Manik Amin

Platelet distribution width (PDW) is increased in vaso-occlusive crisis in sickle cell disease

Considering the multigenic and multifactorial nature of the disease, we argue that a generalized bone marrow hyperplasia—and not merely erythroid hyperplasia—will occur in sickle cell disease. Consequently, we expect the hematological parameters to depict erythroid, myeloid as well as megakaryocyte hyperplasia. In the light of this expectation, we hypothesized that platelet distribution width (PDW) will increase in sickle cell disease. Here, we report the results from a cross-sectional study of 216 children admitted with complaints suggestive of vaso-occlusive crisis. We observed a strong association between PDW and sickle cell disease as compared to children who had HbAA genotype. Our findings bridge previous inconsistencies relating to the role of platelets in sickle cell disease. Implications of this finding are discussed.

A simple method to combine multiple molecular biomarkers for dichotomous diagnostic classification

BackgroundIn spite of the recognized diagnostic potential of biomarkers, the quest for squelching noise and wringing in information from a given set of biomarkers continues. Here, we suggest a statistical algorithm that – assuming each molecular biomarker to be a diagnostic test – enriches the diagnostic performance of an optimized set of independent biomarkers employing established statistical techniques. We validated the proposed algorithm using several simulation datasets in addition to four publicly available real datasets that compared i) subjects having cancer with those without; ii) subjects with two different cancers; iii) subjects with two different types of one cancer; and iv) subjects with same cancer resulting in differential time to metastasis.ResultsOur algorithm comprises of three steps: estimating the area under the receiver operating characteristic curve for each biomarker, identifying a subset of biomarkers using linear regression and combining the chosen biomarkers using linear discriminant function analysis. Combining these established statistical methods that are available in most statistical packages, we observed that the diagnostic accuracy of our approach was 100%, 99.94%, 96.67% and 93.92% for the real datasets used in the study. These estimates were comparable to or better than the ones previously reported using alternative methods. In a synthetic dataset, we also observed that all the biomarkers chosen by our algorithm were indeed truly differentially expressed.ConclusionThe proposed algorithm can be used for accurate diagnosis in the setting of dichotomous classification of disease states.

Immunotherapy in gastrointestinal cancers

Gastrointestinal (GI) cancers such as gastric, esophageal, pancreas, hepatobiliary, colorectal and anal cancers are a major cause of cancer related mortality worldwide. Traditional treatment options such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and anti-angiogenic agents have been the backbone of treatment of GI cancers in various stages. Current cancer research is moving forward to incorporate immunotherapies in the treatment of GI cancers either as single agent or in combination with current available treatment modalities. This review summarizes the existing and ongoing immunotherapies in the treatment of GI cancers.

Insights into age- and sickle-cell-disease- interaction using principal components analysis

BackgroundIn the context of sickle cell anemia, peripheral blood indexes provide key information that is also potentially influenced by age. Therefore, it is necessary to understand the extent and nature of interactions between sickle cell anemia and age, especially in situations where there is a high prevalence of sickle cell anemia.MethodsIn a cross-sectional study of 374 subjects with varying hemoglobin S (HbS) status, we characterized the interaction between age and sickle hemoglobin using principal components analysis.ResultsFactor analysis in subjects with hemoglobin AA identified three orthogonal factors – normal erythropoiesis, presence of thalassemia and the aggregability potential of the blood. These three factors were differentially associated with hemoglobin status. Age influenced the association of factors #2 and #3 with hemoglobin status.ConclusionOur findings suggest that the interaction between age and hemoglobin status needs to be considered in both clinical and public health settings.

Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer

Background Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma. Methods A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment. Pacritinib 400 mg daily was administered orally continuously in 28 day cycles. Results The trial was discontinued prior to reaching the planned accrual due to an FDA hold on pacritinib and a lack of treatment benefit. Eleven patients were enrolled and seven were evaluated for response. Median baseline C-reactive protein level was 12.1 (2.1-147) mg/L. One patient had stable disease at eight weeks by RECIST criteria and six progressed. There were no grade 4 or 5 adverse events while patients were on study. The grade 2 and lower AE events experienced were consistent with prior pacritinib trials. Conclusions In seven evaluable patients there were no objective responses. The trial was discontinued prior to completing planned accrual based on a low likelihood that the progression free survival goal of 4 months would be met.

Phase 2 study of combination SPI-1620 with docetaxel as second-line advanced biliary tract cancer treatment

Background:This multicentre, open-label study evaluated the efficacy and safety of SPI-1620, an analogue of endothelin-1, administered in combination with docetaxel as second-line treatment for patients with advanced biliary tract cancer (ABTC).Methods:Eligible patients received continuous cycles of combination therapy with SPI-1620 (11 μg m−2) and docetaxel (75 mg m−2) intravenously every 3 weeks until disease progression (PD) or intolerable toxicity. Tumour response was evaluated using computed tomography or magnetic resonance imaging every 2 cycles (6 weeks). The primary efficacy end point was progression-free survival (PFS); secondary end points included overall response rate (ORR), duration of response, and overall survival (OS) that were estimated using the Kaplan–Meier method.Results:Of the 30 enrolled patients, 25 patients had qualifying events (PD or death), 1 patient was nonevaluable, and 4 patients were censored at the time of their last tumour assessment. Our primary end point of PFS ⩾5 months was not reached. Median PFS was 2.6 months (95% confidence interval (CI): 1.4–2.8), ranging from 0.7 to 8.4 months. The ORR was 10.3% (95% CI: 0.02–0.27). Eleven additional patients achieved stable disease. The OS was 4.87 months. The most common grade 3–4 toxicities were febrile neutropenia and neutropenia.Conclusions:The addition of docetaxel to SPI-1620 in second-line ABTC did not meet the pre-specified primary end point of PFS ⩾5 months in unselected patient population.

Systemic Therapy for Combined Hepatocellular-Cholangiocarcinoma: A Single-Institution Experience

Background: Combined hepatocellular-cholangiocarcinoma tumors (cHCC-CCA) are a heterogeneous group of rare malignancies that have no established optimal treatment. Patients and Methods: We identified patients with cHCC-CCA treated at a tertiary center and retrospectively examined their histology, interventions, and outcomes. We calculated disease control rate (DCR), disease progression, overall survival, and progression-free survival (PFS) between treatment subgroups. Results: A total of 123 patients were evaluable. Interventions included resection, locoregional therapy, transplant, chemotherapy, and targeted agents. Ultimately, 68 patients received systemic treatment-57 with gemcitabine plus either 5-fluoropyrimidine (5-FU) or a platinum combination. Disease progression was more common in the gemcitabine/5-FU group versus gemcitabine/platinum (P=.028), whereas DCR favored gemcitabine/platinum (78.4% vs 38.5%; P=.0143). Median PFS from time of initial diagnosis favored the gemcitabine/platinum group, but the difference did not reach statistical significance. Targeted agents had minimal to no effect on survival metrics. Conclusions: Gemcitabine/platinum seems to be a superior regimen for patients with cHCC-CCA who require systemic treatment. Further studies are needed to clarify the regimens efficacy and applicability in patient subgroups.

Prospective phase I study of nab-paclitaxel plus gemcitabine with concurrent MR-guided IMRT in patients with locally advanced or borderline resectable pancreatic cancer.

TPS480 Background: Radiotherapy (RT) for locally advanced and borderline resectable pancreatic cancer (LABPC) is controversial as potential local control benefits are often obscured by high rates of distant progression. However, local failure remains a significant cause of morbidity among patients without distant progression after initial chemotherapy, although toxicity concerns may limit delivery of optimal systemic therapy concurrent with RT. Given known systemic efficacy and radiosensitization effects of nab-paclitaxel (A) with gemcitabine (G), we initiated a phase I study of nab-paclitaxel with gemcitabine (AG) and concurrent intensity modulated radiation therapy with magnetic resonance guidance (MR-IMRT) for LABPC. Methods: A planned 24 patients with LABPC will be enrolled to a phase I dose escalation trial using the Time-to-Event Continual Reassessment Method (TITE-CRM) design. Following one lead-in cycle of GA, MR-IMRT is administered daily with concurrent weekly GA for a total of 25 fractions in 5...

A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

TPS471 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single i...

Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer.

763 Background: Despite clinical success of VEGF blockade in mCRC, resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in resistance development to anti-angiogenic therapy. Levocetirizine is a third generation antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850mg/m2 – 7 days on and 7 days off, IV bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily in 14 day cycles. The primary end point was PFS and secondary endpoints included ORR and tolerability. An exploratory endpoint included correlation of PFS with cytokine (IL-8 & IL-6) levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 ...