Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508).

BACKGROUND: Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. METHODS: Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). RESULTS: Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. CONCLUSIONS: The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. CLINICALTRIALS.GOV IDENTIFIER: NCT00955305.

Incidence of traumatic spinal cord injury in Denmark, 1990-2012: a hospital-based study.

STUDY DESIGN: Hospital-based incidence study. OBJECTIVES: To assess the incidence of traumatic spinal cord injuries (TSCIs) and TSCI incidence trends in relation to cause, age, gender, level and completeness of injury. SETTING: Spinal Cord Injury Centre of Western Denmark. METHODS: We reviewed medical records of TSCI patients admitted between 1 January 1990 and 31 December 2012. Proportions, incidence rates and incidence rate ratios were calculated for five time periods; 1990-94, 1995-99, 2000-04, 2005-09 and 2010-12, and were stratified on age, gender, cause, level and completeness of TSCI. TSCI incidence was calculated as the number of new cases divided by person-years at risk. RESULTS: Included were 691 patients (males 81.9%). Within the study period, median age at time of injury rose from 29.0 to 47.5 years. The overall annual TSCI incidence during the study period 1990-94 to 2010-12 was 10.2 per million person-years at risk and varied from 8.3 to 11.8. The proportion of transport-related injuries fell from 56.9% in the first to 36.8% in the most recent time period. Fall-related injuries rose from 11.1 to 35.5%. The proportion of incomplete tetraplegia increased from 32.0% in the first to 40.5% in the last time period. CONCLUSIONS: The overall TSCI incidence is low and remained stable from 1990 to 2012. The proportion of transport-related injuries fell, while age at time of injury and proportion of fall-related injuries and proportion with incomplete tetraplegia all increased.

Estimating the glomerular filtration rate using serum cystatin C levels in patients with spinal cord injuries.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To investigate the relationship between (51)chromium-ethylene-diamine-tetra-acetate ((51)Cr-EDTA) clearance, serum cystatin C (CysC), serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR(MDRD), MDRD stands for modification of diet in renal disease) based on the serum creatinine in patients with complete or incomplete spinal cord injury (SCI) and to develop and evaluate a GFR-estimating equation using serum CysC. SETTINGS: Spinal Cord Injury Unit, Viborg Regional Hospital, Viborg, Denmark. METHODS: Ninety-eight men and 47 women with SCI were included in the study. Serum CysC levels were measured by an automated particle-enhanced nephelometric immunoassay, serum and urine creatinine levels were measured by an enzymatic method traceable to the IDMS creatinine reference method, and (51)Cr-EDTA clearance was measured by a multiple plasma sample method. RESULTS: The area under the curves (AUCs) in the non-parametric receiver operating characteristics (ROC) plots for serum CysC were compared with serum creatinine and to eGFR(MDRD) and revealed a significant difference (P-value < 0.05) for all SCI patients. There was no significant difference between the AUC for serum CysC compared with the AUC for creatinine clearance. GFR (ml min(-1) per 1.73 m(2)) can be calculated from serum CysC values (mg l(-1)) using the equation eGFR(CysC) = 212·exp(0.914·CysC). The model accurately predicted the GFR of 88% of patients within ± 30% of the measured GFR, and it was able to predict the GFR of 50% of patients within ± 10% of the measured GFR. CONCLUSION: In patients with SCI, GFR can be estimated independent of age, sex and muscle mass by a newly developed equation based on a single serum CysC value.

Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer.

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/m2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m2), treatment B (bolus 5-FU at 500 mg/m2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m2, plus weekly cisplatin at 20 mg/m2), treatment C (5-FU at 300 mg/m2 per day by continuous infusion), or treatment D (5-FU at 300 mg/m2 per day by continuous infusion plus weekly cisplatin at 20 mg/m2). 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.

Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside.

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.

Allogeneic bone marrow transplantation for relapsed and refractory lymphoma using genotypically HLA-identical and alternative donors.

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.

Systemic therapy in metastatic colorectal cancer.

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.

Remission of chronic lymphocytic leukemia after smallpox vaccination.

A 78-year-old man with untreated chronic lymphocytic leukemia (CLL) was revaccinated for smallpox. A severe local reaction and generalized rash followed that responded to treatment with vaccinia immune human globulin. After recovery, the leukocyte count fell to normal and all evidence of CLL disappeared. He remains in complete remission three years after smallpox vaccination.

Failure to suspect and diagnose thalassemic syndromes. Interpretation of RBC indices by the nonhematologist.

A three-year review of the medical records of 76 patients with apparent thalassemic syndromes (mean corpuscular volume, greater than 75 cu micron; RBC count, greater than 5 X 10(6)/cu mm) was performed to assess overall physician response to this information at a midwestern teaching institution. Abnormal indices were recognized in only 50% of the cases; in only 32% of cases was a thalassemic syndrome considered in the differential diagnosis. Residents in internal medicine failed to recognize microcytic indices and to consider thalassemic syndromes 42% and 59% of the time, respectively. Even though hemoglobin electrophoresis was performed in 25 patients, in only 15 (56%) of the 25 cases was beta-thalassemia proved or alpha-thalassemia presumptively diagnosed. In 17% of all cases, the patients were treated with iron without diagnostic findings on iron studies and/or in spite of data suggesting a thalassemic syndrome. The RBC indices are an underused portion of the complete blood cell count, and readily apparent thalassemic syndromes are often not considered.

Successful high-dose intravenous cytarabine treatment of parenchymal brain involvement from malignant lymphoma.

A patient with systemic recurrence of large-cell malignant lymphoma developed radiologic evidence of parenchymal brain metastasis. Treatment with systemic high-dose cytarabine resulted in complete regression of peripheral adenopathy and complete radiologic response in the central nervous system, with normalization of the brain computed tomographic scan. This case further demonstrates the ability of high-dose cytarabine to penetrate the blood-brain barrier and achieve therapeutic drug concentrations in the central nervous system, an area that might otherwise remain a pharmacologic sanctuary for tumor cells.

Ketoconazole in the prevention of candidiasis in patients with cancer. A prospective, randomized, controlled, double-blind study.

A prospective, randomized, controlled, double-blind study was performed between 1982 and 1985 to assess the ability of ketoconazole to prevent fungal infections in selected patients with cancer. Fifty-six patients receiving induction chemotherapy for acute leukemia, autologous bone marrow transplant for refractory nonhematopoietic malignant neoplasms, multidrug chemotherapy for malignant lymphoma, or corticosteroids for brain metastases were randomized to receive either oral ketoconazole, 400 mg/d, or placebo and observed until leukopenia resolved or corticosteroid therapy was stopped. Oral candidiasis developed in eight (28%) of 29 patients receiving placebo compared with none of 27 receiving ketoconazole. However, ketoconazole failed to prevent Candida esophagitis and vulvovaginitis in two patients and one patient, respectively. Furthermore, prophylactic use of ketoconazole did not significantly alter the total number of hospital days, febrile days, or antibiotic days or the requirement for amphotericin B in patients with acute leukemia and autologous bone marrow transplant. Since oral candidiasis can be successfully managed by several different treatment modalities when it does occur, we do not think that the routine prophylactic use of ketoconazole is justified.

Benign mesothelial proliferation with effusion. Clinicopathologic entity that may mimic malignancy.

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.

The role of thoracic and cranial irradiation for small cell carcinoma of the lung.

Since 1974, 120 previously untreated patients with small cell carcinoma of the lung seen in Therapeutic Radiology at The Medical College of Wisconsin have been entered into one of 4 successive studies. Study I used thoracic irradiation (TI) alone (4500-6000 rad in 3-6 weeks) with chemotherapy at progression. Study II randomized patients with limited disease to TI (3000 rad in 2 weeks) plus either cyclophosphamide, doxorubicin, vincristine (CAV) or total body irradiation (TBI); patients with extensive disease received TI + CAV. Study III employed prophylactic cranial irradiation (PCI) plus CAV and withheld TI unless there was incomplete response or recurrence. Of 93 evaluable patients from the first three studies, 55 had limited and 38 extensive disease. Study I (37 patients) showed a 62% complete response (CR) rate; 43% failed in the chest, 14% had brain metastases, and the median survival was only 22 weeks in spite of a preponderance of limited disease patients. Study II (27 patients) showed a CR of 59%; 30% had brain metastases and the median survival was 48 weeks. Study II patients (29) had a 69% rate; 72% failed in the chest, 4% with PCI developed brain metastases, and the median survival was 50 weeks. In March, 1979, Study IV was initiated; patients receive PCI (2500 rad in 2 weeks) plus high dose CAV, methotrexate and leucovorin. After 6 cycles, consolidation TI (3750 rad in 3 weeks) is given to patients with complete response. Preliminary results with 27 patients treated on this study show a 67% CR rate, a 41% chest failure rate (but only 11% for the patients who received thoracic irradiation) and no intracranial failures, but a 13% extracranial CNS failure rate. PCI, TI and spinal irradiation may be necessary to maximize the probability of long term disease free survival.

Marked congenital fissure masquerading as splenic laceration: report of a case.

A 26-year-old white woman fell from a ladder striking her back. Clinical evaluation indicated a left renal contusion with microscopic hematuria, and a liver-spleen scan suggested a splenic laceration. The patient was initially stable but evidence of ongoing blood loss forced exploratory laparotomy on the third hospital day. A large, retroperitoneal perirenal hematoma was found but the spleen was intact, with multiple marked congenital fissures. The problem of congenital fissures as a cause of abnormal spleen scan is discussed.

Pupillary changes during dark adaptation in human infants.

Pupillary diameter of 10 infants (age 10 weeks) and four adult subjects was measured during 30 min of dark adaptation following exposure to a full-field adapting light. Adult results confirm that, under these conditions, the course of pupillary recovery was reasonably well described by an exponential time course (t0 = 408 sec; SD = 42 sec), as is rhodopsin regeneration. Pupillary recovery of infants also could be described by an exponential course (average t0 = 399 sec; SD = 31 sec). These results, demonstrating similarities between adaptive functions of infants and adults, suggest that pupillographic techniques can be used to investigate dynamic processes accompanying dark adaptation in preverbal children.

Behavioral measurement of background adaptation in infants.

Thresholds for detecting blue test flashes in the dark-adapted condition and on steady red background fields were measured in 2- to 18-week-old human infants by a two-alternative forced-choice preferential looking method. The results show that dark-adapted sensitivity increases and background adaptation develops during the early postnatal weeks. Thus, the retinal mechanism that underlie (1) detection of brief flashes and (2) neural processing in background adaptation appear to mature postnatally.

Scotopic optokinetic nystagmus thresholds in 10-week-old infants.

PURPOSE: To compare psychophysical and reflexive optokinetic nystagmus (OKN) estimates of dark-adapted scotopic thresholds mediated by the posterior retina in 10-week-old infants and adults. METHODS: A staircase procedure was used to determine the stimulus intensity needed to produce an OKN response to a moving 19 degrees x 19 degrees grating. In the same subjects, a two-alternative, forced-choice procedure was used to obtain thresholds for detecting 10 degrees diameter, 50 ms duration stimuli. RESULTS: Both OKN and psychophysical thresholds of infants are 0.9 log unit higher than those of adults. CONCLUSION: The infant-adult difference in thresholds mediated by retina at the posterior pole is greater than the infant-adult difference in thresholds for full-field stimuli. It is possible that delayed maturation of the posterior retina is the primary determinant of infants' high OKN and psychophysical thresholds.

The development of scotopic sensitivity.

UNLABELLED: PURPOSE. Test the hypothesis that the developmental increases in rod photoreceptor sensitivity and rod-mediated visual sensitivity at 10 degrees, 20 degrees , and 30 degrees eccentric are concurrent. It is known that maturation of the parafoveal (10 degrees eccentric) rod outer segments and visual sensitivity is delayed compared to that at 30 degrees eccentric. METHODS: Rod isolated electroretinographic (ERG) responses to full-field stimuli were obtained from dark-adapted subjects (n = 71), ranging in age from early infancy through middle age. Rod photoreceptor sensitivity was calculated by fitting a model of the activation of phototransduction to the a-wave response. Rod driven b-wave sensitivity was calculated from stimulus-response functions. A logistic growth model was used to summarize the developmental increases in sensitivity of the rod photoreceptors and the b-wave. Previously reported dark-adapted, rod-mediated visual sensitivities at 10 degrees , 20 degrees, and 30 degrees eccentric, obtained using preferential looking procedures, were reanalyzed using the logistic growth model. RESULTS: The logistic growth model accounted for 57% to 85% of the variance of each sensitivity parameter with age in normal subjects. The shape of the growth curve and the age at which sensitivity reaches 50% of the adult value is similar (10.0-13.5 weeks) for the rods, the b-wave, and peripheral visual sensitivity, but is significantly older, 19.5 weeks, for rod-mediated parafoveal visual sensitivity. CONCLUSIONS: Rod photoreceptor sensitivity and peripheral, rod-mediated visual sensitivity develop concurrently. A parsimonious explanation is that rod photoreceptor sensitivity determines dark-adapted, rod-mediated visual sensitivity during development.

The course of maturation of rod-mediated visual thresholds in infants.

PURPOSE: To measure the developmental course of infants' rod-mediated thresholds. METHODS: Thresholds for detecting stimuli (2 degrees diameter, 50 msec duration) presented at 10 degrees (parafoveal site) or 30 degrees (peripheral site) from a central fixation target were estimated using a preferential-looking method. Nine infants were tested at both stimulus positions at ages 10, 18, and 26 weeks. RESULTS: At 10 weeks, infants' thresholds at both sites were significantly higher than those of adults. The infants' average threshold at 10 degrees was 0.5 log unit higher than the infants' average threshold at 30 degrees. Adults' thresholds at the two sites were equal. Thresholds of all infants decreased with age until by age 26 weeks the parafoveal and peripheral thresholds were equal and were the same as those of adults. The rate of change of parafoveal thresholds was significantly faster than the rate of change of peripheral thresholds. CONCLUSIONS: Although postreceptoral factors cannot be ruled out, the results suggest that developmental increases in rod outer segment length and rhodopsin density account for most of the threshold changes during infancy.

Rod-mediated increment threshold functions in infants.

PURPOSE: To obtain and analyze scotopic increment threshold functions to test the hypothesis that rod photoreceptor immaturity accounts for the elevation of infants' over controls' dark-adapted thresholds and elevation of parafoveal over peripheral thresholds in infants. METHODS: Using a preferential looking method, thresholds for detection of 2(o), 50 msec, blue stimuli presented 10(o) (parafoveal) or 30(o) (peripheral) eccentric were measured in the dark and in the presence of steady red backgrounds. Ten 10-week-old infants and four control subjects (8-35 years) were tested. To evaluate pre- and postadaptation site determinants of threshold, a model of the increment threshold function was fit to the data, and the dark-adapted threshold (T(D)) and eigengrau (A(O)) were calculated. The values of T(D) and A(O) were compared between infants and controls and between parafoveal and peripheral eccentricities. RESULTS: At both parafoveal and peripheral eccentricities, infants' values of T(D) and A(O) were significantly higher than those of controls. The locus of the coordinates (A(O), T(D)) differed significantly between parafoveal and peripheral eccentricities. In every infant, the parafoveal value of T(D) was higher (by 0.3-0.6 log unit) and A(O) lower (by 0.2-0.5 log unit) than the peripheral value, whereas controls had no difference in T(D) and A(O) at the two eccentricities. CONCLUSIONS: The results indicate that both receptoral and postreceptoral immaturities have a role in the elevation of infants' over controls' thresholds. In infants, rod photoreceptor immaturity before the site of adaptation accounts for elevation of parafoveal over peripheral thresholds.