A perspective on global access to insulin: a descriptive study of the market, trade flows and prices.

AIM: To describe the global insulin market. METHODS: Market intelligence data, United Nations Commodity Trade Statistics for insulin trade, the International Medical Products Price Guide for prices of human insulin and additional web searches were used as data sources. These sources were combined to gain further insight into possible links among market, trade flows and prices. Descriptive statistics and Spearman's rank order correlation were used for the analysis. RESULTS: A total of 34 insulin manufacturers were identified. Most countries and territories are reliant on a limited number of supplying countries. The overall median (interquartile range) government procurement price for a 10-ml, 100-IU/ml vial during the period 1996-2013 equivalent was US$4.3 (US$ 3.8-4.8), with median prices in Africa (US$ 4.7) and low- (US$ 6.9) and low- to middle- (US$ 4.7) income countries being higher over this period. The relationships between price and quantity of insulin (Spearman's r=0.046; P>0.1) and number of import links (Spearman's r=0.032; P>0.1) were weak. The links between price and percentage of total insulin from a country where a 'big three' manufacturer produces insulin (Spearman's r=0.294; P<0.05) and total insulin from the main import link (Spearman's r=-0.392; P<0.05) were stronger. CONCLUSIONS: This research shows the high variability of insulin prices and the reliance on a few sources, both companies and countries, for global supply. In addressing access to insulin, countries need to use existing price data to negotiate prices, and mechanisms need to be developed to foster competition and security of supply of insulin, given the limited number of truly global producers.

Correlation between pre-ramadan glycemic control and subsequent glucose fluctuation during fasting in adolescents with Type 1 diabetes.

BACKGROUND: Even though patients with type 1 diabetes mellitus (T1DM) are exempted from fasting, the vast majority elect to fast against the advice of their healthcare providers. We have previously reported the incidence of wide fluctuations in blood glucose (BG) along with "unrecognized" severe hypoglycemia during Ramadan fasting in adolescents with T1DM. This report compares the continuous glucose monitoring (CGM) data during fasting in adolescents with T1DM according to their Pre-Ramadan diabetes control. METHODS: Children and adolescents with T1DM who intended to fast the month of Ramadan were asked to wear the CGM during fasting for a minimum of 3 days. Hypoglycemia, hyperglycemia, and severe hyperglycemia were identified as BG <70 mg/dL (3.9 mmol/L), BG 201-300 mg/dL (11.2-16.7 mmol/L), or BG >300 mg/dL (16.7 mmol/L) respectively, while normoglycemia was identified as BG 70-200 mg/dL (3.9-11.1 mmol/L). Patients were categorized as well-controlled (Group 1) and poorly controlled (Group 2) if the pre-fasting HbA1C was ≤8% (64 mmol/mol) and >8%, respectively. We compared the mean BG and the percentages of time spent in hypoglycemia, hyperglycemia, and severe hyperglycemia between the two groups using Chi-square (significant difference when P value was <0.05). RESULTS: A total of 21 patients were enrolled (15 females), age 15 ± 4 years, duration of diabetes 6 ± 3 years, and HbA1C 8.5 ± 1.0% (70 mmol/mol). There were 7 subjects in Group 1, mean HbA1C 7.5 ± 0.4, and 14 subjects in Group 2, mean HbA1C 9.1 ± 0.9. The mean ± SD BG was 174 ± 76 mg/dL versus 199 ± 98, (P < 0.05) in Group 1 and Group 2, respectively. The percentages of hypoglycemia, hyperglycemia, and severe hyperglycemia were significantly higher in Group 2, while there was a higher percentage of normoglycemia in Group 1. The overall durations of hypoglycemia, hyperglycemia, and severe hyperglycemia in Group 2 were longer by 30, 14, and 135%, respectively, than those in Group 1. CONCLUSIONS: Glycemic control before Ramadan in adolescents with T1 DM appears to correlate with blood glucose profile during Ramadan fasting. Our data suggest that optimal glycemic control before Ramadan may reduce the potential risks associated with fasting and minimize glucose fluctuation.

The effect of Fe-coverage on the structure, morphology and magnetic properties of α-FeSi2 nanoislands.

Self-assembled α-FeSi(2) nanoislands were formed using solid-phase epitaxy of low (~1.2 ML) and high (~21 ML) Fe coverages onto vicinal Si(111) surfaces followed by thermal annealing. At a resulting low Fe-covered Si(111) surface, we observed in situ, by real-time scanning tunneling microscopy and surface electron diffraction, the entire sequence of Fe-silicide formation and transformation from the initially two-dimensional (2 × 2)-reconstructed layer at 300 °C into (2 × 2)-reconstructed nanoislands decorating the vicinal step-bunch edges in a self-ordered fashion at higher temperatures. In contrast, the silicide nanoislands at a high Fe-covered surface were noticeably larger, more three-dimensional, and randomly distributed all over the surface. Ex situ x-ray photoelectron spectroscopy and high-resolution transmission electron microscopy indicated the formation of an α-FeSi(2) island phase, in an α-FeSi(2){112} // Si{111} orientation. Superconducting quantum interference device magnetometry showed considerable superparamagnetism, with ~1.9 µ(B)/Fe atom at 4 K for the low Fe-coverage, indicating stronger ferromagnetic coupling of individual magnetic moments, as compared to high Fe-coverage, where the calculated moments were only ~0.8 µ(B)/Fe atom. Such anomalous magnetic behavior, particularly for the low Fe-coverage case, is radically different from the non-magnetic bulk α-FeSi(2) phase, and may open new pathways to high-density magnetic memory storage devices.

Assessment and referral of patients with short stature by primary care physicians in the Arabian gulf region: Current perspectives from a regional survey.

Children with short stature are frequently referred late to pediatric endocrinologists in the Arabian Gulf region. This is likely a contributing factor to late initiation of treatment despite current evidence suggesting that children with short stature have better outcomes with earlier treatment. This delay in referral could be due to a lack of identification or proper assessment of short stature by front-line physicians. To analyze the assessment and perception of short stature in this group of physicians, an expert group of pediatric endocrinologists developed and disseminated an anonymous online survey of 22 multiple choice questions amongst general pediatricians, pediatric subspecialists, and family medicine physicians in the Arabian Gulf region. Of the 640 respondents, 450 completed the survey (70.3% completion rate). While most surveyed physicians use the correct definition for short stature in children, only 24% reported a consistent use of a wall-mounted stadiometer. Of the respondents, 50% or less would consider referring clinical conditions other than growth hormone (GH) deficiency or idiopathic short stature, 41% would refer a child with short stature as soon as height dropped below the 5th percentile, 57% considered GH a treatment option for short stature, and only 60% consider GH treatment safe. The results of this survey demonstrate knowledge gaps in short stature assessment and referral that need to be addressed through education on short stature amongst target physicians, and lay groundwork for future recommendations to address those gaps in the Arabian Gulf region.

Shape-controlled nanopores in single crystals.

Nanometer length-scale holes (nanopores) are often formed in amorphous materials for fundamental studies of molecular mass transport. In the current study, electron beam irradiation in the transmission electron microscope was used to form nanopores in a crystalline material (Si). Analysis of the nanopores showed that they are formed by knock-on of atoms by the high energy incident electron beam, and surface diffusion is partially responsible for the hour-glass shapes that are found for some nanopores. Energetically favorable three-dimensional shapes of nanopores were simulated, and the nanopores simulated in the model crystalline material were found to be more stable than the nanopores simulated in the amorphous material. The nanopore shape was also found to depend on the nanopore diameter-to-length ratio. Based on the above, we demonstrate the advantage in using a crystalline material for nanopore formation and show that control of the three-dimensional shape of nanopores formed by electron beam irradiation is possible.

An experimental method for calibration of the plasmon mean free path.

Transmission electron microscopy specimens in the form of elongated, conical needles were made using a dual-beam focused ion beam system, allowing the specimen thickness to be geometrically determined for a range of thickness values. From the same samples electron energy loss maps were acquired and the plasmon mean free path (lambda) for inelastic scattering was determined experimentally from the measured values of specimen thickness. To test the method lambda was determined for Ni (174 +/- 17 nm), alpha-Al(2)O(3) (143 +/- 14 nm), Si (199 +/- 20 nm) and amorphous SiO(2) (238 +/- 12 nm), and compared both to experimental values of lambda taken from the literature and to calculated values. The calculated values of lambda significantly underestimate the true sample thickness for high accelerating voltages (300 kV) and large collection angles. A linear dependence of lambda on thickness was confirmed for t/lambda < 0.5-0.6, but this method also provides an approach for calibrating lambda at sample thicknesses for which multiple scattering occurs, thus expanding the thickness range over which electron energy loss spectroscopy can be used to determine the absolute sample thickness (t/lambda > 0.6). The experimental method proposed in this contribution offers a means to calibrate lambda for any type of material or phase that can be milled using a focused ion beam system.

Quantitative HRTEM analysis of FIB prepared specimens.

The preparation of good transmission electron microscopy specimens with minimum milling damage can be very complicated, especially from a specific area in a sample. Therefore, a novel approach for transmission electron microscopy specimen preparation using a focused ion beam system is proposed, based on the use of low energy (5 kV)Ga ions and a low incident ion angle (approximately 1 degree ) from a thickness of approximately 500 nm until the sample is electron transparent. Transmission electron microscopy specimens prepared by this method have significantly less irradiation damage, demonstrated by successful quantitative high-resolution transmission electron microscopy conducted on sapphire from data acquired using an aberration-corrected field emission gun transmission electron microscopy. Quantitative analysis was conducted by iterative digital image matching. The accuracy and sensitivity of the matching process is discussed.

Optical control of capacitance in a metal-insulator-semiconductor diode with embedded metal nanoparticles.

This paper describes a metal-insulator-semiconductor (MIS) capacitor with flat capacitance voltage characteristics and a small quadratic voltage capacitance coefficient. The device characteristics resemble a metal-insulator-metal diode except that here the capacitance depends on illumination and exhibits a strong frequency dispersion. The device incorporates Fe nanoparticles (NPs), mixed with SrF2, which are embedded in an insulator stack of SiO2 and HfO2. Positively charged Fe ions induce dipole type traps with an electronic polarization that is enhanced by photogenerated carriers injected from the substrate and/or by inter nanoparticle exchange of carriers. The obtained characteristics are compared with those of five other MIS structures: two based on Fe NPs, one with and the other without SrF2 sublayers. Additionally, devices contain Co NPs embedded in SrF2 sublayers, and finally, two structures have no NPs, with one based on a stack of SiO2 and HfO2 and the other which also includes SrF2. Only structures containing Fe NPs, which are incorporated into SrF2, yield a voltage independent capacitance, the level of which can be changed by illumination. These properties are essential in radio frequency/analog mixed signal applications.

Prices and availability of locally produced and imported medicines in Ethiopia and Tanzania.

BACKGROUND: To assess the effect of policies supporting local medicine production to improve access to medicines. METHODS: We adapted the WHO/HAI instruments measuring medicines availability and prices to differentiate local from imported products, then pilot tested in Ethiopia and Tanzania. In each outlet, prices were recorded for all products in stock for medicines on a country-specific list. Government procurement prices were also collected. Prices were compared to an international reference and expressed as median price ratios (MPR). RESULTS: The Ethiopian government paid more for local products (median MPR = 1.20) than for imports (median MPR = 0.84). Eight of nine medicines procured as both local and imported products were cheaper when imported. Availability was better for local products compared to imports, in the public (48% vs. 19%, respectively) and private (54% vs. 35%, respectively) sectors. Patient prices were lower for imports in the public sector (median MPR = 1.18[imported] vs. 1.44[local]) and higher in the private sector (median MPR = 5.42[imported] vs. 1.85[local]). In the public sector, patients paid 17% and 53% more than the government procurement price for local and imported products, respectively. The Tanzanian government paid less for local products (median MPR = 0.69) than imports (median MPR = 1.34). In the public sector, availability of local and imported products was 21% and 32% respectively, with patients paying slightly more for local products (median MPR = 1.35[imported] vs. 1.44[local]). In the private sector, local products were less available (21%) than imports (70%) but prices were similar (median MPR = 2.29[imported] vs. 2.27[local]). In the public sector, patients paid 135% and 65% more than the government procurement price for local and imported products, respectively. CONCLUSIONS: Our results show how local production can affect availability and prices, and how it can be influenced by preferential purchasing and mark-ups in the public sector. Governments need to evaluate the impact of local production policies, and adjust policies to protect patients from paying more for local products.

Radiolocalization of human mammary tumors in athymic mice by a monoclonal antibody.

Monoclonal antibody B6.2 reacts with a protein found on the surface of primary and metastatic human mammary tumors. B6.2 immunoglobulin G (IgG) was purified, F(ab')2 and Fab' fragments were generated by pepsin digestion, and the IgG and its fragments were radiolabeled with 125I; all were successful in localizing human mammary tumors transplanted into athymic mice, with tumor:tissue ratios increasing over a 4-day period. The 125I-labeled IgG gave tumor:spleen, tumor:liver, and tumor:kidney ratios of greater than 10:1 and tumor:brain and tumor:muscle ratios of 50:1 to 110:1. The F(ab')2 fragment gave higher tumor:tissue ratios than did the IgG, with tumor:liver and tumor:spleen ratios of 15:1 to 20:1. No localization of the labeled B6.2 monoclonal antibody or its fragments was observed in athymic mice bearing a human melanoma or with isotype-identical control immunoglobulin or its fragments in athymic mice bearing the mammary tumors. Imaging experiments confirmed the ability of radiolabeled monoclonal antibody B6.2 and its fragments to detect the presence of transplanted human mammary tumor lesions of less than 0.4 cm without the aid of background subtraction manipulations.

Pharmacokinetics of radiolabeled monoclonal antibody B6.2 in patients with metastatic breast cancer.

Thirteen patients with metastatic breast carcinoma were given injections of 50-1593 micrograms of 131I-monoclonal antibody (MAb) B6.2 immunoglobulin G and F(ab')2 for pharmacokinetic evaluation and radioimmunoimaging. Blood clearance of the 131I-MAb-B6.2 was biphasic. The mean half-times (t 1/2 alpha, t 1/2 beta) for the immunoglobulin G were 3.5 +/- 1.7 and 20.9 +/- 11.0 h, respectively. The t 1/2 alpha for the F(ab')2 was 1.7 +/- 1.3 h, and the t 1/2 beta was 31.0 +/- 5.7 h. The percentage of protein bound 131I for the immunoglobulin G and for the F(ab')2 at 72 h was 73.7 +/- 11.4% and 58.2 +/- 14.5%, respectively. In vitro reactivity of MAb B6.2 with granulocytes isolated from normal subjects and patients was demonstrated by cytofluorometric and radioimmunoassays. MAb B6.2 was shown to bind with normal cross-reacting antigen, a cell surface antigen known to be expressed on normal human granulocytes. Reactivity with normal cross-reacting antigen on granulocytes is consistent with the skeletal images obtained during immunoscintigraphy of all 13 patients. A specific tumor image was observed in one patient. No toxicity was encountered. In spite of extensive preclinical data suggesting that 131I-MAb B6.2 would be a useful agent for radioimmunoimaging, the clinical utility of this reagent is probably limited because of the reactivity with granulocytes.

Protection against daunorubicin cytotoxicity by expression of a cloned human carbonyl reductase cDNA in K562 leukemia cells.

Carbonyl reductase (CBR) catalyzes the reduction of daunorubicin (DN) to its corresponding alcohol, daunorubicinol (DNOL), and changes the pharmacological properties of this cancer chemotherapeutic drug. The DN reductase associated with CBR reduces the C13 methyl ketone group and does not metabolize the quinone ring of DN. Reports comparing DN and DNOL toxicity have resulted in various conclusions depending on the cells tested. Differences in toxicity could be due to variations in several enzymes involved in DN metabolism. In this report, the effects of CBR expression on DN metabolism and cell toxicity were determined by cloning and expressing a human CBR cDNA in DN reductase-deficient myeloid erythroleukemia K562 cells. CBR activity increased 83-fold in the K562-transfected cells and was associated with a 2-3-fold reduction in DN toxicity. Maximum protection occurred at 30 nM DN where 94% of the intracellular DN was converted to DNOL within 2 h. The reduced toxicity was specific for DN. Other CBR substrates such as menadione, phenanthrenequinone, and doxorubicin were equally toxic to both the CBR expresser cells and the control cells under the conditions tested. Our results suggest that high levels of CBR in tumor cells could contribute to drug resistance. The results also suggest that reduction of DN to DNOL protects against DN toxicity by altering interaction of the drug at one or more of the many target sites.

Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen.

A preliminary serotherapeutic trial was undertaken with a monoclonal antibody designated antibody 89 (Ab 89) directed against a lymphoma-associated antigen. In vitro studies demonstrated that Ab 89 could mediate complement-dependent lysis and macrophage adherence but not antibody-dependent cell-mediated cytotoxicity. To evaluate toxicity and therapeutic efficacy, two courses of Ab 89 were administered to a patient with an Ab 89-reactive tumor. Transient decreases in the number of circulating tumor cells and the appearance of circulating dead cells were noted with the infusion of Ab 89. Following administration of 150 mg or more of Ab 89, small amounts of antibody could be demonstrated on circulating tumor cells at a time when no free antibody was found in the serum. The inability to deliver a significant amount of Ab 89 to tumor cells in vivo is thought to be secondary to a circulating tumor antigen. Following each infusion, the amount of this blocking antigen decreased but could not be entirely cleared from the serum. This study provides preliminary evidence for the lack of clinical toxicity of a monoclonal antibody and identifies circulating blocking antigens as a significant obstacle to serotherapy.

Porcine class pi glutathione S-transferase: anionic ligand binding and conformational analysis.

The equilibrium binding of the non-substrate ligands 8-anilino-1-naphthalene sulfonate and bromosulfophthalein to porcine class pi glutathione S-transferase (pGSTP1-1) was studied using a variety of techniques (size-exclusion HPLC, steady-state fluorescence, second-derivative spectroscopy, and chemical modification of cysteines). Both ligands share the same binding site which has a highly hydrophobic surface. Occupation of the site inhibits catalytic function with glutathione and 1-chloro-2,4-dinitrobenzene in a non-competitive manner. Data obtained from different structural probes either located at strategic regions of pGSTP1-1 (Trp-28, Trp-38 and Cys-45) or distributed throughout the protein molecule (tyrosine residues) suggest that binding induces a microstructural change that impacts on the functional conformation of the active site.

Early restaging gallium scans predict outcome in poor-prognosis patients with aggressive non-Hodgkin's lymphoma treated with high-dose CHOP chemotherapy.

PURPOSE: This prospective study assessed the predictive value of early restaging gallium (Ga) and computed tomographic (CT) scans in poor-prognosis patients with aggressive non-Hodgkin's lymphoma (NHL) who were treated with high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Thirty newly diagnosed patients with bulky (> or = 10 cm) advanced-stage aggressive NHL were treated with a four-cycle high-dose CHOP regimen (22 patients at maximum-tolerated dose [MTD]: cyclophosphamide 4 g/m2, doxorubicin 70 mg/m2, vincristine 2 mg, and prednisone 100 mg orally for 5 days). All patients had chest/abdominal/pelvic CT scans and 10-mCi Ga scans at baseline and following two and four cycles of therapy. Scans were reviewed in a blinded manner for CT-documented rates of response and sizes of residual masses and Ga avidity of residual masses. The results of early (post-cycle 2) and final (post-cycle 4) restaging were subsequently associated with clinical outcome. RESULTS: CT-documented rates of response and residual mass sizes were indistinguishable in complete responders who remained continuously disease-free (CR-Cont), complete responders who subsequently relapsed (CR-Rel), and partial responders who then progressed (PR/Prog). In marked contrast, early restaging (post-cycle 2) Ga scans accurately delineated these three categories of patients: CR-Cont 90% Ga-negative (18 of 20 patients) versus CR-Rel 25% Ga-negative (one of four patients) versus PR/Prog 0% Ga-negative (zero of six patients) (P = .000014). At a median follow-up duration of 31 months (range, 21 to 46), 94% of patients who had negative early restaging Ga scans remain free from progression (FFP), whereas only 18% of patients who had positive early restaging Ga scans remain FFP (P = .000007). Early restaging Ga scans were more predictive for FFP than final restaging Ga scans because patients who required four full cycles of therapy to become Ga-negative were more likely to develop recurrent disease. CONCLUSION: Early restaging Ga scans delineate patients who are likely to have prolonged disease-free survival from those who fail to respond to intensive induction therapy. Patients whose tumors remain Ga-positive midway through high-dose CHOP therapy have a poor outcome and may be candidates for alternative treatment.

Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients.

PURPOSE: A retrospective study was performed to define clinical characteristics and therapeutic outcome for patients with large-cell and immunoblastic lymphoma of the mediastinum. PATIENTS AND METHODS: Fifty-seven patients who presented with primary, mediastinal large-cell and immunoblastic lymphoma were retrospectively studied to determine initial sites of disease, radiologic characteristics, treatment, outcome, and factors that have prognostic significance for progression-free and overall survival. RESULTS: Fifty-six of the 57 patients had disease that was confined to sites above the diaphragm. Bulky disease and extensive intrathoracic infiltration were common in these patients. All patients were treated with intensive chemotherapy regimens, and 44% of patients received chest irradiation. The overall 5-year survival by Kaplan-Meier estimation was 50% with a freedom-from-relapse rate of 45%. Predictors of disease relapse after chemotherapy included the presence of a pleural effusion (P = .015), a number of involved extranodal sites (P < .01), and a lactic dehydrogenase (LDH) ratio > 3.0 (LDH value/upper limit of assay; P = .04) as well as an incomplete treatment response as evidenced by residual mass on chest radiograph (P = .02) or persistent gallium 67 avidity (P = .01) after chemotherapy. Predictors of decreased survival included the presence of pleural effusion (P = .001), the number of involved extranodal sites (P = .022), and a positive posttreatment 67Ga scan (P = .027). CONCLUSION: Patients with primary mediastinal large-cell and immunoblastic lymphoma have an approximate 50% chance of surviving disease-free after initial therapy. The presence of pleural effusion at presentation was associated with an extremely poor outcome. Bulk disease per se was a negative predictive factor only in patients without pleural effusions when compared with patients who did not have bulk disease. In addition, all patients with involvement of two or more extranodal sites relapsed when treated with standard chemotherapy.

Pulmonary uptake of technetium 99m macroaggregated albumin: a predictor of gastrointestinal toxicity during hepatic artery perfusion.

Hepatic artery infusion of 5-fluoro-2-deoxyuridine (5-FUdR) provides high hepatic drug levels but little systemic toxicity, since, by this route of administration, the drug is detoxified by the hepatocytes. Slow infusion of technetium 99m- (99mTc) labeled macroaggregated albumin (MAA) through the hepatic artery is an aid in catheter placement, in predicting response of liver metastases to therapy, and in identifying extra-hepatic flow in the gastroduodenal or splenic arteries as an indicator of systemic toxicity. Marked pulmonary uptake of this tracer after slow radionuclide hepatic angiography was noted in four patients who showed major gastrointestinal (GI) toxicity. A retrospective examination of pulmonary accumulation of 99mTcMAA as a predictor of GI toxicity is the subject of this paper. Two groups of patients were evaluated. The first group consisted of 14 consecutive patients in whom continuous infusion of drug was administered by an external pump by way of a percutaneous catheter. Patients received baseline and follow-up (seven to 27 days) slow-infusion tracer studies (2 to 4 mCi 99mTcMAA at 10 to 21 mL/h). The second group included 14 consecutive patients who were receiving intraarterial chemotherapy by a totally implantable pump system. All received baseline slow-infusion studies (2 to 4 mCi 99mTcMAA at approximately 0.5 to 1.0 mL/min). The percentage of the injected dose in the lung was determined. Patients with greater than 20% of tracer in the lung after radionuclide hepatic angiography had significantly greater severe GI toxicity than patients with baseline values of less than 20%. Our findings support the existence of hepatic arteriovenous (A-V) communications in some patients and suggest that they are present pretherapy. Presence of these A-V communications, which can result in a vascular bypass of normal hepatic parenchyma and the subsequent decrease in hepatic detoxification of chemotherapeutic agents, is the likely cause of GI toxicity. Pulmonary uptake of tracer injected in the hepatic artery may be useful in quantifying the degree of shunting and facilitate the monitoring of potential systemic toxicity.

Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma.

Durable complete remissions (CRs) can be achieved in patients with diffuse large-cell lymphoma (DLCL) with multidrug chemotherapy. The length of time to reach CR may be predictive of treatment outcome. However, defining CR by chest radiograph or computed tomography (CT) is often difficult since residual abnormalities do not always indicate residual disease. We have prospectively evaluated the ability of gallium-67 citrate (Ga-67) imaging to define residual disease and predict outcome in 37 consecutive patients with DLCL. Patients received 296 to 370 megabecquerels (MBq) Ga-67 and were imaged prior to, following cycles 4 to 6, and at completion of intensive chemotherapy. Ga-67 scan results were correlated with radiographic studies. Seventeen of 37 patients (46%) showed persistent, abnormal Ga-67 uptake halfway through chemotherapy. Of these, four were in CR, 11 were in partial remission (PR), and two showed no change in tumor size. At follow-up, 10 (59%) have died (three who were scored as CR and seven who were in PR halfway through therapy), two are alive with active tumor, one relapsed and survives following bone marrow transplant, and four (three in PR and one in CR at the therapeutic halfway point) are without disease at a median of 28 months from presentation. Of the 20 patients who were Ga-67-negative halfway through therapy, 11 were in CR and nine were in PR. Five of 20 patients (25%) have died. Three, in radiographic CR died at 11, 26, and 28 months, and two in radiographic PR died at 15 and 17 months. One patient is alive with active tumor, and 14 patients (70%) are alive without disease at a median of 34 months from presentation. Ga-67 imaging proved to be an excellent indicator of residual viable tumor; a positive scan halfway through therapy predicted for a poor outcome and may well justify a change in treatment.

Long-term hepatic arterial infusion of 5-fluorodeoxyuridine for liver metastases using an implantable infusion pump.

Twenty-one patients with liver metastases of various histologies (predominantly colorectal carcinoma) underwent Infusaid pump implantation for long-term hepatic arterial 5-fluorodeoxyuridine (5-FUdR) infusion. Patients received 5-FUdR infusion on a 2-wk cycle alternating with a 2-wk saline--heparin infusion. A dosage of 0.2-0.3 mg/kg/day (average 0.23 mg/kg/day) was infused for a cumulative 5-FUdR administration of 1940 days. Six patients (29%) responded to therapy (five colorectal, one carcinoid); median response duration was 6 mo. Median survival for the treated group was 17 mo from diagnosis of liver metastases and 13 mo from pump implantation. Median survival among the six responding patients was 15 mo from diagnosis of liver metastases and 11 mo from pump implantation. Comparison of survival from the diagnosis of liver metastases of the treated group to ten patients found ineligible for the study by virtue of extrahepatic metastases revealed no significant difference in median (18 mo for ineligible group) or overall survival. However, median survival for the treated group after pump implantation (13 mo) was significantly better than the median survival of the ineligible group after evaluation for this study (4 mo). Toxicities of therapy included fatigue, anorexia, nausea, vomiting, toxic hepatitis, epigastric pain, and diarrhea. No patients died of toxicity, but six patients required hospitalization for management of pain or vomiting. No serious technical complications developed in any patient except separation of the infusion catheter at its junction with the pump in one patient, necessitating pump replacement for continuation of therapy. These survival data suggest identification of new anticancer agents for hepatic arterial infusion.

Genetic manipulation of an abnormal jump response in Drosophila.

The hyperkinetic mutants, Hk(1) and Hk(2), jump and fall over when an object moves near them. This behavior, the kinetogenic response, has been measured by the experimenter moving his hand above a vial containing a single fly and scoring the number of positive responses in fifty trials. The response is higher in Hk(1) than in Hk(2) and has remained so over a period of several years and in different genetic backgrounds. The Hk(1)/Hk(2) heterozygote also responds to movements, establishing the allelism of the two mutants.-When Sh(5), a shaker mutant at another locus on the X chromosome, is introduced into the same chromosome as Hk(1) or Hk(2), the response is reduced in proportion to the number of Sh(5) mutant genes added.-When Hk(1) or Hk(2) is heterozygous with a deficiency for the hyperkinetic region of the X chromosome, the expression is more abnormal than the respective Hk(1) or Hk(2) homozygote. This shows that the mutant genes are producing an altered gene product, or less of the normal, since one mutant gene by itself has a more abnormal expression than two. A tentative explanation has been offered for the observed mutant behaviors.