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Purpose: Physical activity (PA) is a promising intervention for cancer-related cognitive decline, yet research assessing its use during chemotherapy is limited. This study evaluated patterns of PA before, during, and after chemotherapy in patients with breast cancer and the association between PA and cognitive function., Methods: In a nationwide, prospective cohort study, we assessed PA (Aerobics Center Longitudinal Study PA measure) and perceived and objectively measured cognitive functioning (Functional Assessment of Cancer Therapy-Cognitive, Delayed Match to Sample, and Rapid Visual Processing measures) at prechemotherapy (T1), postchemotherapy (T2), and 6 months postchemotherapy (T3) in patients with breast cancer and cancer-free, age-matched controls at equivalent time points. Longitudinal linear mixed-effects models (LMMs) characterized PA changes over time between patients and controls, adjusting for demographic and clinical factors. LMMs further estimated the role of prechemotherapy PA and changes in PA during chemotherapy on cognitive changes over time., Results: Patients with stage I-IIIC breast cancer (n = 580; age M [standard deviation] = 53.4 [10.6] years) and controls (n = 363; age M [standard deviation] = 52.6 [10.3] years) were included. One third of patients met national PA guidelines at T1, dropping to 21% at T2 before rising to 37% at T3. LMMs revealed declines in PA from T1 to T2 in patients compared with controls (all P < .001). Patients meeting guidelines at T1 demonstrated better cognitive scores over time on the Functional Assessment of Cancer Therapy-Cognitive and Rapid Visual Processing (all P < .05), with similar patterns of objectively-measured cognitive function as controls. In patients, greater moderate-to-vigorous PA at the previous time point was significantly associated with better cognitive trajectories (all P < .05), and adherence to PA guidelines throughout chemotherapy was associated with better self-reported cognition ( P < .01)., Conclusion: This nationwide study demonstrates that PA maintenance before and during chemotherapy is associated with better cognitive function immediately and 6 months after chemotherapy completion., Competing Interests: Alison ConlinConsulting or Advisory Role: Pfizer, Novartis, Seattle Genetics/Astellas, BioTheranosticsSpeakers' Bureau: Seagen Jerry MitchellEmployment: Immunomedics, Amgen, Seattle Genetics, Foundation MedicineStock and Other Ownership Interests: Seattle GeneticsConsulting or Advisory Role: Regeneron, BioTheranostics, RigelSpeakers' Bureau: Sun Pharma, Regeneron Michelle C. JanelsinsConsulting or Advisory Role: Charles River AnalyticsNo other potential conflicts of interest were reported.

Background: Frailty is associated with an increased risk of chemotherapy toxicity. Cellular markers of inflammation can help identify patients with frailty characteristics. However, the role of cellular markers of inflammation in identifying patients at risk of developing chemotherapy-induced frailty and their clinical utility are not fully understood., Methods: This study was a secondary analysis of a large nationwide cohort study of women with stage I-IIIC breast cancer (n = 581, mean age 53.4; range 22-81). Measures were completed pre-chemotherapy (T1), post-chemotherapy (T2), and 6 months post-chemotherapy (T3). Frailty was assessed at all three time points using a modified Fried score consisting of four self-reported measures (weakness, exhaustion, physical activity, and walking speed; 0-4, 1 point for each). Immune cell counts as well as neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ratio (LMR) were obtained at T1 and T2 time points. Separate linear regressions were used to evaluate the associations of (1) cell counts at T1 with frailty at T1, T2, and T3 and (2) change in cell counts (T2-T1) with frailty at T2 and T3. We controlled for relevant covariates and frailty at the T1 time point., Results: From T1 to T2, the mean frailty score increased (1.3 vs 2.0; p < 0.01) and returned to T1 levels by the T3 time point (1.3 vs 1.3; p = 0.85). At the T1 time point, there was a positive association between cellular markers of inflammation and frailty: WBC (β = 0.04; p < 0.05), neutrophils (β = 0.04; p < 0.05), and NLR (β = 0.04; p < 0.01). From T1 to T2, a greater increase in cellular markers of inflammation was associated with frailty at T2 (WBC: β = 0.02, p < 0.05; neutrophils: β = 0.03, p < 0.05; NLR: β = 0.03; p < 0.01). These associations remained significant after controlling for the receipt of growth factors with chemotherapy and the time between when laboratory data was provided and the start or end of chemotherapy., Conclusions: In patients with breast cancer undergoing chemotherapy, cellular markers of inflammation are associated with frailty. Immune cell counts may help clinicians identify patients at risk of frailty during chemotherapy., Trial Registration: ClinicalTrials.gov , NCT01382082.

Objective: To determine whether our health care employees were undergoing mammography screening according to American Cancer Society guidelines and to determine whether aggressive outreach, education and streamlining of mammography scheduling could improve compliance., Study Design: All female employees at North Shore University Hospital (NSUH) and several other health system facilities (SF) were sent mailings to their homes that included breast health education and mammography screening guidelines, a questionnaire regarding their own mammography screening history and the opportunity to have their mammography screening scheduled by the Mammography Screening Employee Inreach Program (MSEIP) coordinator., Results: Of the approximately 2,700 female employees aged 40 and over at NSUH and SF, 2,235 (82.7%) responded to the questionnaire, and 1,455 had a mammogram done via the MSEIP. Of the 1,455, 43% either were overdue for a mammogram or had never had one. During a second year of the MSEIP at NSUH and SF, an additional 1,706 mammograms were done., Conclusion: People employed in health care jobs do not necessarily avail themselves of appropriate health care screening. An aggressive program that utilized education, outreach and assistance with scheduling was effective in increasing compliance with mammography screening.

Background: In vitro experiments suggest that administration of vinorelbine preceding paclitaxel results in synergistic cytotoxic effects. A phase I dose escalation trial of vinorelbine daily x 3 with paclitaxel on day 3 repeated every 28 days in metastatic breast cancer patients was completed., Patients and Methods: Female patients, PS 0-2, without evidence of CNS disease or prior neuropathies were treated with vinorelbine at dose levels 7, 10, 13 mg/m2 per day and paclitaxel over three hours at dose levels of 135, 175, and 200 mg/m2., Results: Twenty-eight patients with six dose levels were studied. At dose level 1, patients developed intolerable but reversible neutropenia. Subsequent dose levels required filgrastim. Dose limiting toxicities were myalgia and fatigue at vinorelbine 13 mg/m2/day and paclitaxel 200 mg/m2. Neuropathy was minor. Twelve of twenty-five patients with measurable disease had a rapid response which did not correlate with dose level., Conclusions: Sequential administration of these two agents demonstrates activity in breast cancer patients. Phase II dosing on this schedule should be vinorelbine 13 mg/m2/day x 3 and paclitaxel 175 mg/m2. With proper selection of patients, concern about neurologic toxicity should not impede future trials of vinorelbine with paclitaxel.

Strumal ovarii has been rarely associated with other tumors, such as carcinoid tumor, carcinoma, and primary ovarian malignant lymphoma. We report the coexistence of a strumal ovarii and ovarian involvement by malignant lymphoma in a 70-year-old woman. The tumors were detected 10 years following exposure to ionizing radiation during the Chernobyl nuclear tragedy.

Purpose: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes., Patients and Methods: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m(2) as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m(2) every 14 days with granulocyte colony-stimulating factor support., Results: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed., Conclusion: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.

Zeniplatin, a more water-soluble organoplatinum than cisplatin, was evaluated for clinical pharmacology in the context of a phase II trial in previously treated patients with ovarian carcinoma. A total of 12 patients were given zeniplatin at 120 mg/m2 by rapid intravenous infusion over 90 min, with both blood and urine being sampled. All platinum moieties were analyzed in whole blood, plasma, plasma ultrafiltrate, and urine by atomic absorption, and free zeniplatin was analyzed in plasma ultrafiltrate by specific high-performance liquid chromatography (HPLC). In a comparison of the platinum-time concentration curve, AUC (area under the curve) values indicated that approximately 90% of platinum moieties were bound to circulating plasma proteins. There was no evidence of drug accumulation after repetitive dosing. The terminal half-life (t1/2) of this drug in plasma ultrafiltrate (3.7-7.2 h.) as measured by HPLC was slightly longer than that of carboplatin, whereas total platinum moieties in plasma displayed a long t1/2 (124-154 h). Approximately 60% of platinum moieties could be recovered in the urine within 24 h. These findings suggest that zeniplatin has a pharmacokinetic profile similar to that of carboplatin.

Six cases of large granular T-cell lymphoproliferative disorder with a selected immunophenotype (CD3+, CD4-, CD8+, CD16+) were studied to characterize a homogeneous group of patients. It was found that most of these patients did not exhibit the clinical features frequently described in large granular T-cell lymphoproliferative disorder--recurrent infection, rheumatoid arthritis, and splenomegaly. The laboratory tests usually positive in large granular T-cell lymphoproliferative disorder, including rheumatoid factor and anti-nuclear antibodies, also were frequently negative. The pathognomonic features were found to be neutropenia and large granular lymphocytosis with positive killer cell markers. All six cases showed T-cell receptor gene rearrangement that indicated a monoclonal proliferation of lymphoid cells, which were natural killer-like T cells by immunophenotyping. B cells were essentially absent in all cases. It should be emphasized that bone marrow aspirates are as informative as peripheral blood samples for the diagnosis of large granular T-cell lymphoproliferative disorder; indeed, phenotypes of blood and marrow in one case were identical in terms of percentages of markers. In this selected group of patients, the clinical courses were indolent with uncomplicated outcomes. In three patients, chemotherapy did not induce an obvious clinical response, but all patients' conditions remained stable with only supportive care.

The ageing of the population has resulted in a greater emphasis on cancer treatment effects in elderly patients. This population has often had arbitrary dose modification of chemotherapy owing to fear of excessive side-effects. A review was undertaken to evaluate cisplatin toxicity in patients of 70 years of age or older. Thirty-four patients were evaluated. Their mean age was 72.8 years and 85.3% were women. Fourteen of 34 (41%) patients completed the planned therapy. Treatment was terminated because of disease progression (35%), renal toxicity (9%) and non-renal toxicity (15%). Our conclusion is that cisplatin can safely be administered to elderly patients. Arbitrary dose modification or elimination of cisplatin from a treatment programme on the grounds of patient age alone is not justified.

Thirty two patients with refractory or recurrent acute leukemia or blast crisis of chronic myelocytic leukemia were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight doses. Two of 13 (15.3%) evaluable patients in group I achieved a complete response, both of whom had acute myelocytic leukemia. In group II, seven of 14 evaluable patients (50%) obtained objective responses--six with complete responses (42.8%) and one with partial response (7%). Myelosuppression was seen in all patients with a median duration of 32.5 days (group I) and 36.3 days (group II), respectively. Non-hematologic toxicity consisted of nausea, vomiting, diarrhea, conjunctivitis, skin rash, hepatocellular toxicity, hemorrhage, and renal toxicity. Pharmacokinetic studies revealed, for group I, mean peak plasma Ara-C levels at 3 h (Cp3h) of 1254 ng/ml, area under the curve (AUC) 4651 ng x h/ml, total body clearance (TBC) 32.65 l/h/m2, renal clearance (RC) 7.04 l/h/m2 with a mean of 12.36% of the injected amount of Ara-C excreted unchanged in urine over the first 24 h. The corresponding mean values for group II are Cp3h 3305 ng/ml, AUC 15080 ng x h/ml, TBC 20.48 l/h/m2, RC 7.02 l/h/m2 and 26.23%. Ara-C 200 mg/m2 combined with THU gave serum Ara-C levels and response rates comparable to those achieved with high dose Ara-C (HiDAC) (greater than or equal to 1 g/m2). Central nervous system toxicity associated with HiDAC was not seen. Pharmacokinetics for uracil arabinoside (Ara-U) in patients treated with Ara-C 200 mg/m2 plus THU, were comparable to values seen with Ara-C for Cp3h, AUC and 24 h urine, amounting to 3160 ng/ml, 21717 ng x h/ml and 23.62% whereas TBC was significantly lower (p less than 0.001) for Ara-U than for Ara-C (3.02 versus 20.48 l/h/m2).

A pilot study was undertaken to assess the feasibility, toxicity, and efficacy of combined radiation therapy and chemotherapy in the adjuvant treatment of node-positive. Stage II patients with breast carcinoma who had undergone lumpectomy. Therapy consisted of three phases, starting with a six-week CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone) induction, followed by radiation therapy to the breast, and concluding with four cycles of VATH (vinblastine, Adriamycin, thiotepa, Halotesin). Twenty-seven patients were entered with an average age of 51.5 years (median 50 yrs) and a mean follow-up of 46.2 months. Twenty-three patients (85.2%) are alive and 19 (70.3%) disease free. There were no ipsilateral local recurrences. Cosmetic results were good to excellent in 26/27 patients. The doses of VATH were not compromised by the prior therapy. The regimen was found to be tolerable and is a reasonable approach in the adjuvant treatment of this particular patient population.

The stereologic characteristics of monocytes from patients with acute nonlymphocytic leukemia containing a monocytic component (FAB M4 and M5), and the monocytes from normal individuals were determined by morphometric analysis. The cells studied were monocytic cells beyond the promonocyte stage of development, as defined by ultrastructural criteria. Parameters evaluated included cell and nuclear volumes and surface areas, mitochondrial and myeloperoxidase (MPO)-positive secretory granule volume and numerical density as well as volume and number of the organelles/cell. Peripheral blood and bone marrow monocytes of leukemic patients could not be distinguished by their cell or organelle stereologic characteristics. Monocytes from patients with both M4 and M5 acute leukemia had relatively large cell and nuclear volumes. Mitochondrial volume density and volume/cell were also high in monocytes from leukemic patients (M4; 21 microns 3/cell, M5 20 microns 3/cell) as compared with monocytes from normal individuals (8.5 microns 3/cell). On the other hand, MPO-positive secretory granule stereologic parameters in monocytes from leukemic patients were indistinguishable from those of normal individuals. A small number (3 of 18) patients showed very low monocyte MPO-positive granule volume densities. There was a slight positive correlation between MPO-positive granule volume density and patient survival time. No relationship between mitochondrial characteristics and survival was noted.

Vinzolidine (VZL) is a semisynthetic vinca alkaloid with broad antitumor activity in animal models of malignancy but had unpredictable toxic effects when given orally to humans. To minimize the toxic effects due to potential erratic gastrointestinal absorption, this drug was restudied in man as an intravenous preparation given as a rapid injection every two weeks. The maximum tolerated dose (MTD) on this schedule was 9.0 mg/m2 with unpredictable leukopenia (usually occurring 5-14 days post treatment but appearing erratically), constipation, paralytic ileus, and inappropriate ADH syndrome as major toxicities. Nonhematologic toxicities were dose-limiting. Repetitive dosing at two week intervals was associated with leukopenia at D 14-15 in some but not all patients treated above 5.0 mg/m2 precluding further treatment on schedule. In contrast, the oral MTD of this agent in our prior studies was 45 mg/m2 with no evidence of delayed leukopenia. Intrapatient variability of toxicity was small; interpatient variability of toxicity was substantial and did not correlate with prior therapy. Because of the presence of delayed hematologic toxicity on repetitive dosing schedules, intravenous VZL should be given on a dosing schedule longer than 14 days. No antitumor activity was seen in this study.

A role for vinblastine (VBL) in lung cancer has never been clearly defined. Because of recent pharmacokinetic data suggesting a biweekly schedule for VBL and recent antitumor activity shown for vindesine, a phase II trial of divided-dose VBL was initiated. Among 22 evaluable patients, a 27% major response rate was seen, with a median duration of 5.5 months (range 3.5-12+). The major toxic effect was myelosuppression but was easily manageable and tolerated. These results suggest schedule dependency for VBL and open the question of its efficacy in lung cancer.

A patient with Philadelphia chromosome positive CML was studied to characterize the blast transformation. Peripheral blood and bone marrow at the onset of the blast crisis were evaluated with cytochemistry, chromosome analysis, cell surface markers, terminal transferase assay, and electron microscopy. Although light microscopic examination and cytochemistry suggested lymphoblastic morphology, ultrastructural cytochemistry demonstrated the myelomonocytic features of the transformation. This study suggests that electron microscopic cytochemistry is useful in evaluating the heterogeneous nature of the blast phase of CML.

A phase II trial of mitomycin, vinblastine, and cisplatin was undertaken in 26 patients with non-small cell carcinoma of the lung. A major response rate of 46% was seen in measurable and evaluable disease, with a complete response rate of 12%. Median duration of response is 6.5+ months (range, 2.5-19+). Toxic effects included moderate myelosuppression, mild neuropathy, mild azotemia, and severe nausea and vomiting. These results are similar to previously reported studies using vinca alkaloids and cisplatin alone.

We describe two patients with acquired idiopathic sideroblastic anemia and a terminal deletion of chromosome No. 11. In spite of the marked chromosomal abnormality neither patient has developed acute leukemia.

Sixteen patients with previously treated acute nonlymphocytic leukemia or chronic myelogenous leukemia in blast crisis were given one to three courses of esorubicin by continuous infusion over 48 h. Dosage levels extended from 35 to 85 mg/m2. Four patients showed partial responses of short duration. Nonhematological toxicity observed at dosages of 55 to 85 mg/m2 were mucositis, diarrhea, skin rash, transaminitis, nausea, vomiting, and cardiac dysfunction. One patient receiving 85 mg/m2 developed acute florid congestive heart failure within hours of administration of the drug. Pharmacokinetic analysis revealed large interpatient variation in plasma drug levels. At the end of infusion, plasma decay of esorubicin was rapid initially but slow thereafter, with a terminal half-life of 20 to 54 h. The metabolite 4'-deoxy-13-hydroxydoxorubicin reached significant plasma levels. Total body clearance, renal clearance, volume of distribution at steady state, and mean residence time show little variation during dose escalation for both esorubicin and 4'-deoxy-13-hydroxydoxorubicin. Urinary excretion of esorubicin and 4'-deoxy-13-hydroxydoxorubicin accounted for 10.5 and 1.5%, respectively, of the administered dose.

Vinzolidine is a new, orally active, semisynthetic vinca alkaloid which shows broad anti-tumor activity against murine tumor test systems. This phase I study established a 1 day every 2 week schedule of 35 mg/m2 in good-risk patients and of 30 mg/m2 in poor-risk patients. Maximal tolerated dose was 45 mg/m2 with severe neutropenia, syndrome of inappropriate antidiuretic hormone, and paralytic ileus. Significant antitumor responses were seen in two patients with lymphoma and in one with squamous cell cancer of the lung.

Estrogen receptors have been demonstrated in human hypernephroma (renal cell carcinoma). Antiestrogens have been demonstrated to have antitumor activity in animal models of this disease. A prospective trial of tamoxifen therapy was undertaken in 10 consecutive patients with unresectable hypernephroma. No major responses to tamoxifen were observed. A review of the literature on antiestrogen therapy for this tumor reveals 148 published cases of hypernephroma treated with tamoxifen or nafoxidine. The overall response rate was 7.4%. Antiestrogens appear to have little clinical usefulness in the treatment of advanced hypernephroma.

When 1-beta-D-arabinofuranosylcytosine (ara-C), 25 mg/m2, is infused over 3 h together with tetrahydrouridine (THU) at 10 to 350 mg/m2 to heavily pretreated patients with solid tumors, Michaelis-Menten type kinetic values are observed with leveling off of delta area under the curve, delta ara-C levels at 3 h, and delta total body clearance after 150 mg/m2 of THU. When the ara-C dose was increased to 50, 75, and 100 mg/m2 coinfusion of 250 or 350 mg/m2 of THU significantly increased plasma ara-C at peak and area under the curve. In contrast, total body clearance and volume of distribution decreased significantly. At 100 mg/m2 of ara-C coinfused with high doses of THU, i.e., at 350 mg/m2, the pharmacokinetics of plasma ara-C was changed from a biphasic decay of plasma ara-C at peaks (control) to a curve similar or identical to a monophasic curve, indicating that THU not only inhibits deamination but also changes the distribution of ara-C. This combination provides plasma ara-C levels (greater than or equal to 10 microM) comparable to high dose ara-C at 1 g/m2. Such plasma ara-C levels are considered to be sufficient for saturation of the kinases catalyzing the production of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. This reduced ara-C dose necessary to achieve saturation of kinases also reduces plasma 1-beta-D-arabinofuranosyluracil levels substantially. Toxicity of this combination was predominantly confined to bone marrow and gastrointestinal toxicity.

The pharmacokinetic parameters of low dose 1-beta-D-arabinofuranosylcytosine (ara-C) infusions were studied in 11 patients, 6 males and 5 females, with a mean age of 68.5 +/- 13.8 (SD) years. The drug was infused to 4 patients with pre-leukemia (refractory anemia with excess blasts), 5 patients with acute myelogenous leukemia, and 2 patients with secondary leukemia due to chemotherapy, at a dosage of 20 mg/m2/day over 21 days. The patients' blood and urine were analyzed for ara-C content by radioimmunoassay. Mean steady state plasma levels of 7.7 +/- 4.7 ng/ml (31.7 +/- 19.3 nM) (n = 189) and a range 0.6 (2.5 nM) (lower limit of assay) to 29.7 ng/ml (122.1 nM), with significant inter- and intra-patient variations, were reached within about 2.7 h. The plasma levels of ara-C decreased rapidly, with a t1/2 alpha of about 12 min following discontinuation of the infusion, followed by a very slow t 1/2 beta of about 19 h. Other parameters (mean values of 10 or 11 patients) were: area under the curve, 182.1 +/- 64.8 ng X day/ml; total body clearance, 188.7 +/- 54.8 liters/h; renal clearance, 3.1 +/- 1.4 liters/h; volume of distribution at steady state, 53,913 +/- 17,626 liters; and recovery of ara-C in urine, 1.43 +/- 0.69% (n = 226) of daily administered ara-C. A linear relationship was observed with administered dose when the mean plasma levels of our study were compared with the ones reported for conventional ara-C infusions. Plasma clearance was comparable to that observed in conventional dose, when the observed values were extrapolated to the dose administered in this study.