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Achieving successful outcomes in chronic phase‐chronic myeloid leukemia (CP‐CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CP‐CML receiving first‐line imatinib (n = 416), dasatinib (n = 418) or nilotinib (n = 408) in the US and 6 European countries in routine clinical practice. Twelve‐month follow‐up data of 1242 prospective patients (enrolled October 01 2010‐September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib‐treated patients enrolled earlier in the study, with subsequent shift toward dasatinib‐ and nilotinib‐treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P

Individuals concerned about their risk of lung cancer are recommended to talk with their physicians about computed tomographic screening for lung cancer. To provide the necessary information, the survival benefit of the screening, specific to a particular person for a particular round of screening, is needed. The probability of survival gain from the first, baseline, round of screening was addressed as the product of: 1) the screening resulting in a diagnosis of lung cancer; 2) not dying from some other cause for a sufficiently long period of time; and 3) cure resulting from pre-symptomatic treatment of lung cancer. These probabilities were estimated using the International Early Lung Cancer Action Program data on individuals aged 40-85 yrs with a cigarette smoking history of 0-150 pack-yrs. The estimated probability of survival gain ranged from 0.4% for a 60-yr-old with a 10-pack-yr smoking history who quit smoking 20 yrs ago, to 3.1% for a 70-yr-old current smoker with a 100 pack-yr history and 2.0% for an 85-yr-old current smoker with a 150-pack-yr history. When seeking counsel about initiation of screening for lung cancer, an estimate of the probability of survival gain from the first round of computed tomographic screening, specific to the person's age and history of smoking, can be provided.

Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer.Eligible women were treated with POH four times daily at 1,200-1,500 mg m(-2) dose(-1) on a 28-day cycle. Patients tolerating 1,200 mg m(-2) day(-1) four times daily after one cycle were dose-escalated to 1,500 mg/m(2). The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations.Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m(2). Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-beta1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability.Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.

9091Background: Cx is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type receptor 1 (IGF1R) that can potentially reverse resistance and enhance the efficacy of chemothera...

This phase I study of 36 patients was performed to identify the maximal tolerated dose of oral calcium leucovorin (CLV) that could be concomitantly administered with protracted 5-fluorouracil (5-FU) infusion (greater than 30 days). Administration of CLV in very small doses (5 mg p.o. q8h) with 5-FU, 200-300 mg/m2/day, resulted in excessive toxicity requiring treatment interruption in all patients. Subsequent reduction in the dose of 5-FU to 100 mg/m2/day with simultaneous administration of CLV, 5 mg p.o. q8h, decreased the toxicity and allowed for protracted administration of the combination. In subsequent patients the dose of oral CLV was increased to 22.5 mg p.o. q8h, which resulted in treatment-limiting toxicity in the majority of patients. Toxicity consisted almost exclusively of mucositis. No myelosuppression or significant organ toxicity was observed. We conclude that even low doses of oral CLV potentiate the biological effect of infusion 5-FU. If the combination is to be given on a protracted basis, 5-FU must be administered at a much smaller dosage than has been traditionally utilized.

Twenty evaluable patients with newly diagnosed brain metastases underwent treatment with a novel dose/schedule of dexamethasone aimed at reducing steroid toxicity during palliative radiation therapy. All patients received twice daily dexamethasone starting at 8 mg bid for four days then 4 mg bid for four days then 2 mg bid until the last day of radiation therapy. The radiation prescriptions were not standardized varying from 2000 cGy/5 fractions to 5800 cGy/29 fractions. Fourteen patients received dexamethasone for a minimum of 24 hours before their first radiation treatment and 7 (50%) experienced improvement in neurologic symptoms/signs prior to starting radiation treatments. Fourteen patients completed the planned course of radiation and dexamethasone. Only 1 patient needed to restart dexamethasone within 30 days of finishing radiation because of steroid reversible neurologic deficits. Steroid toxicity was mild including hyperglycemia (1), candida esophagitis (1), steroid pseudorheumatism (2), peripheral edema (1) and steroid withdrawal syndrome (1). Only two toxic events were recorded in patients receiving steroids less than 21 days. Twice daily dexamethasone appears to provide good clinical results with minimal morbidity.

Twenty patients with metastatic prostatic cancer were treated on an ambulatorybasis with continuous 5 fluorouracil (5-FU) infusion 250–300 mg/M 2 per day through a chronic indwelling central venous catheter. All patients had symptomatic, progressive disease despite previous standard therapies. Partial remission was seen in 2 of 20 patients (10%), stable disease in 9 of 20 (45%), and progressive disease in 9 of 20 (45%); mean duration of benefit in responding and stable disease patients was six months. Improvement in pain and ECOG performance status were seen in most of the patients in the responding and stable disease categories. Forty percent of the patients experienced no significant drug toxicity; treatment interruption was necessary for stomatitis in 6 patients (30%), hand/foot syndrome in 3 patients (15%), and diarrhea in 1 patient (5%). No significant myelosuppression or other significant organ toxicities were encountered, Continuous systemic venous infusion of 5-FU may provide significant palliative effect for some patients with symptomatic, refractory carcinoma of the prostate.

Twenty-four patients with advanced metastatic cancer were treated with continuous intravenous 5-fluorouracil infusion 200-300 mg/m2/day and alpha interferon 3 million units subcutaneously 3 times per week. The average duration of treatment was 87 days (range 22-204 days). 5-fluorouracil could be infused 66% of the planned time on treatment, and patients received an average of 60% of the planned interferon injections. Objective tumor responses were seen in 6 of 17 previously untreated patients (35%). Twenty-two of the 24 patients (92%) experienced toxicity (greater than or equal to ECOG grade II) that required treatment interruption and subsequent dose reduction predominantly for the following reasons: mucositis (67%), hand-foot syndrome (21%), and leukopenia (25%). The incidence of treatment limiting toxicity is higher than previously observed with 5-fluorouracil infusion alone. This suggests true augmentation of 5-fluorouracil effect by interferon. 5-Fluorouracil infusion and alpha interferon is a potentially useful combination that needs further evaluation in future phase II and phase III trials.

Thirty four patients treated with mastectomy and axillary node dissection for potentially curable breast cancer received a seven month combined adjuvant chemotherapy and radiation therapy program. These patients were considered to be at high risk for recurrence because they had either three or more positive axillary lymph nodes or their primary tumor was greater than 5 cm in diameter. The chemotherapy given at 3-week intervals consisted of cyclophosphamide, 600 mg/m2, Adriamycin 40 mg/m2, and methotrexate 40 mg/m2 during cycles 1 through 3 and 7 through 9. Radiation therapy was administered during cycles 4 through 6 with concomitant administration of 5-fluorouracil 600 mg/m2, vincristine 1.4 mg/m2, and prednisone 40 mg/m2 for 7 days. Median follow up time from initiation of study is 60 months (range 36-93). Seventeen of 34 patients (50%) remain free of recurrent breast cancer. Distant metastases and local-regional recurrence have occurred in 16 (47%) and 4 (12%) patients, respectively. Significant myelosuppression and infections requiring hospitalization were seen in 4 patients, with 1 treatment-related death. Adriamycin-containing chemotherapy and post-operative radiotherapy can thus be combined in an adjuvant treatment program with acceptable toxicity.

It has been suggested that the addition of weekly low-dose cisplatin (DDP) may potentiate the efficacy of continuous infusion 5-fluorouracil (5-FU) without adding significant toxicity. To investigate the extent of added toxicity, an analysis of toxicity was completed in 18 patients with advanced cancers treated with continuous ambulatory 5-FU infusion 300 mg/m2/day and weekly low-dose cisplatin (DDP) 20 mg/m2. Ten of the 18 patients (56%) developed multiple (four or more) toxicities during treatment. In addition, toxicity categorized as severe occurred in 10 patients (56%). Seventeen of the 18 patients (94%) required treatment interruption or dose attenuation due to toxicity and most patients experienced a decline in Eastern Cooperative Oncology Group performance status due to treatment-related toxicity. Compared with historical toxicity patterns when 5-FU infusion is administered alone, the addition of DDP has resulted in significant increases in nausea and vomiting, anorexia, diarrhea, stomatitis, and myelosuppression. The addition of low-dose weekly DDP adds significant toxicity and morbidity to the continuous 5-FU infusion regimen.

Background: The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin. Patients and Methods: Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m2. Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria. Results: Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia. Conclusion: The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.

Forty women with breast cancer underwent imaging by internal mammary lymphoscintigraphy (IMLS), which was correlated with the results of CT and MRI of the chest. IMLS was performed and interpreted using the previously described methods of Ege. It identified 22 instances of ipsilateral internal mammary nodal involvement, none of which corresponded to cases of abnormally enlarged (diameter greater than 1.0 cm) internal mammary nodes on CT and/or MRI. Positive IMLS was associated with axillary nodal metastases in 15 out of 22 instances. The authors conclude that IMLS provides information on regional nodal spread of breast cancer that is not available with either CT/MRI imaging or axillary biopsy.

Evidence suggests that interferon-alpha (IFN-alpha) augments the antineoplastic activity of 5-fluorouracil (5-FU) in human adenocarcinoma cell lines in vitro and may enhance the efficacy of 5-FU in patients with advanced colorectal carcinoma. In addition, 5-FU may be more effective when given as a prolonged, continuous i.v. infusion (PCI). The Eastern Cooperative Oncology Group performed a Phase II trial of PCI 5-FU plus IFN-alpha in patients with advanced pancreatic carcinoma. Twenty-six patients with advanced, surgically incurable adenocarcinoma of the pancreas received PCI 5-FU (250 mg/m2 daily for 28 days) in combination with IFN-alpha (5 x 10(6) IU/m2 s.c. thrice weekly). Treatment cycles were repeated 14 days or longer after completion of the previous cycle. Treatment was interrupted prior to day 28 if intolerable toxicity developed, and the dose of 5-FU was reduced in subsequent cycles. Partial response occurred in two of 24 evaluable patients (8%; 95% confidence interval, 0-19%). The majority of the study group (88%) had liver metastases. Patients whose serum lactate dehydrogenase (LDH) was more than twofold elevated developed 5-FU-related toxicity significantly sooner than patients with smaller elevations in serum LDH (9 vs. 22 days; p = 0.003). A similar trend was observed for patients with a more than twofold elevation in serum glutamic-oxaloacetic transaminase (SGOT; 9 vs. 15 days; p = 0.07). In conclusion, PCI 5-FU plus IFN-alpha has minimal activity in patients with advanced pancreatic carcinoma, and elevated serum LDH and/or SGOT may be useful for predicting greater toxicity from 5-FU-based therapy in patients with liver metastases.

Background : Phase II studies of fluorouracil (5-FU) administered by protracted intravenous infusion have suggested an improved response rate and decreased toxicity profile when compared with 5-FU given by bolus injection in patients with metastatic colorectal cancer. Additional studies have suggested further enhancement of infusion 5-FU activity when it is combined with low-dose weekly cisplatin administration. Purpose : This phase III study in adults with metastatic colorectal cancer was planned as a comparison of objective response rates, toxicity, and survival in patients receiving bolus versus protracted-infusion 5-FU with or without cisplatin. Methods : Four hundred ninety-seven previously untreated patients with advanced, measurable metastatic colorectal cancer were randomly assigned to receive treatment A (bolus 5-FU at 500 mg/m 2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m 2 ), treatment B (bolus 5-FU at 500 mg/m 2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m 2 , plus weekly cisplatin at 20 mg/m 2 ), treatment C (5-FU at 300 mg/m 2 per day by continuous infusion), or treatment D (5-FU at 300 mg/m 2 per day by continuous infusion plus weekly cisplatin at 20 mg/m 2 ). All drugs were administered intravenously. Enrollment in the trial occurred from August 1987 through December 1990, and follow-up was through September 1995. The Kaplan-Meier method was used to estimate overall and disease-free survival, and Cox regression models were used to assess the effects of patient characteristics on survival. All P values resulted from two-sided tests. Results : Objective tumor response was observed in 28 (18%) of 153 patients receiving treatment A, in 45 (28%) of 159 patients receiving treatment C (C versus A ; P =.045), and in 47 (31%) of 153 patients receiving treatment D (D versus A ; P =.016). Because of excessive toxicity, treatment B was discontinued after only 12 patients had begun treatment. Median time to disease progression was 5.1 months for patients in arm A compared with 6.2 and 6.5 months for patients in arms C and D, respectively (C versus A, P = .007 ; D versus A, P =.017). Patterns of toxic effects differed substantially among the treatment arms. Forty-five percent of the patients receiving bolus 5-FU alone (A) experienced grade 3-4 leukopenia, with two sepsis-related deaths. Hand-foot syndrome and mucositis were the major treatment-limiting toxic effects for patients in the two treatment arms involving infusion. Despite the improvement in response rates and time to disease progression with infusion 5-FU with or without cisplatin (C and D, respectively) (P = .003), the overall survival for the three groups (A, C, and D) was similar (P = .307). This may have been due in part to a longer median survival time of 10.4 months for patients in arm A, compared with an anticipated survival of 7 months. Conclusion : 5-FU given as a continuous infusion produced a higher objective response rate, a modest prolongation in time to disease progression, and less life-threatening myelosuppression in patients than bolus 5-FU. Concomitant treatment with low-dose cisplatin caused added toxicity and complexity of treatment and did not provide a major clinical benefit. No statistically significant survival differences were observed among the three treatment groups.

A study was undertaken to assess the natural history of periocular lymphoproliferative diseases, identify key prognostic factors, and clarify the role of orbital irradiation. Thirty-four patients with periocular lymphoproliferative disease were treated with orbital irradiation between 1975 and 1990. Eight patients had atypical lymphoid infiltrate, and 26 had malignant lymphoma. Forty-three eyes were irradiated with en-face electrons or 6-MV photons. Five-year disease-free survival for all stages was 65%; it was not significantly affected by bilaterality or site. Stage, distinction between atypical lymphoid infiltrate and malignant lymphoma, and working formulation grade were important prognostic indicators. A complete response during irradiation was achieved in 24 of 43 (56%) eyes at a median dose of 2,400 cGy, and a partial response was achieved in 19 (44%), with resolution at a median of 2.8 months. Patients with periocular reactive lymphoid hyperplasia or atypical lymphoid infiltrate may have or are at significant risk of developing lymphoma and dissemination. Local treatment remains important; orbital irradiation achieves prompt local control with acceptable morbidity.

Twenty-two patients, ages 16.6 to 43.9 years (median age, 30 years), with relapsed or refractory lymphoma were treated by allogeneic bone marrow transplantation after high-dose chemotherapy with or without total body irradiation (TBI). Seven patients had Hodgkin's disease, four had low-grade histology non-Hodgkin's lymphoma (NHL), seven had intermediate-grade NHL, and four had high-grade NHL. Of the 22 patients, 17 received T-cell (CD-3)-depleted marrow after intensive pretransplant chemoradiotherapy, and five received T-cell-replete grafts after chemotherapy-based preparative regimens. Five patients were transplanted from donors other than genotypically HLA-identical siblings: four from partially HLA-matched relatives, and one from a phenotypically HLA-identical unrelated donor. Acute graft-versus-host disease (GVHD) was less than or equal to grade II in all patients, and chronic GVHD was limited or absent in all but one patient. Of the 21 assessable patients, 17 (80.9%) achieved complete remissions. Death due to transplant-associated complications occurred in five patients, and five patients have relapsed. Thirteen patients are alive, and 12 are continuously relapse-free at a median follow-up of longer than 28 months (range, greater than 10 to greater than 58 months) from transplant. The cumulative probability of treatment failure from relapse or progression of lymphoma was 29% (95% confidence interval [CI], 12% to 51%), while the actuarial lymphoma-free (ie, event-free) survival plateau is 54.6% (95% CI, 34% to 76%). For young patients with advanced malignant lymphoma, allogeneic bone marrow transplantation appears superior to salvage chemotherapy for achievement of long-term, lymphoma-free survival and may be preferable to autologous bone marrow transplantation for selected patients.

The pharmacokinetics of continuous infusion 5-fluorouracil make it an ideal drug to administer as a protracted infusion (continuous infusion more than 30 days). During the last decade numerous clinical studies have been conducted to evaluate the efficacy of 5-fluorouracil (5FU) administered as a protracted venous infusion. Phase II studies in metastatic colorectal cancer in 345 patients have demonstrated an average response rate of 36% (range 15-59%) and a prospective randomized study performed by the Mid-Atlantic Oncology Program (MAOP) has confirmed a higher response rate with 5FU infusion compared with a bolus schedule. Phase II studies in refractory carcinoma of the breast in 177 patients have demonstrated a 30% response rate (range 17-50%); studies in pancreatic, gastric, and refractory prostate cancer have also demonstrated clinical utility. The major toxicities of 5FU infusion are mucositis and hand-foot syndrome; life-threatening myelosuppression is rare and treatment-related deaths have not been reported. 5FU infusion is a useful palliative treatment for many adult patients with advanced malignancies.

7272 Background: Exisulind (E) is an oral selective apoptotic antineoplastic drug that exerts its antitumor effect via the inhibition of tumor-related cGMP phosphodiesterase and activation of protein kinase G. E caused growth inhibition when used alone and with chemotherapy in multiple in vitro and in vivo tumor models. The aim of this study is to define the maximum tolerated dose (Phase I) and efficacy (Phase II) of V + E in elderly patients with IIIB/IV NSCLC. Methods: Patients (pts) were > 69 yrs of age. No prior chemotherapy was allowed. PS 0–1. Pts were entered on 3 dose levels of E (125 mg BID, 125 mg qAM and 250 mg qPM, and 250 mg BID) with V (25 mg/m2) given weekly in a 4 week cycle. Pts with clinical benefit (CR/PR/SD) after 6 cycles of V + E were allowed to continue on E alone Results: 14 pts were enrolled in the phase I portion of the study: 3 on dose level 1, 4 on dose level 2 and 7 on an expanded dose level 3. Median age of this group was 78 yrs (range 72–84). Dose limiting toxicities include...

• Fluorouracil-based chemotherapy regimens have been utilized in metastatic colorectal cancer for more than 30 years. Early attempts at defining an optimal treatment schedule and use in combination with other drugs failed to significantly improve results. In contrast, the clinical effectiveness of fluorouracil has been improved by continuous infusion administration and modulation with folinic acid. Both approaches have increased the response rate compared with results achieved with traditional bolus schedules; the effect on survival has been less significant. Unfortunately, expense and, in some instances, toxicity have also been increased, which detracts from their overall usefulness. Clinical studies that evaluate fluorouracil chemotherapy in combination with biological-response modifiers are ongoing and will be areas of intense research during the next few years. ( Arch Intern Med . 1990;150:2265-2269)

Three patients with primary malignant lymphoma of the uterine cervix are reported and the literature is reviewed. All of the patients in the current cases presented with irregular menstruation. Two patients were found to have diffuse histiocytic lymphoma, and one patient had diffuse mixed lymphoma. Histologic diagnosis was confirmed by outside expert pathologists in all cases. In spite of locally advanced disease according to FIGO's classification (Stage IVA-2 and Stage IIB-1), they responded well to external irradiation, and had control of tumor within the pelvis. All are alive at 13, 7, and 3 years, respectively, after the completion of irradiation. One patient developed disseminated disease 4.25 years after the completion of external irradiation, but was successfully treated with combination chemotherapy for 2 years, and is alive at 6.75 years after the completion of chemotherapy without disease. Review of the other 21 cases reported in the literature reveals that 14 were free of disease after treatment. The importance of distinguishing malignant lymphoma from undifferentiated carcinoma or sarcoma is emphasized since cervical malignant lymphoma can be successfully treated with irradiation in spite of locally advanced disease.

A 40-year-old woman presented with splenomegaly, macrocytic anemia, and red cell aplasia. Although lymphocytosis was absent in the peripheral blood, large atypical lymphoid aggregates were present in the bone marrow. Splenectomy resulted in partial remission of red cell aplasia, but a gradual increase in the number of peripheral blood lymphocytes followed during the next 36 months. Flow cytometric analysis demonstrated that the majority of these peripheral blood lymphocytes had suppressor, natural killer T-cell phenotype. No other treatment was given until red cell hypoplasia worsened 42 months after initial presentation. Repeat bone marrow evaluation again demonstrated severe erythroid hypoplasia and large abnormal lymphocytic infiltrates. Cyclophosphamide given for 8 months resulted in complete resolution of the red cell aplasia and complete clinical remission of CLL. However, flow cytometric analysis revealed persistent increase in bone marrow T-cells, and bone marrow co-culture studies demonstrated residual ability of peripheral blood mononuclear cells to inhibit erythropoiesis in vitro, suggesting that residual, clinically undetectable leukemia persists in spite of complete clinical remission.

The feces of the Shasta ground sloth (Nothrotheriops shastense), preserved by the arid climate of the lower Grand Canyon, were collected at various levels and examined by microhistological analyses to identify and quantify plant taxa in the diet. Over 500 pieces of different Shasta sloth coprolites were examined. Sloth dung from the nearby Muav Caves was examined and compared with that from Rampart Cave.Seventy-two genera of plants were identified in the sloth dung deposited discontinuously from over 40,000 to about 11,000 yr BP. The major plant taxa in the Rampart Cave sloth diets were desert globemallow (Sphaeralcea ambigua = 52%), Nevada mormontea (Ephedra nevadensis = 18%), saltbushes (Atriplex spp. = 7%), catclaw acacia (Acacia greggii = 6%), Cactaceae spp. (= 3%), common reed (Phragmites communis = 5%), and yucca (Yucca spp. = 2%).Six of the most abundant plants in sloth diets were collected in the environs of Rampart Cave and were analyzed for their energy, fiber and nutrient values. The simulated diets of Rampart Cave sloths averaged 1679 cal/g in digestible gross energy and 7.9% for digestible protein. Apart from a substantial increase in digestible energy and in mormontea there was no unusual change in the sloth diet immediately prior to the time of their extinction.The ecological role of Nothrotheriops shastense is less dramatically different from that of extant desert herbivores than was previously believed.

Twenty-five patients with refractory, metastatic carcinoma of the breast were treated with continuous ambulatory 5-fluorouracil (5 FU) infusion (200 to 300 mg/m2/day) through a chronic indwelling central venous catheter. All patients had had extensive previous treatment, including hormonal therapy in 20/25 patients (80%), radiation therapy in 18/25 patients (72%), and an average of 4.6 previous chemotherapy drugs per patient (range 1–10). Twenty-three of 25 patients (92%) had had previous bolus 5 FU. Seventeen of 25 patients (68%) had two or more metastatic sites of involvement and 17/25 patients (68%) had visceral involvement. Results: complete remission −1/25 (4%), partial remission −7/25 (28%), stable disease −6/25 (24%), and progressive disease −11/25 (44%), for an overall response rate of 8/25 (32%). Median duration of response was 6 months. Toxicities included hand-foot syndrome, mucositis, diarrhea, and nausea and vomiting, and required treatment interruption and/or dose attenuation in 9/25 patients (36%). No myelosuppression or serious catheter-related problems were seen. We conclude that continuous 5 FU infusion is a potentially effective salvage treatment that may provide meaningful palliation in some patients with carcinoma of the breast, in spite of extensive previous treatment.

To better define the prognostic factors influencing the response to therapy and survival in small cell carcinoma of the lung (SCCL), an expanded "TNM" type staging system was developed and investigated in a series of 73 protocol treated patients. Because serum LDH levels at disease presentation have been correlated to disease extent, response to therapy, and treatment outcome in a number of malignancies, including SCCL, these interrelationships were also analyzed in the protocol patients. The TNM system was found to be a more descriptive and specific "shorthand" for denoting sites of involvement and for indicating the body burden of tumor than the traditional limited-extensive disease (LD-ED) system. A clear statistical advantage could not be shown over the LD-ED system for predicting chemotherapy response or survival, although there were trends suggesting the TNM system could divide patients into three prognostic subgroups. Serum LDH proved to be a useful index of disease extent and therapy outcome. LDH levels at presentation were proportionately higher with more extensive tumor, measured by either the LD-ED or TNM staging. High LDH predicted poorer responses to chemotherapy and lower survival within similar stage subgroups compared to patients with normal LDH levels. The negative effect of elevated LDH was independent of hepatic involvement and did not predict subsequent hepatic failure in any consistent way. The SCCL TNM staging system proposed needs further refinement and should be tested with larger patient numbers. LDH, along with other tumor markers recently identified, need to be integrated into the staging system to form an overall prognostic index.

Conventional therapy for leukemic meningitis includes cranial irradiation and intrathecal chemotherapy administered by repeated lumbar punctures or direct intraventricular instillation via an Ommaya reservoir. Several clinical reports have indicated that high doses of cytosine arabinoside (ara-C) are effective in the treatment of acute leukemia refractory to standard induction therapy. Pharmacokinetic studies have demonstrated that high doses of ara-C given intravenously obtain sustained therapeutic drug concentrations in the cerebrospinal fluid, suggesting that this approach may be useful in the treatment of systemic disease associated with meningeal involvement. Five consecutive patients with overt meningeal leukemia were treated using only systemic chemotherapy containing high-dose ara-C. In all patients there was prompt resolution of neurologic symptoms and signs accompanied by cytologic clearing of leukemic cells from the cerebrospinal fluid.

Ninety-one patients with metastatic colorectal cancer were treated with continuous ambulatory 5-fluorouracil (5FU) infusion 250-300 mg/m2/day through a chronic indwelling central venous catheter. Twenty-six of the 91 patients (29%) had received previous bolus 5FU. Fifty-eight of the 91 patients (64%) had two or more sites of disease, and 74 of 91 patients (81%) had liver metastases. Results were complete remission in 5 of 91 (6%), partial remission in 25 of 91 (27%), stable disease in 33 of 91 (36%), and progressive disease in 28 of 91 (31%), for an overall response rate of 30 of 91 (33%); median duration of response was 7 months. Twenty-six of 65 previously untreated patients (40%) experienced objective response. Median survival from initiation of treatment for all patients was 11 months. Forty-one percent of patients experienced no significant toxicity and were able to continue therapy without treatment interruption. Toxicities necessitating treatment interruption included stomatitis in 35 patients (39%), hand-foot syndrome in 33 patients (36%), and diarrhea in 10 patients (11%). No significant myelosuppression or serious catheter-related complications were encountered. We conclude that continuous systemic venous infusion of 5FU produces a higher response rate than traditional bolus 5FU schedules, with apparent enhancement of survival and easily managed toxicity.

Severe aortic and mitral valvular insufficiency developed in a 52-year-old woman with systemic lupus erythematosis after previous treatment with corticosteroids, splenectomy, and cyclophosphamide for immune thrombocytopenia and hemolytic anemia. After aggressive management of the thrombocytopenia, simultaneous prosthetic replacement of both valves was satisfactorily performed; pathologic examination revealed myxoid degeneration. The patient was doing well with excellent valve function 26 months after the operation. The relationship of steroid therapy to lupus valvulitis is reviewed.

5-Fluorouracil (5FU) administered by prolonged intravenous infusion may more effectively treat advanced, slow-growing tumors with low growth fractions and long doubling times. Protracted infusion provides continual cancer cell exposure to 5FU; limitations due to cell cycle specificity and a short plasma half-life are theoretically circumvented. Advances in catheter composition and pump technology now make ambulatory infusion therapy widely available. Clinical trials suggest that prolonged infusion may improve the response rate in colorectal cancer. In addition, preliminary results suggest clinical activity against gastric, pancreatic and refractory breast cancers with minimal toxicity. Despite the potential logistic problems of infusion chemotherapy, many patients report improved quality of life. Increased costs incurred from infusion therapy are probably justifiable if survival is prolonged and quality of life maintained.

Three patients with previously undiagnosed renal cell carcinoma presented with complaints of shoulder pain secondary to tumor metastases involving the clavicle or upper humerus. In two patients, bone scintigraphy and/or gallium scintigraphy demonstrated the primary renal lesion. One patient had been treated with anti-inflammatory drugs and intra-articular steroid injections for presumed arthritis before the cause of the symptoms was recognized. Review of the literature reveals that renal cell carcinoma frequently metastasizes to bones of the shoulder girdle, and that presenting complaints may relate to osseous metastases. Careful evaluation should be carried out before patients with shoulder pain are treated for presumed arthritis.

The clinical and pathologic features of five cases of a previously poorly defined syndrome, benign mesothelial proliferation with effusion, are described. Although this is a benign process, both the gross and the microscopic findings may mimic metastatic papillary adenocarcinoma. Three of five patients had dysynchronous Involvement in more than one body cavity developing over intervals of one, two, and six years. The clinical course is unpredictable and is usually associated with a good prognosis, but two of three patients with pericardial involvement required pericardectomy for pericardial tamponade. The entity of benign mesothelial proliferation with effusion and its distinction from true malignant conditions are discussed.

Nieświszcze, Cynomys ludovicianus (Ord, 1817), wystepują licznie na preriach amerykanskich na wschod od Gor Skalistych, od poludniowej Kanady az po Meksyk. Na pastwiskach mogą one konkurowac z bydlem domowym, poniewaz odzywiają sie tymi samymi roślinami. Na 20 dorastających nieświszczach, w ciągu trzech miesiecy wykonano 4 kolejne serie doświadczen zywieniowych, z ktorych kazda trwala 15-18 dni. Zwierzeta trzymano dwojkami w klatkach metabolicznych, karmiono je standardową paszą (Tabela 1), określano dokladnie konsumpcje i fekalia.

Until now, the value of Mima mounds to pocket gophers has been speculative. I found a higher rate of survival for adults than young in a live-trapping study from 1955 to 1959 on Black Mesa, Gunnison County, Colorado. The vegetation is spruce-fir and aspen forest with large grass-forb parks which are grazed by cattle during the summer. The study area was in the eastern part of Long Gulch Park at about 10,300 ft elevation on a south exposure with a slope of about 1%o. The study area is characterized by Mima-type microrelief (cf. Scheffer 1958). Mima mounds are presumed to be the result of activity by pocket gophers (Figure 1).

A patient with refractory acute myelogenous leukemia was treated with high-dose cytosine arabinoside (3.0 g/m2 every 12 hours). Following ten doses over five days the patient developed excessive tearing, photophobia, burning ocular pain, and blurred vision. Ophthalmologic examination revealed conjunctival injection, central punctate corneal opacities with subepithelial granular deposits, and decreased visual acuity. Symptoms gradually resolved over the following four days; however, impaired visual acuity persisted for two weeks and corneal opacification did not disappear until four weeks following therapy. Prior and subsequent administration of cytosine arabinoside according to the same dose schedule for only four doses over two days and eight doses over four days were well tolerated and did not produce ocular toxicity. It is suggested that ocular toxicity results from inhibition of corneal epithelial DNA synthesis and is related to both drug dosage and duration of drug exposure. Strategies should be explored to eliminate this treatment-limiting adverse effect of potentially effective therapy.

An unresectable, intraabdominal recurrence of a nonfunctioning islet cell carcinoma of the pancreas developed in a 56-year-old man 9 years after he achieved complete remission from extensive radiotherapy. Chronic renal failure secondary to radiation nephritis precluded the use of streptozotocin. 5-fluorouracil (5-FU) (300 mg/m2 per day) was given as a continuous, systemic infusion through a chronic indwelling central venous catheter for 1 year's duration. Treatment resulted in the prompt disappearance of all signs and symptoms of cancer, and computed tomography (CT) of the abdomen documented complete response. The patient continues in complete clinical remission 16 months after 5-FU was stopped. Continuous 5-FU infusion may be a potentially efficacious and less toxic alternative to streptozotocin in the treatment of islet cell carcinoma. Further clinical evaluation will be necessary to define its overall role in the management of these patients.

On caracterise la vegetation et les sols des Terriers abandonnes de Cynomys ludovicianus et utilises pour nidifier par Athene cunicularia et on les compare avec ceux des terriers non occupes par l'oiseau

A 30-year-old white man with Stage IV B Hodgkin's disease, mixed cellularity type, developed leptomeningeal involvement shortly after relapsing on nitrogen mustard, Oncovin (vincristine), procarbazine, and prednisone (MOPP), and while receiving Adriamycin (doxorubicin), bleomycin, Velban (vinblastine), and dacarbazine (ABVD). Whole brain irradiation and intrathecal methotrexate were successfully incorporated into his treatment program. The patient has now been in complete remission for more than 40 months. A review of this rare complication of Hodgkin's disease is presented.

A case of diffuse histiocytic lymphoma with sclerosis and chylous pleural and peritoneal effusions spanning four years from onset to diagnosis is presented. Treatment with combination chemotherapy and consolidative radiotherapy resulted in clinical improvement and the patient remains free of disease 14 months after stopping treatment. The problems of chylous effusions and the subgroup of diffuse histiocytic lymphoma with sclerosis are discussed.

The length of time between feeding and egestion of plants was determined by the identification of plant fragments in fecal pellets with a microscope at 125× for 3 species of grasshoppers. Aeoloplides turnbulli (Thomas), Melanoplus angustipennis (Dodge), and M. joedus Scudder. Lambsquarter was digested more rapidly by these grasshoppers than was Kentucky bluegrass, possibly because these insects are adapted for feeding mainly on forbs.

The dry-weight composition of the diet and the food preferences were determined for Anabrus simplex Haldeman, inhabiting an arid ponderosa pine-bunchgrass community in northern Colorado. Thirty-five plant species were microscopically identified from the crops of this insect. Only 2-4 staple foods occurred in the diet during any period. Although primarily herbivorous, Mormon crickets were found to be carnivorous and fungivorous. Forbs contributed an average of about 50% of the diet, while arthropods and fungi contributed about 21 and 16%, respectively. Grasses, clubmoss. and grasslike plants comprised about 6, 5, and 2% of the diet, respectively. Diet and food preference changed as the season progressed.

SUMMARY The lymphoproliferative disorders and the myelodysplastic syndromes are thought to result from the clonal expansion of a single abnormal precursor cell. Seven patients who were found to have concurrent myelodysplasia and lymphoproliferation are described. In all cases myelodysplasia and lymphoproliferation were diagnosed simultaneously or myelodysplasia preceded overt lymphoproliferation by a brief interval. Thus, myelodysplasia in these patients was not related to treatment given for a lymphoproliferative disorder. Stem cell theory is reviewed with special reference to evidence for an adult human stem cell common to both haemopoietic and lymphoid cell lines (CFU-L-M). The presence of concurrent myelodysplasia and lymphoproliferation in these seven patients may be the result of the clonal expansion of an abnormal pluripotential stem cell. It may be possible in some cases to achieve remission of the lymphoproliferative disorder with return of normal haematopoiesis if residual normal stem cells are present and repopulate the marrow following cytotoxic therapy.

Thirteen patients with metastatic colorectal adenocarcinoma underwent treatment with continuous ambulatory 5-fluorouracil (5-FU) infusion 300 mg/m2/day and intermittent bolus methotrexate (MTX) (200 mg/m2) with calcium leucovorin (LCV) 10 mg/m2 orally every 6 h X four to eight doses given 24 h after MTX. Although MTX administration was planned every 14 days, the average time between treatments exceeded 19 days (range 14-42) because of excessive toxicity. All patients experienced toxicity at some time in their treatment course, requiring interruption of 5-FU infusion in 12 of 13 patients. Significant toxicities included stomatitis (13 of 13 patients), hand-foot syndrome (8 of 13 patients), and diarrhea (3 of 13 patients). Toxicity did not appear to be minimized by attenuation of MTX and/or 5-FU dosage or by increasing the dose and/or duration of LCV. At this dosage schedule the addition of MTX/LCV to 5-FU infusion results in excessive and unacceptable toxicity and does not appear to improve treatment results.

Excerpt The administration of lithium has been associated with granulocytosis in psychiatric patients and those with Felty's syndrome. Lithium can attenuate neutropenia in patients receiving cancer...

Forty-four patients with locally recurrent or metastatic colorectal adenocarcinoma were treated with methotrexate (MTX) 100 mg/m2 i.v. followed 1 h later by 5-fluorouracil (5-FU) 600 mg/m2 i.v. Calcium leucovorin 10 mg/m2 p.o. q 6 h X four doses was given 24 h after MTX. The regimen was given on days 1 and 8 and repeated every 28 days. Six of 44 patients (14%) obtained either complete or partial response with a mean response duration of 6.8 months. Of 26 previously untreated patients there were one complete response (4%), four partial responses (15%), and 12 (46%) instances of stabilization of disease. Patients obtaining response or stabilization of disease experienced improved survival compared to those with progressive disease. Toxicity consisted of stomatitis and hematopoietic suppression requiring dose attenuation in six patients (14%); there were no treatment-related deaths. Sequenced MTX/5-FU is modestly active with acceptable toxicity in previously untreated patients with colorectal adenocarcinoma but offers no apparent advantage over single-agent 5-FU.