusion: report of two cases.

The WHO Classification of Tumors of Soft Tissue and Bone divides rhabdomyosarcoma (RMS) into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing types. Advances in molecular diagnostics have allowed for further refinement of RMS classification including the identification of new subtypes. Very rare RMS with epithelioid and spindle cell morphology, female predominance, marked osseous predilection, ALK expression, EWSR1/FUS-TFCP2 gene fusions, and highly aggressive clinical behavior have recently been recognized with only 23 cases reported in the English language literature. Herein, we report two additional cases with detailed clinicopathologic description and molecular confirmation. In brief, two young women presented each with a primary bone tumor-one with a frontal bone tumor and another with an osseous pelvic tumor. Both tumors showed epithelioid to spindle cell morphology, ALK expression, and EWSR1/FUS-TFCP2 gene fusions. Both patients died of disease less than 17 months from diagnosis despite administration of multiple lines of aggressive treatment. In addition, we review the literature and discuss differential diagnostic and potential treatment considerations.