Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer.

CONTEXT: Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies. AIMS: To determine the safety, dose-limiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD). SETTINGS AND DESIGN: Phase 1, open-label, dose-escalation study in men and women ≥18 years of age. MATERIALS AND METHODS: An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD). STATISTICAL ANALYSIS USED: All data summaries were descriptive. PK parameters were estimated using compartmental analysis. RESULTS: 25 patients (16 male, 9 female, 26-66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days. CONCLUSIONS: 2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.

Pattern of bloodstream infections in patients with hematological malignancies in a tertiary care centre.

BACKGROUND: The purpose of our study was to evaluate the clinical characteristics, to understand the pattern of bloodstream infections (BSIs), and to determine the risk factors contributing to high-risk febrile neutropenia in patients with hematological malignancy. MATERIALS AND METHODS: A comprehensive review of retrospective data was done from 2004 till 2012 from a single center. RESULTS: There were total 171 consecutive febrile episodes with 103 acute lymphoblastic leukemia (ALL) patients and 63 acute myeloid leukemia (AML) patients. The highest number of febrile neutropenia episodes occurred during ALL and AML induction followed by consolidation treatment with high-dose cytarabine. In our study population, the most common organisms isolated were Gram-positive (20%) followed by Gram-negative (6.4%) organisms. The incidence of fungal sepsis was only 3%. In our study, it was seen that the recovery from febrile neutropenia depends upon the disease, ALL recovered rapidly compared to AML (P < 0.001) and also the on the phase of treatment, i.e consolidation recovered earlier than induction (P < 0.001). There was no death recorded in this study population during febrile neutropenia. CONCLUSIONS: The incidence of febrile neutropenia depends upon the type of haematological malignancy and the aggressiveness of therapy required treating the disease especially during induction. The improvement in antimicrobial coverage and its prompt use leads to the selective growth of Gram-positive organisms.

Report of chronic myelogenous leukemia in chronic phase from, Asian Institute of Oncology, Mumbai, 2002-2010.

Chronic myeloid leukemia (CML) has paradigm shift in its treatment modality after the discovery of targeted therapy Imatinib. At our centre we collected data of 100 consecutive patients over a period of 8 years. The interesting finding in our study was difference in the survival of patients presenting in early chronic phase (81%) versus late chronic phase (16%). Also the patients with primary resistance did poorly compared to the patients who developed secondary resistance to Imatinib.

Targeting mTOR pathway: A new concept in cancer therapy.

This article highlights the current knowledge of mTOR biology and provides new insights into the role of mTOR in different cancers. An active mTOR coordinates a response in cell growth directly through its effects on cell cycle regulators and indirectly by sustaining nutrient supply into the cell through the production of nutrient transporters and also through the promotion of angiogenesis. A primary way that mTOR exerts its regulatory effects on cell proliferation is by controlling the production of cyclin D1. mTOR increases the translation of hypoxia-inducible factor 1 (HIF-1)/HIF-2. The HIF transcription factors drive the expression of hypoxic stress response genes, including angiogenic growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor ß (PDGF-ß), and transforming growth factor a (TGF-α). mTOR also increases the surface expression of nutrient transporters proteins. An increase in these proteins results in greater uptake of amino acids and other nutrients by the cell leading to adequate nutrient support to abnormal cell growth and survival. There is also emerging evidence that mTOR activation may play a role in promoting cell survival through the activation of antiapoptotic proteins that contribute to tumor progression. Given that the mTOR pathway is deregulated in a number of cancers, it is anticipated that mTOR inhibitors will have broad therapeutic application across many tumor types. Until now, no treatment demonstrated Phase III evidence after disease progression on an initial VEGF-targeted therapy in advanced renal cell carcinoma. Everolimus is the first and only therapy with Phase III evidence after failure of VEGF-targeted therapy. Everolimus is a once-daily, oral inhibitor of mTOR (mammalian target of rapamycin) indicated for the treatment of advanced renal cell carcinoma in patients, whose disease has progressed on or after treatment with VEGF-targeted therapy.

Granulocyte colony-stimulating factor (filgrastim) in chemotherapy-induced febrile neutropenia.

BACKGROUND: The use of granulocyte colony-stimulating factors to treat patients with chemotherapy-induced neutropenia is well accepted. To assess whether administration of filgrastim along with standard empiric antibiotic therapy is beneficial for patients with chemotherapy-induced febrile neutropenia (FN), we conducted an open, non-randomized clinical trial. MATERIALS AND METHODS: This was a prospective, open, Phase IV clinical trial in patients receiving chemotherapy for histologically confirmed cancer, with an oral temperature of >38.2°C and absolute neutrophil count (ANC) of <500/mm (3). Filgrastim was administered subcutaneously in a dose of 5 mcg/kg/day, 24 hours after administration of cytotoxic therapy, for up to two weeks or until the ANC reached 10,000 cells/mm (3). The parameters of assessment included duration of neutropenia, fever, hospitalization and antibiotic usage. RESULTS: All 24 evaluable patients recovered from neutropenia, fever and FN in a median duration of two days. This result is similar to that reported in earlier studies with filgrastim. Despite the acceleration in recovery from neutropenia and fever, it also reduced the duration of hospital stay and usage of intravenous (IV) antibiotic. Only two adverse events were reported, which were of mild nature. CONCLUSION: Filgrastim, when used in patients with chemotherapy-induced neutropenia, exhibited efficacy in accelerating the recovery from neutropenia and fever comparable to that reported with filgrastim in literature. The data from this study suggest that filgrastim is effective in the treatment of chemotherapy-induced neutropenia and is well tolerated by Indian patients.

Safe and efficacious use of procedural sedation and analgesia by non-anesthesiologists in a pediatric hematology-oncology unit.

BACKGROUND: Children often require relief of pain and anxiety while undergoing diagnostic and therapeutic procedures. Procedural sedation and analgesia (PSA) is the safe and effective control of pain, anxiety and motion so as to allow a necessary procedure to be performed and to provide an appropriate degree of memory loss or decreased awareness. OBJECTIVE: To prospectively describe procedural sedation and analgesia as performed in the pediatric oncology unit and to report the success of sedation and the incidence of complications. METHODS: IV Midazolam and IV Ketamine were used for PSA in pediatric oncology patients undergoing painful procedures. RESULTS: Between June 2004 and December 2004, 55 diagnostic and therapeutic procedures were performed using PSA in 16 children. There were 9 boys and 7 girls with a median age of 11 years. Twelve patients had hematolymphoid malignancies and 4 patients had solid tumors. The indication for PSA were bone marrow aspiration and or biopsy in 7 patients, therapeutic lumbar puncture in 43 patients, bone marrow aspiration and lumbar puncture in 4 patients and skin biopsy in 1 patient. All 55 procedures were successfully completed. Adverse events occurred in 15 (27%) episodes and included transient drop in oxygen saturation, vomiting, dizziness and disinhibition with crying spells. Average time to arousable state and full recovery was 22 minutes and 31 minutes respectively. None of the patients complained of post procedure pain nor recalled the procedure at the follow up visit. CONCLUSION: Procedural sedation and analgesia using midazolam and ketamine is a safe and efficient method of limiting anxiety and procedure related pain and can be successfully administered by non-anaesthesiologists. The complication rate is low and can be easily managed.

Impaired cell motility in chronic myeloid leukemic granulocytes related to altered cytoskeletal pattern.

The bactericidal activity of polymorphonuclear leucocyte (PMNL) against infection stimulates cytoskeletal changes accompanied with alteration in adhesion and locomotion. Microfilaments, the motile apparatus is known to regulate these changes by polymerization of monomeric G-actin to fibrous F-actin. PMNL from chronic myeloid leukemia (CML) patients have been reported to be defective in locomotion in response to synthetic peptide, n-formyl-methionyl-leucyl-phenylalanine (fMLP) but the mechanism leading to defective locomotion and their spatial reorganization remains unclear. Therefore, in order to study the cause of defective motility of PMNL from CML patients the spatial distribution and reorganization of microfilaments and microtubules in response to fMLP have been examined by transmission electron (TEM) and scanning electron microscopy (SEM). Under SEM, the PMNL-CML surface appeared smoother with reduced ruffling resulting in rounding off cells with lesser polarized morphology. Unstimulated PMNL from normal as well as CML subjects showed shorter and fewer microtubules and evenly distributed microfilaments as compared to fMLP stimulated PMNL. It is proposed that the cause of defective locomotion was due to reduced surface activity as a consequence of altered cytoskeletal configuration. This phenomenon seems to be related to impaired functional appendages and as a whole led to the defective cell motility and hence reduced chemotaxis in PMNL from CML patients.

Primary non-Hodgkin's lymphoma of the spleen presenting as space occupying lesion: a case report and review of literature.

Primary splenic lymphoma (PSL) is rare with a reported incidence of less than 1%. Diffuse large cell pathology has been reported in 22-23% of the cases and is felt to have poor outcome. This study reports a 50 year old male who presented with fever and weakness. He was found to have a mass lesion in the spleen documented by CT scan. A splenectomy was performed which showed non-Hodgkin's lymphoma. Immunohistological studies showed a positivity for CD20 and CD30.

Myelomatous pleural effusion.

Serous effusions in multiple myeloma are uncommon but a myelomatous pleural effusion occurring in these patients is extremely rare. Here we report a rare case of a 38 years lady who was diagnosed to have multiple myeloma and subsequently developed pleural effusion. The myelomatous nature of the effusion was first diagnosed on cytology and subsequently confirmed by a pleural biopsy. The pleural effusion showed an initial response to chemotherapy but subsequently recurred.

First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study.

BACKGROUND: This randomized, phase III study compared the efficacy and safety of first-line gemcitabine versus epirubicin in the treatment of postmenopausal women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients aged > or = 60 years (median 68 years) with clinically measurable MBC received either gemcitabine 1200 mg/m(2) or epirubicin 35 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. RESULTS: Of 410 patients entered, 397 (198 gemcitabine and 199 epirubicin) were randomized and qualified for the time to progressive disease (TTP) and survival analyses. Total cycles administered in 185 gemcitabine and 192 epirubicin patients, respectively, were 699 (mean 3.5, range 0-12) and 917 (mean 4.6, range 0-10). Epirubicin demonstrated statistically significant superiority in TTP (6.1 and 3.4 months, P=0.0001), overall survival (19.1 and 11.8 months, P=0.0004), and independently assessed response rate (40.3% and 16.4% in 186 and 183 evaluable patients, P <0.001). For gemcitabine (n=190) and epirubicin (n=192), respectively, common WHO grade 3/4 toxicities were neutropenia (25.3% and 17.9%) and leukopenia (14.3% and 19.3%). Of the 28 on-study deaths (17 gemcitabine, 11 epirubicin), three were considered possibly or probably related to treatment (gemcitabine). CONCLUSIONS: Postmenopausal women > or =60 years of age with MBC tolerate chemotherapy well. In this study, epirubicin was superior to gemcitabine in the treatment of MBC in women age > or =60, confirming that anthracyclines remain important drugs for first-line treatment of MBC.

Cumulative risk and trends in prostate cancer incidence in Mumbai, India.

BACKGROUND: Information relating to cancer incidence trends in a community forms the scientific basis for the planning and organization of prevention, diagnosis and treatment of cancer. We here estimated the cumulative risk and trends in incidence of prostate cancer in Mumbai, India, using data collected by the Bombay Population-based Cancer Registry from the year 1986 to 2000. METHODS: During the 15 year period, a total of 2864 prostate cancer cases (4.7% of all male cancers and 2.4% of all cancers) were registered by the Bombay Population-based Cancer Registry. For evaluation of the trend, we applied a linear regression model based on the logarithm of the observed incidence rates. The annual percentage changes were also computed for the evaluation. Cumulative incidence rates percentages were calculated by adding up the age specific incidence rates at single ages and then expressed as a percentage. RESULTS: Analysis of the trends in age-adjusted incidence rates of prostate cancer during the period 1986 to 2000 showed no statistically significant increase or decrease and the rates proved stable across the various age groups (00-49, 50-69 and 70+) also. The probability estimates indicated that one out of every 59 men will contract a prostate cancer at some time in his whole life and 99% of the chance is after he reaches the age of 50. CONCLUSION: The stability in age adjusted-incidence rates indicates that there are no changes in the etiological factors for prostate cancer in Mumbai, India. These findings may be of general interest because changes in diagnostic practices are confounded in the time trends of prostate cancer change in many western countries preventing inferences on the changes in risk.

Oral cancers in Mumbai, India: a fifteen years perspective with respect to incidence trend and cumulative risk.

OBJECTIVE: We estimated the time trends in the incidence and the risk of developing an oral cancer in Mumbai, Indian population using the data collected by the Bombay Population Based Cancer Registry during the 15 year period from 1986 to 2000. METHODS: A total of 9,670 oral cancers (8.2% of all neoplasms) were registered, of which 6577 were in males and 3093 in females (10.7% and 5.4% of the respective totals for the two genders). For evaluation of the trend, we applied a linear regression model based on the logarithm of the observed incidence rates. The annual percentage changes were also computed for the incidence rates to evaluate the time trend. RESULTS: In males, a statistically significant decreasing trend in the overall age-adjusted incidence rates were observed during the period 1986 to 2000, with an yearly decrease of 1.70%. This decrease was significant for men above the age of 40, but for young adult men below the age of 40, there was no significant decrease, the level being stable. In females, the overall decreasing trend in the age-adjusted incidence rates of oral cancers was not significant, but in the age group 40-59, a significant decline was observed. The probability estimates indicated that one out of every 57 men and one out of every 95 women will contract any oral cancer at some time in their whole life and 97% of the chance is after he or she completes the age of 40. CONCLUSION: The observed decreasing trend in oral cancers in Indian men may be attributed to a decrease in the usage of pan and tobacco. The high prevalence of the usage of smokeless tobacco among young adult men and women may explain the stable trend in oral cancer incidence in this group. These findings help to strengthen the association between tobacco use and oral cancer risk.

Decreasing trend in the incidence of stomach cancer in Mumbai, India, during 1988 to 1999.

The time trend in incidence of stomach cancer in males and females in Mumbai, India during 1988 to 1999 was estimated using data collected by the Bombay Population-based Cancer Registry. During the 12-year period, a total of 3657 stomach cancer cases (3.9% of all cancers) were registered by the Bombay Population-based Cancer Registry of which 2467 (5.1% of all male cancers) were in males and 1184 (2.6% of all female cancers) in females. For evaluation of the trend, we applied a linear regression model based on the logarithm of the observed incidence rates. The annual percentage changes were also computed for the incidence rates for evaluating the time trend. A statistically significant decreasing trend in the overall age-adjusted incidence rates of stomach cancer was observed during the period 1988 to 1999, with an yearly decrease of 4.44% in males and 2.56% in females. This decrease was most striking in males in the age groups 40-59 and 60+, and in females only in the age group 40-59. The probability estimates indicated that one out of every 92 men and one out of every 187 women will contract a stomach cancer at some time in their whole life and 95% of the chance is after his or her 40th birthday. The decreasing trend in the age-adjusted incidence rates of stomach cancer in both the sexes indicates that there is a critical change in the etiology of this cancer. The findings may provide clues relating to various life-style and environmental changes impacting on stomach cancer incidence.

Activation of HHV-6 in lymphoproliferative disorders: a polymerase chain reaction-based study.

HHV-6 is a latent herpes virus persisting throughout the adult life of the infected host in an integrated form and is often activated in immunocompromised situations. Detection of HHV-6 DNA in the plasma of an individual indicates the presence of active viral replication in the host. Because lymphomas are known to be associated frequently with host immunosupression, we studied activation of HHV-6 in 98 patients diagnosed with Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL). HHV-6 activation was documented in 34% of cases of non-Hodgkin's lymphoma and 39% of those of Hodgkin's disease; however, no correlation of activation status with pathological types of Hodgkin's disease and between copy numbers in peripheral blood mononuclear cell DNA and the corresponding plasma DNA was noticeable.

Imatinib in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of gastrointestinal tract. The tumors express the cell surface transmembrane receptor KIT that has a tyrosine kinase activity and is a protein product of KIT protoeoncogene. These tumors occur in the whole of Gastrointestinal tract. Treatment includes surgical resection for localized tumors. For metastatic disease treatment options include systemic chemotherapy, radiation therapy, with a response rate of less than 10%. Presently Imatinib; a tyrosine kinase inhibitor has shown promising result with response rates upto 59-69% in phase II results in metastatic setting; and ongoing phase II & phase III trials in adjuvant setting will help to establish its role as an adjuvant to surgery. We have treated eleven patients of metastatic GIST with Imatinib and we hereby present these cases.

Benign multilocular cystic nephroma.

This article reports a case of cystic nephroma to bring awareness about the benign nature of this condition. The patient presented with a painless abdominal mass. Computed tomography showed a homogeneous, multicystic tumor of the superolateral portion of the left kidney with thin septa without solid parts. Histology confirmed the diagnosis of cystic nephroma.