A review of treatment options employed in relapsed/refractory AML.

INTRODUCTION: Acute myeloid leukemia [AML] is a heterogenous group of primary hematopoietic neoplasms arising from myeloid precursor cells. Up to 50% of patients failed to achieve remission with initial therapy and go on to develop refractory AML. Whenever possible, enrollment in a clinical trial in view of the paucity of evidence surrounding a clearly superior treatment modality is recommended, and the therapy which provides the best chance for cure post remission is allogeneic hematopoietic stem cell transplantation [HCT], with much of everyday clinical decision-making in relapsed/refractory (R/R) AML surrounding the choice of the least toxic regimen that could achieve remission and enable prompt HCT. DISCUSSION: We discuss a variety of treatment modalities employed in the R/R AML setting beginning with traditional cytotoxic regimens. We then turn our attention to targeted therapies that have shown efficacy in specific patient populations such as the IDH inhibitors and FLT3 inhibitors and lastly, we turn our attention to immunotherapeutic agents employed in the R/R in the setting, such as CD33 inhibitors and bispecific antibodies. CONCLUSION: It appears increasingly clear that approaching AML as a homogenous disease entity is unsatisfactory in view of the variations in such disease factors as cytogenetic and molecular markers, age, and disease severity at presentation; all of which contribute significantly to heterogeneity of the disease. Moving forward, treating AML would likely require tailored therapy following advances in technology such as molecular profiling, drug sensitivity and resistance testing.

Detection of lung cancer using weighted digital analysis of breath biomarkers.

BACKGROUND: A combination of biomarkers in a multivariate model may predict disease with greater accuracy than a single biomarker employed alone. We developed a non-linear method of multivariate analysis, weighted digital analysis (WDA), and evaluated its ability to predict lung cancer employing volatile biomarkers in the breath. METHODS: WDA generates a discriminant function to predict membership in disease vs no disease groups by determining weight, a cutoff value, and a sign for each predictor variable employed in the model. The weight of each predictor variable was the area under the curve (AUC) of the receiver operating characteristic (ROC) curve minus a fixed offset of 0.55, where the AUC was obtained by employing that predictor variable alone, as the sole marker of disease. The sign (+/-) was used to invert the predictor variable if a lower value indicated a higher probability of disease. When employed to predict the presence of a disease in a particular patient, the discriminant function was determined as the sum of the weights of all predictor variables that exceeded their cutoff values. The algorithm that generates the discriminant function is deterministic because parameters are calculated from each individual predictor variable without any optimization or adjustment. We employed WDA to re-evaluate data from a recent study of breath biomarkers of lung cancer, comprising the volatile organic compounds (VOCs) in the alveolar breath of 193 subjects with primary lung cancer and 211 controls with a negative chest CT. RESULTS: The WDA discriminant function accurately identified patients with lung cancer in a model employing 30 breath VOCs (ROC curve AUC=0.90; sensitivity=84.5%, specificity=81.0%). These results were superior to multilinear regression analysis of the same data set (AUC=0.74, sensitivity=68.4, specificity=73.5%). WDA test accuracy did not vary appreciably with TNM (tumor, node, metastasis) stage of disease, and results were not affected by tobacco smoking (ROC curve AUC=0.92 in current smokers, 0.90 in former smokers). WDA was a robust predictor of lung cancer: random removal of 1/3 of the VOCs did not reduce the AUC of the ROC curve by >10% (99.7% CI). CONCLUSIONS: A test employing WDA of breath VOCs predicted lung cancer with accuracy similar to chest computed tomography. The algorithm identified dependencies that were not apparent with traditional linear methods. WDA appears to provide a useful new technique for non-linear multivariate analysis of data.

Scleroderma-like illness as a presenting feature of multiple myeloma and amyloidosis.

A 31-year-old woman with a history of bilateral carpal tunnel surgery complained of worsening hand pains and swelling. Subsequently, she presented for rheumatologic evaluation with generalized arthralgias, symmetric polyarthritis of the hands and feet, shiny skin with tightness and thickening, tender periungual erythema, malar rash, and photosensitivity. The only laboratory abnormality found then was a positive antinuclear antibody. Her joint symptoms were responsive to low-dose prednisone and hydroxychloroquine. However, the skin tightness progressed proximally and centrally and developed around the mouth. At that point, more specific autoimmune work-up showed negative relevant antibodies, and repeat antinuclear antibody tests turned out negative. Later, she reported dysphagia and hoarseness, and ecchymotic rashes appeared on the face and forearm. Biopsy of the forearm lesion showed leukocytoclastic vasculitis. Staining for amyloid was negative. Subsequently, she was found to have hypogammaglobulinemia and Bence-Jones proteinuria; the progression of her skin symptoms provoked a repeat skin biopsy with special stains that demonstrated amyloidosis. Bone marrow biopsy showed >75% plasma cells, skeletal survey revealed multiple lytic lesions, and a diagnosis of multiple myeloma with associated amyloidosis was made. Despite the initial features of connective tissue disease in this young woman, a steadfast workup revealed the source of her problem.

Malignant eccrine spiradenoma.

Malignant transformation of eccrine spiradenoma is extremely rare. We describe the case of a 70-year-old man with malignant eccrine spiradenoma of the forearm and metastases to the axillary lymph nodes. Surgical excision with adequate margins and lymph node dissection was performed. Tamoxifen therapy was instituted after obtaining positive immunostaining results for estrogen receptor. After 41 months of follow-up, there has been no recurrence or distant metastases. Wide local excision and close follow-up are crucial in the management of malignant eccrine spiradenoma. The role of other therapeutic modalities, including hormonal therapy, remains to be determined.

Phase II trial of weekly docetaxel/irinotecan combination in advanced pancreatic cancer.

BACKGROUND: Docetaxel and irinotecan have activity in pancreatic cancer. The combination of docetaxel and irinotecan is attractive because of preclinical evidence of synergy between the two drugs. We have previously demonstrated the safety of docetaxel 35 mg/m(2) and irinotecan 50 mg/m(2) given on days 1, 8, 15, and 21 of a 35-day schedule. PATIENTS AND METHODS: Patients who had unresectable or metastatic adenocarcinoma of the pancreas, bidimensionally measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and normal bilirubin levels were eligible. Tumor assessment was performed with computed tomography, computed tomographic angiography, or magnetic resonance imaging every 2 cycles. Response was graded according to World Health Organization criteria. RESULTS: We enrolled 37 eligible patients. Principal grade 3/4 toxicities were diarrhea (21%), neutropenia (30%), and hyperglycemia (30%). There were 3 patients with febrile neutropenia and no toxic deaths. There were 4 early deaths. Among 36 evaluable patients, 9 (24%) attained a partial response and 1 (3%) attained a complete response for an objective response rate of 27%. One patient enrolled because she had been deemed to have unresectable disease but then underwent resection with negative margins after attaining a confirmed partial response. Median survival for all eligible patients is 9.4 months (range 0-68+ months) with minimum follow-up for surviving patients of 23.4 months. One-year survival is 43%. The patient who attained a complete response is alive with recurrent disease at 68 months. CONCLUSIONS: The docetaxel/irinotecan combination given on a weekly schedule is an active treatment for advanced pancreatic cancer.

Prediction of lung cancer using volatile biomarkers in breath.

BACKGROUND: Normal metabolism generates several volatile organic compounds (VOCs) that are excreted in the breath (e.g. alkanes). In patients with lung cancer, induction of high-risk cytochrome p450 genotypes may accelerate catabolism of these VOCs, so that their altered abundance in breath may provide biomarkers of lung cancer. METHODS: VOCs in 1.0 L alveolar breath were analyzed in 193 subjects with primary lung cancer and 211 controls with a negative chest CT. Subjects were randomly assigned to a training set or to a prediction set in a 2:1 split. A fuzzy logic model of breath biomarkers of lung cancer was constructed in the training set and then tested in subjects in the prediction set by generating their typicality scores for lung cancer. RESULTS: Mean typicality scores employing a 16 VOC model were significantly higher in lung cancer patients than in the control group (p<0.0001 in all TNM stages). The model predicted primary lung cancer with 84.6% sensitivity, 80.0% specificity, and 0.88 area under curve (AUC) of the receiver operating characteristic (ROC) curve. Predictive accuracy was similar in TNM stages 1 through 4, and was not affected by current or former tobacco smoking. The predictive model achieved near-maximal performance with six breath VOCs, and was progressively degraded by random classifiers. Predictions with fuzzy logic were consistently superior to multilinear analysis. If applied to a population with 2% prevalence of lung cancer, a screening breath test would have a negative predictive value of 0.985 and a positive predictive value of 0.163 (true positive rate =0.277, false positive rate =0.029). CONCLUSIONS: A two-minute breath test predicted lung cancer with accuracy comparable to screening CT of chest. The accuracy of the test was not affected by TNM stage of disease or tobacco smoking. Alterations in breath VOCs in lung cancer were consistent with a non-linear pathophysiologic process, such as an off-on switch controlling high-risk cytochrome p450 activity. Further research is needed to determine if detection of lung cancer with this test will reduce mortality.