t(1:14) and trisomy 4 in a patient with concomitant leukaemias.

Cytogenetic abnormalities have long been recognized as the genetic basis of the occurrence of various malignancies. Specific cytogenetic abnormalities have shown to occur recurrently in particular subtypes of leukaemias and lymphomas. t(1;14) is an infrequently occurring recurrent chromosomal translocation that has been described in literature to be associated with haematological malignancies. Trisomy 4 is another rare genetic abnormality which has been reported in association with both acute myeloid and lymphoid leukaemias. The concomitant occurrence of a myeloid malignancy in association with a lymphoproliferative disorder is a distinctly unusual phenomenon. We report the case of a young patient with concomitant T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia with a novel cytogenetic abnormality i.e. t(1;14) with trisomy 4. We believe this is the first reported case where a patient with two concomitant haematological malignancies, harboured this karyotype.

Single centre study of using bendamustine in the treatment of B-cell malignancies.

OBJECTIVE: To evaluate the experience of bendamustine in the treatment of B-cell malignancies at a tertiary care centre. METHODS: The retrospective descriptive analysis included data of all adult patients with B-cell malignancies treated with bendamustine from 2009 to 2011 at the Aga Khan University Hospital, Karachi. Data was analysed using SPSS 17.0. Frequencies and percentages were computed for baseline characteristics, responses and toxicities. RESULTS: Of the 19 patients 15 (79%) were males and 4 (21%) were females.The mean age was 59.53+/-12.14 (with a range of 46-86). Eight (42%) had follicular lymphoma, 6 (32%) had mantle cell lymphoma, 2 (11%) had diffuse large B-cell lymphoma, and 3 (16%) had chronic lymphocytic leukaemia. Four (21%) patients experienced grades 3 and 4 cutaneous toxicities. Eight (42%) patients were treated with bendamustine as first-line therapy. Six of them (75%) were included for response evaluation; 3 (50%) had complete response, and 3 (50%) had partial response. Eleven (58%) patients had relapsed disease out of which 3 (27.27%) had complete response, and 7 (63.63%) had partial response, whereas 1 (9%) had disease progression. CONCLUSION: Bendamustine given as monotherapy or in combination is safe and useful in the treatment of patients with B-cell malignancies.

A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) and 5-FU based chemotherapy regimens in Pakistani adult cancer patients at Shaukat Khanum Memorial Cancer Hospital & Research Center.

OBJECTIVE: To study cardiotoxicities, especially bradycardia in cancer patients treated with 5-Fluouracil and 5-Fluouracil based chemotherapy regimens in Pakistani population. METHODS: Data was extracted from the medical records of all diagnosed cancer patients at Shaukat Khanum Memorial Cancer Hospital and Research Center registered between January 2002 and December 2004 receiving 5- Fluouracil based chemotherapy regimens. The data was analysed retrospectively, including electrocardiogram and cardiac markers. Pearson's Correlation coefficient was calculated to see any possible correlation between 5-Fluouracil alone and 5-Fluouracil based regimens and cardiotoxicity, and other variables. RESULTS: Symptomatic cardiotoxicity was observed in 60 (19.93%) out of 301 patients whose cases were part of the study. Bradycardia was the most common cardiotoxicity and was observed in 36 (11.96%) patients. Nine (2.99%) mortalities were also observed. The incidence of cardiotoxicity was not significantly different between the patients with and without pre-existing cardiovascular disease (p = 0.095) and having negative correlation - 0.305. Cardiotoxicities were more common with Continuous Infusion (CI) of 5-Fluouracil, radiotherapy concurrent with 5-Fluouracil and when 5-Fluouracil was used in combination with Cisplatinum (CDDP). CONCLUSION: Cardiotoxicities were more prevalent when 5-Fluouracil was used along with concurrent radiotherapy and with Cisplatinum and when administered in continuous infusion pattern. Hence, 5-Fluouracil and 5-Fluouracil based chemotherapy regimens cause cardiotoxicities, especially bradycardia, in a significant number of cancer patients in Pakistani population.

Psychosocial impact of cancer on adult patients.

OBJECTIVES: To explore the effects of cancer on psychosocial aspects of Pakistani patients and their families, assessing the need for interventions to improve their quality of life. METHODS: A prospective, Cross-sectional study was performed on 200 patients visiting the oncology outpatient facility of AKUH from December 2010 to May 2011 through an interview. Responses were recorded on pre-designed questionnaires including FACT-G QOL (Functional Assessment of Cancer Therapy-General Quality Of Life) component. RESULTS: Out of the 200 patients 52 (26%) were males and 148 (74%) were females. Mean age was 51.8 +/- 14.2 years. Breast cancer accounted for the commonest cancer in females 116 (58%) and lung in males 30 (15%), 100 (50%) patients were currently undergoing chemotherapy. In all 148 (74%) patients were well aware of their diagnosis and were able to cope better and 142 (71%) were well supported by families (majority being financially stable). Major financial impact was found in 42 (21%) cases. Religious/spiritual help was sought by 138 (69%) patients predominantly females- 113 (76%) and 22 (11%) patients consulted a psychiatrist; 20 (94%) subjects of this group felt this intervention was helpful. Responses regarding effect on the patient's sexual life were poor and 126 (63%) denied answering the question. CONCLUSION: In our study one third of cancer patients were found to be depressed mainly affecting those who were receiving multimodality treatment or facing financial issues. Religious help was the main coping strategy for them.

Four year experience of sarcoma of soft tissues and bones in a tertiary care hospital and review of literature.

BACKGROUND: Sarcoma encompasses an uncommon group of cancer and the data is insufficient from Pakistan. We report our four years experience of Sarcoma of soft tissues and bones. METHODS: This cross sectional study was carried out at Aga Khan University Hospital from 2004 to 2008. The patients were divided into two groups from the outset i.e. initially diagnosed and relapsed group and separate sub group analysis was conducted. RESULTS: Out of 93 newly diagnosed patients, 58 belonged to bone sarcoma and 35 to soft tissue sarcoma group. While for relapsed patients, 5 had soft tissue sarcoma and 9 had bone sarcoma. Mean age was 32.5 years. At presentation, approximately two third patients had localised disease while remaining one third had metastatic disease. The Kaplan Meier estimate of median recurrence free survival was 25 months, 35 months, and 44 months for Osteogenic sarcoma, Ewing's sarcoma and Chondrosarcoma respectively. For Leiomyosarcoma and Synovial sarcoma, it was 20 and 19 months respectively. The grade of the tumour (p = 0.02) and surgical margin status (p = 0.001) were statistically significant for determination of relapse of disease. CONCLUSION: The median recurrence free survival of patients in our study was comparable to the reported literature but with significant lost to follow rate. Further large-scale, multi centre studies are needed to have a more comprehensive understanding of this heterogeneous disease in our population.

Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial.

INTRODUCTION: Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy. METHODS: This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated. RESULTS: A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42-63) and 92% (95% CI: 84-96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5-not reached) months. CONCLUSIONS: Almonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.

Old disease, new targets--part-I, solid malignancies.

Targeted agents are now an integral part of treatment regimens for some cancers. Trastuzumab is established in treatment of human epidermal receptor 2 (Her2) positive breast cancers, with improvements in both, the disease free and over all survival. Monoclonal antibody (MoAB) against vascular growth factor receptor (VEGF), bevacizumab and cetuximab a MoAB against epidermal growth factor receptor (EGFR) are establishing their role in a many cancers after making their mark in colorectal cancer. Sorafenib and sunitinib have success stories in renal carcinoma. The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial has established sorafenib role in advanced hepatocellular carcinoma, while in gastrointestinal tumors; imatinib and sunitinib have proven role. At this point in time side effect profile of all these agents appears relatively safe however cost for developing countries remains an issue.

Old disease, new targets. Part-II, haematological malignancies.

In last two decades newer therapies in cancer treatment have emerged and have opened new horizons. New term of targeted therapy has emerged and for certain malignancies the paradigm has really changed after the introduction of these agents. We have learnt and have seen the outcome of some diseases after the addition of these monoclonal antibodies (MoABs) and tyrosine kinase inhibitors (TKIs). Rituximab a MoAB against CD-20 has really paved its role in the treatment of B-cell lymphomas and become the sort of standard therapy. The TKIs are newer agents available in a pill form and have inhibited many pathways at cellular level which are necessary for cancer development. Imatinib has really changed the prognosis and outcome of chronic myeloid leukemia (CML) remarkably. For those patients who develope intolerance to imatinib or their disease became resistant to the imatinib the newer agents like dasatinib and nilotinib are second line options. The major edge of these newer agents is more potency with low side-effect profile. The major concern remains the cost.

Knowledge, attitude and preventive practices for breast cancer among health care professionals at Aga Khan Hospital Karachi.

OBJECTIVE: To assess the knowledge and practice of risk factors, symptoms and screening for breast cancer among health care professionals. METHODS: A cross sectional study was carried out at The Aga Khan University Hospital from January 2008 to March 2008. A total of 336 health care workers including consultants (48), fellows (17), residents (76), medical officers (14), interns (37), nurses (94) and fourth and final year medical students (50) were requested to fill a questionnaire designed to assess the knowledge about the risk factors, signs and symptoms, screening tools, breast self examination (BSE) and treatment. RESULTS: More than two third participants had good knowledge about the risk factors and signs of breast cancer except some dissociation regarding association of menarche status and smoking. Majority was aware of the benefits of mammography. More than 80% had the consensus that breast cancer is curable if detected early and more than 50% thought that a surgeon should be consulted first if lump is palpable. CONCLUSIONS: This study reveals that health care professionals have fairly good awareness regarding the risk factors, symptoms and role of mammography. But some are still deficient in their knowledge regarding screening modalities and BSE method and time and role of chemotherapy. And this can be improved with further education.

Determination of complication rate of PICC lines in oncological patients.

OBJECTIVE: To determine the complication rate of (PICCs) peripherally inserted central catheters in cancer patients with a 1 year prospective cohort study. METHODS: All PICCs inserted in adult cancer patients in Radiology Department of The Aga Khan University Hospital were followed prospectively till removed or patient expired and pattern of complications noted. RESULTS: One hundred and fourty six PICCs were inserted over a period of 1 year and followed for a total of 3329 catheter-days; median placement, 14 days: range 3-218 days. Of these 67 (32.8%) PICCs were complicated and removed earlier, for a rate of 14.4/1000 PICC-days. Patients with haematologic malignancies were more likely to have complications as compared to those with solid tissue malignancies. CONCLUSIONS: Despite a significant complication rate, PICCs are a relatively safe and cost effective method of establishing central venous access.

Primary cutaneous B cell lymphoma--leg type (NEW EORTC--WHO classification), with nasal sinuses involvement.

Primary Cutaneous lymphomas of B cell origin are rare, there remains a controversy in truly classifying these lymphomas and an updated EORTC classification divides them on the basis of their distinct histopthological grounds rather than on the basis of their anatomic location as in WHO classification, while the new WHO- EORTC joint classification maintains some characteristics of both systems, We report an elderly gentleman who primarily had a typical Leg dominant Cutaneous lymphoma of B cell origin uniquely with involvement of nasal Sinusues, bearing the Immunohistochemical staining features of "Cutaneous lymphoma - Leg Type" befitting the new joint WHO-EORTC classification of Cutaneous B cell Lymphoma.

Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study.

BACKGROUND: In patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC), outcomes with first-line chemotherapies are improved by adding weekly cetuximab. The APEC study investigated first-line once-every-2-weeks cetuximab plus chemotherapy for patients with KRAS wt mCRC; additional biomarker subgroups were also analyzed. PATIENTS AND METHODS: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated. RESULTS: In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations. CONCLUSION: The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.

5-Fluorouracil-induced vasculitic injury manifesting as a multiorgan dysfunction in a patient with esophageal carcinoma.

5-Fluorouracil (5-FU) is an active chemoetheraputic agent in many malignancies, used both in the curative and metastatic setting. Therefore, the side effect profile of 5-FU is well-described and recognized. Here, we present a case of a 28-year-old male, who received 5-FU and carboplatin concurrently, with radiation, for esophageal carcinoma. On Day 3 of his 5-FU infusion, he developed simultaneous cardiac arrhythmias, renal dysfunction, and aphasia. Magnetic resonance imaging (MRI) of his brain revealed acute demyelination of the white matter corresponding to diffusion restriction, pointing toward a small vessel injury. The 5-FU infusion was promptly discontinued and stress dose steroids were administered. The patient's symptoms resolved rapidly with no residual effects. We believe this is the first case of multisystem, small-vessel, vasculopathy secondary to 5-FU. Early recognition and prompt discontinuation of the offending drug is essential for resolution of symptoms. Steroids, with their anti-inflammatory effects can aid in rapid recovery.

Plasmablastic lymphoma of the oral cavity with breast recurrence: a case report.

BACKGROUND: Plasmablastic lymphoma is an aggressive variant of diffuse large B cell lymphoma, mostly found in the oral cavity and associated with human immunodeficiency virus. There are no clear guidelines for its treatment. Therapies more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone are not associated with a prolonged survival. Lymphomas of the breast are rare, in one series representing 0.14% of all female breast malignancies, with diffuse large B cell lymphoma comprising up to 55% of all cases. Only one case of plasmablastic lymphoma involving the breast has been reported in the literature. CASE PRESENTATION: A 30 year old Pakistani woman, presented with a small nodule in the floor of the mouth. An excisional biopsy revealed CD20, CD3, and CD117 negative and CD138, CD79a, CD56, MUM1/IFR4 and CD30 positive lesion with Ki-67 of 60% with cells which were plasmablastic in appearance. The morphological and immunohistochemistry features were consistent with plasmablastic lymphoma. The staging scans did not reveal any lymphadenopathy and the bone marrow biopsy and human immunodeficiency virus test were both negative. After treatment with four courses of CHOP and later radiation to the floor of the mouth, her disease was in complete remission. Two months later, she presented with velvety red lesions in both breasts and its trucut biopsy was consistent with plasmablastic lymphoma. Her CT scans revealed multiple nodules involving both breasts with no lymphadenopathy. The bone marrow was now positive for disease. Her disease continued to progress despite second and third line chemotherapy with DHAP (dexamethasone, cisplatin and cytarabine) and ICE (ifosfamide, carboplatin and etoposide) respectively. Her last CT scans revealed progressive disease with new lung lesions. The patient decided to opt for best supportive care. CONCLUSION: To our knowledge this is the second report of plasmablastic lymphoma involving the breast. The patient who was human immunodeficiency virus negative and immune competent had progressive disease despite three lines of chemotherapies with an overall survival (to date) of 15 months.

Frequency and Outcome of Graft versus Host Disease after Stem Cell Transplantation: A Six-Year Experience from a Tertiary Care Center in Pakistan.

Objective. The objective of this study was to evaluate the frequency and outcome of graft versus host disease after stem cell transplantation for various haematological disorders in Pakistan. Materials and Methods. Pretransplant workup of the patient and donor was performed. Mobilization was done with G-CSF 300 µ g twice daily for five day. Standard GvHD prophylaxis was done with methotrexate 15 mg/m(2) on day +1 followed by 10 mg/m(2) on days +3 and +6 and cyclosporine. Grading was done according to the Glucksberg classification. Results. A total of 153 transplants were done from April 2004 to December 2011. Out of these were allogeneic transplants. There were females and males. The overall frequency of any degree of graft versus host disease was 34%. Acute GvHD was present in patients while had chronic GvHD. Grade II GvHD was present in patients while grade III and IV GvHD was seen in patients each. Acute myeloid leukemia and chronic myeloid leukemia were most commonly associated with GvHD. The mortality in acute and chronic GvHD was 8.8% and 12% respectively. Conclusion. The frequency of graft versus host disease in this study was 34% which is lower compared to international literature. The decreased incidence can be attributed to reduced diversity of histocompatibility antigens in our population.

Successful engraftment and survival following allogeneic hematopoietic stem cell transplant in a child with familial hemophagocytic lymphohistiocytosis.

Hemophagocytic syndrome is a rare disorder mainly affecting children. Symptoms include prolonged fever, hepatosplenomegaly and cytopenias. Allogeneic stem cell transplant appears to provide the best overall cure rate in this disease. The authors report a young boy, the second child of consanguineous parents, diagnosed with familial hemophagocytic lymphohistiocytosis (HLH) who underwent allogeneic stem cell transplant form HLA matched father.

Impact of unplanned excision on prognosis of patients with extremity soft tissue sarcoma.

Unplanned excision of soft tissue sarcomas (STSs) outside comprehensive tumor management centers necessitates the need for wide reexcision to achieve adequate margins. We retrospectively reviewed medical records of 135 patients with STS operated at our hospital with the goal of examining outcomes, in terms of local recurrence (LR) and metastasis rate (MR), of reexcision following unplanned excision of STS and comparing results with those of first-time planned surgery. Eighty-four patients had their first-time surgery and 51 patients had come to us following unplanned excision at prereferral hospital. Mean age of all patients was 41.8 ± 21.9 years. The LR and MR was 14.3% and 8.3%, respectively, in patients undergoing first resection, whereas it was 21.4% and 13.7%, respectively, in patients undergoing revision surgery. Average duration from previous unplanned excision was 8 months. Twelve patients were referred immediately after excised specimen revealed STS, while 39 patients presented after evident local recurrence. Wide reexcision was attempted in 48 patients while three patients need amputation. Adjuvant radiotherapy was administered in all patients undergoing limb-sparing surgery. Ten patients needed adjuvant chemotherapy. We conclude that wide reexcision of STS has poorer outcomes compared to planned excision. Therefore, patients with soft tissue masses should be managed by multidisciplinary oncology team at specialized cancer centers.

Temozolomide for relapsed primary CNS lymphoma.

Primary CNS lymphoma (PCNSL) is an aggressive form of non-Hodgkin's lymphoma that accounts for 3% of all primary brain tumours. No clear risk factors for PCNSL in immunocompetent patients are known. The disease is more common in men and in elderly persons. Patients with AIDS who have low CD4+ counts are at the greatest risk for PCNSL. Virtually all PCNSLs in patients with AIDS express an Epstein-Barr virus (EBV)-related genome. PCNSL is less frequently associated with EBV in patients without AIDS. A 42 years old gentleman diagnosed with primary CNS lymphoma with negative serological test for human immunodeficiency virus was initially treated with Modified De Angelis protocol relapsed after treatment. He underwent gamma knife stereotactic surgery which lead to further deterioration clinically and progression of disease on imaging. Later, he was treated with salvage high dose methotrexate, but after completion of six cycles there was a radiological progression of disease. Relapsed disease was further treated with a single agent temozolomide and the disease went in remission.

Allogeneic stem cell transplantation in acute myeloid leukemia.

We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients). Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

Breast carcinoma with asymptomatic metastasis to the gallbladder.

The biliary tract is an unusual site of metastasis from breast carcinoma, and this has rarely been reported in the literature. We report the case of a 42-year-old woman diagnosed with invasive lobular carcinoma of the breast who underwent laparoscopic cholecystectomy for an incidental finding of gallbladder wall thickening on ultrasonography, which was subsequently confirmed to be consistent with metastasis from the breast primary.