Management of Neglected Rupture of Tendoachilles with Long Gap by Flexor Hallucis Longus Tendon Transfer.

The tendo achilles is one of most important tendon in human body which often injured through direct trauma or indirect stress on a weakened tendon. Longer the duration after injury the injured parts likely to move apart, fibrosis and degeneration leading to difficulty in repair or reconstruction. Usually a phase of 4 weeks or more without specific treatment is regarded as chronic or neglected rupture. Different authors described many management protocols about the tendo achilles rupture but there is no procedure of choice for neglected rupture with long gap. Prospective case series of 21 patients of neglected tendo achilles rupture with long gap treated with flexor hallucis longus tendon (FHLT) transfer was taken for study from January 2019 to December 2020 in Mymensingh Medical College Hospital, Bangladesh. Average age of patients was 39.47 years with range 22-65 years. Fifteen (15) cases of traumatic rupture in this study with average age 32.66 years and pathologic 6 cases with average age 56.5 years were recorded. We grafted FHLT from channel by incising Henry's knot. Krackow et al.'s technique was followed for tendon mobilization and bone fixation. We made procedure simpler and cheaper; instead of using interference screw the sutured tendon pulled through the heel and anchored over rubber tube or button by Cole method. Post-operative complications were less with one patient with superficial infection which eventually recovered 3 cases of mild pain and 2 cases of numbness. Questionnaire for surgical outcome measure are satisfactory in 19 patients (90.47%). Final follow up AOFAS score at 6 month (91.61±5.41) was highly significant (p<0.001) in comparison to preoperative score (38.71±9.78). These are comparable to other study. Above mentioned scores indicate the reliability of the surgical system. But our study is a prospective case series with minimum cases. To establish the best procedure for neglected tendo achilles rupture with long gap we recommend further study with larger group and Randomized Controlled Trial (RCT) study among different procedure.

Organophosphate poisoning in pregnancy.

Organophosphate poisoning during pregnancy is rarely reported in the literature. In our retrospective study, we report the outcome of 21 cases of organophosphate poisoning during pregnancy. All patients received atropine injection until the tracheobronchial tree is cleared of the secretions and most secretions were dried. In addition, ventilatory care was needed in five women. Two patients (9.52%) died of the organophosphorus poisoning during the acute stage of poisoning and three patients were lost to follow-up. One woman had a spontaneous abortion. The remaining 15 women had no significant complication during pregnancy or labour and delivery. There was no congenital abnormality and no neurological deficit in any baby. However, long-term follow-up of neonates was lacking in our study population.

Clinical Outcome in Intra Articular Distal Humerus Fractures in Adults Treated with Different Hardware in a Tertiary Level Hospital of Bangladesh.

In adults, distal humerus fractures are infrequent and frequently intra-articular. Customarily encompass both medial and lateral columns. Operative management gives constructive outcomes. The aim of this study was to evaluate clinical outcome in intra articular distal humerus fractures in adults treated by different hardware. This prospective study consists of 20 purposively selected patients with intra articular distal humerus fractures treated by surgical intervention with different hardware who were admitted to Mymensingh Medical College and Hospital, Bangladesh in between November 2016 to October 2018. Surgical approaches were standard dorsal with or without olecranon osteotomy. The mean age of the patients was 32.3 years, range between 18-55 years. The maximum patients i.e. 85% were between 18-45 years. Seventy percent (70%) of the cases admitted were due to Road traffic accident (RTA). Most of the patients were males 14(70%) with right upper limb was involved in 13(65%) cases. Mean Mayo Elbow Performance Score was 81.5 post-operatively. According to Mayo Elbow Performance (MEP) score clinical outcome was excellent in 20%, good in 50%, fair in 25% and poor in 10% of patients. Distal humerus fractures are censorious in nature. Proper anatomical articular reconstruction and stable fixation by surgical intervention helps in fruitful results.

Clinical Outcome on Comminuted Femoral Shaft Fractures in Adults Treated by Minimally Invasive Plate Osteosynthesis (MIPO) with Locking Plate.

Intramedullary nailing is a pillar in the treatment of femoral shaft fractures. But it is not possible in all cases especially in comminuted fractures. This study has been designed to explain the importance of Minimally Invasive Plate Osteosynthesis (MIPO) with the locking plate in the treatment of comminuted Femoral Shaft Fracture. Twenty (20) such patients were treated by MIPO and analysis has been done in this study to get fruitful result and to find out the effectiveness of this procedure who were admitted at Mymensingh Medical College Hospital, Mymensingh, a tertiary level hospital of Bangladesh from February 2018 to January 2019. Mean age of the patients were 49.20±14.41 years. Based on AO classification, there were 4, 8 and 8 patients belong to type A, B and C respectively. The union period for all the patients was in between 12 to 14 weeks. The mean union period was 12.90±1.997 weeks. Mean follow up period was 19.70±2.77 weeks. Mean full weight bearing period was 16.50±1.10 weeks. In Thoresen scoring system excellent result was 9(45%), good result was 10(20%) and fair result was 01(5%). Mal-alignment happened in two cases. However, delayed union and broken screws were found in two cases each of which was treated accordingly. Comminuted Femoral shaft fracture with MIPO procedure is more effective treatment than intramedullary nailing. Furthermore, mal-alignment is the basic complexity that must be taken away intraoperatively.

Hearing status of elderly people: study in a tertiary level hospital.

A study was carried out from April 2003 to March 2004 at the Department of Otolaryngology and Head-Neck Surgery, BSMMU, with the aim to evaluate the prevalence of hearing loss and to find out the pattern and extent of hearing loss among the elderly people. The study included 100 people aged over 50 years. Out of 100 cases 59% were found with normal hearing and 41% had variable degree of hearing impairment. The highest prevalence of hearing impairment was found 100% in 9th decade with gradually decreasing tendency and lowest was 29.50% in 6th decade. Most of the cases were found to be bilateral (65.85%). Majority (65.85%) of the hearing impaired people had sensorineural type of loss with a significant number (21.95%) of conductive loss. Irrespective of type of impairment. Most of the people (73%) had no complaint of ear problem during presentation. Only 27% had some sorts of otological symptoms like hearing loss, tinnitus and vertigo and among them about 96.29% complained of hearing loss. About 44.44% of the hearing impaired person of 6th decade, showed mild hearing loss. In the 7th decade maximum (50%) had moderate to severe hearing loss. About 31% of persons of 8th decade and 50% of 9th decade had severe degree of hearing loss.

Intranasal meningoencephalocoele-a rare childhood condition.

Congenital or acquired intranasal meningocoele or meningoencephalocoele is a rare condition ever reported in world literature. We report a case of intranasal meningoencephalocoele in which a 10 month old male child presented with left sided progressive nasal obstruction, nasal mass and reluctant to feed. On examination slight broadening of the bridge of the nose with obliteration of left nasomaxillary fold, mucoid discharge and a pinkish, polypoidal, non tender, non pulsatile mass with prominent blood vessels on the surface occupying almost 3/4(th) of the nasal cavity was observed. On probing it appeared to be attached to roof of left nasal cavity. Computed tomography revealed a hypodense area in the nasal cavity but there was no bony defect in the skull base. Peroperatively on aspiration of nasal cystic mass revealed free flow of clear fluid which was biochemically CSF. A one stage, Lynch Howarth approach, correctional procedure was performed. We present here a discussion of findings and surgical treatment. Early diagnosis and referral are of paramount importance, because failure to identify this leads to fatal outcome if surgery performed.

Clinical Significance of Circulatory miRNA-21 as an Efficient Non-Invasive Biomarker for the Screening of Lung Cancer Patients

Dysregulation in the miRNA-21 expression has been previously observed in a number of malignancies and not only in the tumor cell itself but also in the body fluids of the cancer patients. The present study aimed to find out the clinical significance of cell-free circulating miRNA-21 as an efficient non-invasive biomarker for the screening of lung cancer patients. The present case-control study included plasma samples from 80 lung cancer patients and 80 healthy controls. Magnetic bead technology was used for efficient miRNA isolation and advanced TaqMan miRNA assays were used for the quantification of miRNA-21 level in the plasma of the lung cancer patients and healthy individuals.The overall mean relative expression level of plasma miRNA-21 among lung cancer patients (2.32±1.7) was higher when compared to healthy individuals (0.715 ± 0.48) and it showed a significant difference of p<0.0001. The area under ROC curve was 0.8913 [95% confidence interval (CI): 0.8394 to 0.9431, p< 0.0001] and the sensitivity and specificity were both 80.0% when the cut-off value was 1.207. In conclusion, plasma miRNA-21 can be efficiently extracted by the magnetic bead technology and quantified by the advanced TaqMan miRNA assay. Plasma miRNA-21 showed a high ability to distinguish between lung cancer patients and healthy individuals, therefore can be used as an efficient non-invasive biomarker for the screening of Lung cancer patients.

Outcome of management of differentiated thyroid carcinoma.

A prospective study was done on 93 cases of differentiated thyroid carcinoma to find out the outcome of management according to the protocol followed in the Department of ENT-Head and Neck Surgery of Bangabandhu Sheikh Mujib Medical University Hospital. Here Papillary carcinoma is more common (76.35%) than follicular carcinoma. Papillary carcinoma affected in the younger patients more commonly than the follicular carcinoma with a mean age of 34.37years (SD=12.81) for papillary carcinoma and 44.93 years (SD=16.01) for follicular carcinoma; but age as a risk factor showed no significant difference between two histological types (p>0.05). Female was the predominant sex with a ratio of 3.04:1. In this series majority of patients were categorized as high risk group (75.27%). There is strong association between histological type & risk group (P<0.05). High risk group is more common in follicular carcinoma (95.45% Vs 69.01%). There was a significant differences between the two histological types for extrathyroidal extention and distant metastasis as risk factors (p<0.01 and p<0.001); but tumour size and lymphatic metastasis showed no significant difference (p>0.05). All low risk patients were treated by hemithyriodectomy followed by life long thyroxine. All high risk cases were treated with total thyroidectomy with (35.71%) or without (62.86%) different types of neck dissection (according to the degree of lymph node involvement) followed by radioiodine ablasion and lifelong thyroxine therapy routinely. Overall rate of complication of thyroid surgery was 23.08%. The commoner complications were vocal cord palsy (5.5%), hypoparathyroidism (5.5%) and haemorrhage (4.4%). Less common complications were laryngeal oedema (2.2%), wound infection (2.2%), tracheal injury (1.1%) and death (2.2%). Many cases lost to follow up. Sixty seven cases (73.64%) responded well for follow-up. Mean duration of follow up was 3.40 years (SD=1.41). There was recurrence in thyroid remnant in 9.09% of hemithyroidectomy cases and were treated by completion thyroidectomy followed by radioiodine ablasion. Regional lymphatic metastasis was seen in six cases and was treated by different types of neck dissection. Recurrence at distal site was seen in 4 cases (18.18% of follicular carcinoma). These were treated by radioiodine ablation; two of them died during the period of follow-up.

Head and neck squamous cell carcinoma (HNSCC) 5 year study at BSMMU.

Head and Neck Squamous Cell Carcinoma (HNSCC) are generally similar in their clinical features, epidemiology and etiology although their natural and clinical history and treatment differ. Despite lot of improvement in diagnostic and management technique, there is little improvement in survival rate over the last few decades. This study was carried-out in a multidisciplinary tertiary level hospital (BSMMU), with a country-wide catchment area to see the burden of HNSCC existing in our country and their clinical pattern. The overall incidence rate of HNSCC in this study was (0.15%) i.e. 150 person in 1,00,000 population. Male incidence (0.19%) was higher than female (0.12%). This study revealed that carcinoma of the larynx (25.22%) and pyriform fossae (20.57%) were the main culprit, whereas buccal carcinoma was the main component (37.70%) in the female series. Highest incidence was found in the 6th decade in both sexes. As the treatment of HNSCC may be time consuming, requires multidisciplinary approach, demands lot of clinical, social and financial consideration, therefore, the best treatment can be offered through a combined board consisting of Surgical, Radiation, Medical oncologists, Histopathologist and Speech therapist as required.

Enhanced tumor uptake of macromolecules induced by a novel vasoactive interleukin 2 immunoconjugate.

Low uptake of monoclonal antibodies (MAbs) in cancer lesions is a significant problem in cancer therapy. Recent studies have shown that antibody uptake in tumor is controlled in large part by the tumor blood flow and the vascular permeability of the tumor endothelium. We have hypothesized that these physiological properties of tumor vessels may be altered by pretreatment with vasoactive drugs or peptides linked to tumor-specific MAbs. To test this hypothesis, two MAbs, Lym-1 directed against human malignant lymphomas and B72.3 reactive with the TAG-72 antigen expressed in solid tumors, were chemically conjugated with human recombinant interleukin 2 (IL-2). IL-2 has been used in humans to activate lymphokine-activated killer cells for the treatment of cancer but is also known to produce a generalized vascular permeability by an unknown mechanism when used systemically. Chemical conjugation of IL-2 to MAbs appears to destroy its cytokine function as shown by T-cell proliferation studies in vitro. Despite this finding, MAb/IL-2 immunoconjugates retain their ability to produce an enhanced vascular permeability when injected i.v. into nude mice bearing relevant tumor models only. Biodistribution studies using 125I-labeled tracer Lym-1 have demonstrated that the Lym-1/IL-2 immunoconjugate can increase antibody uptake in tumor by a factor of 4 in a time (2.5-h pretreatment)- and dose (30 micrograms/mouse)-dependent manner. In contrast, treatment of mice with free IL-2 and antibody showed this effect in all organs of the mouse including the tumor. Bidirectional crossover imaging studies in individual tumor-bearing nude mice showed improved uptake and decreased blood pool when the MAb/IL-2 immunoconjugates were used compared to controls. Finally, tumor blood flow and vascular permeability studies demonstrate that the physiological effect of the MAb/IL-2 is due to a reversible and specific vascular leakage at the tumor site. These studies indicate that pretreatment with this novel immunoconjugate may enhance the diagnostic and therapeutic potential of MAbs, drugs, and other macromolecules for the treatment of cancer.

Brain trace element concentrations in aging.

Trace element concentrations were determined in various human brain regions over the complete life span using instrumental neutron activation analysis. Several different patterns of trace element alteration were observed with age. Brain Al, Cl and Na concentrations increase with advancing age, while K, P and Rb decline. Ag, Co, Fe, Sb and Sc concentrations increase up to the 40 to 79 age range then decline. Br, Se and Zn remain relatively constant throughout adult life. Hg, Mn and Cs show no consistent trend with age. In infant brains Br and Cl increase and Al, Cr, Cs, Fe, Mn, P, Rb, Sc, Se and Zn decrease compared to adults. The essential elements that remain within narrow concentration limits throughout adult life suggest the presence of an efficient homeostatic mechanism for their regulation in the brain, while those that are altered with age suggest modifications in control mechanisms or altered relationships with other elements. Increased concentrations of non-essential elements may reflect accumulation from our environment, impaired removal or altered balance with other elements.

Synthesis and in vitro activity of 3 beta-substituted-3 alpha-hydroxypregnan-20-ones: allosteric modulators of the GABAA receptor.

Two naturally occurring metabolites of progesterone, 3 alpha-hydroxy-5 alpha- and 5 beta-pregnan-20-one (1 and 2), are potent allosteric modulators of the GABAA receptor. Their therapeutic potential as anxiolytics, anticonvulsants, and sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series of 3 beta-substituted derivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5 alpha- and 5 beta-series as determined by inhibition of [35S]TBPS binding. In the 5 alpha-series, 3 beta-ethyl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as substituents of the form 3 beta-XCH2, where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [35S]TBPS binding. In the 5 beta-series, the unsubstituted parent 2 is a two-component inhibitor, whereas all of the 3 beta-substituted derivatives of 2 inhibit TBPS via a single class of binding sites. In addition, all of the 3-substituted 5 beta-sterols tested are full inhibitors of [35S]TBPS binding. Electrophysiological measurements using alpha 1 beta 2 gamma 2L receptors expressed in oocytes show that 3 beta-methyl- and 3 beta-(azidomethyl)-3 alpha-hydroxy-5 alpha-pregnan-20-one (6 and 22, respectively) are potent full efficacy modulators and that 3 alpha-hydroxy-3 beta-(trifluoromethyl)-5 alpha-pregnan -20-one (24) is a low-efficacy modulator, confirming the results obtained from [35S]TBPS binding. These results indicate that modification of the 3 beta-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABAA receptor. In animal studies, compound 6 (CCD 1042) is an orally active anticonvulsant, while the naturally occurring progesterone metabolites 1 and 2 are inactive when administered orally, suggesting that 3 beta-substitution slows metabolism of the 3-hydroxyl, resulting in orally bioavailable steroid modulators of the GABAA receptor.

Preclinical evaluation of the penciclovir analog 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)guanine for in vivo measurement of suicide gene expression with PET.

UNLABELLED: The gene for herpes simplex virus thymidine kinase (HSV-tk) is widely used as a suicide gene in experimental gene therapy of cancer. 9-(4-Fluoro-3-hydroxymethylbutyl)guanine (FHBG) is an antiviral nucleoside analog that is rapidly phosphorylated by viral thymidine kinase but is a poor substrate for mammalian thymidine kinase. Recently, FHBG labeled in the 4-fluoro position with (18)F has shown promise relative to other similar compounds for imaging in vivo expression of HSV-tk using PET. In this study, we evaluated the uptake of [(18)F]FHBG in vitro and in vivo using transduced and wild-type human colon cancer cells (HT-29). We also imaged [(18)F]FHBG and measured the radioactivity concentrations of circulating [(18)F]FHBG and its metabolites in monkeys. METHODS: Sterile, pyrogen-free [(18)F]FHBG was produced routinely in good yields. Cells were transduced with the retroviral vector G1Tk1SvNa containing HSV-tk gene. In vitro uptake studies were performed by incubating cells with [(18)F]FHBG at 37 degrees C for 1 and 5 h. Biodistribution studies were performed at 2 and 5 h after injection in nude mice bearing tumors grown from wild-type or transduced cells. Sequential, whole-body PET scans of cynomolgus monkeys were obtained over a period of >2 h after intravenous injection of [(18)F]FHBG. Arterial plasma samples obtained from monkeys 15-120 min after intravenous injection were subjected to acid extraction, and the acid-soluble fractions were analyzed by high-performance liquid chromatography. RESULTS: In vitro studies showed 31 and 71 (P < 0.001) times higher uptake of the probe at 1 and 5 h, respectively, in transduced cells compared with nontransduced cells. In vivo studies in mice showed that tumor uptake of the radiotracer was 4-fold (P < 0.05) and 13-fold (P < 0.001) higher at 2 and 5 h, respectively, in tumors grown from transduced cells compared with control cells. Transduced tumor-to-normal tissue ratios ranged from 2 to 25 at 2 h and from 2 to 22 at 5 h. Recirculating labeled metabolites had only a minor effect on the biodistribution of radiolabel from [(18)F]FHBG in monkeys. CONCLUSION: These results indicate that [(18)F]FHBG may yield high-contrast PET images of HSV-tk expression in tumors and, therefore, it is a very promising radiotracer for monitoring of gene therapy of cancer with PET.

Technetium-99m-labeled monoclonal antibodies: influence of technetium-99m binding sites.

UNLABELLED: A number of 99mTc-labeled monoclonal antibodies (Mabs) are being evaluated for diagnostic applications. Preparations are carried out using both direct and indirect (bifunctional chelating agent, BFCA) labeling procedures in which nonspecific 99mTc binding has been postulated. METHODS: By using the ascorbic acid (AA) reduction mediated direct labeling procedure and diaminotetrathiol (N2S4) as a BFCA method, we examined the role of specific binding sites and aliphatic E amino groups of lysine as nonspecific binding sites for 99mTc. RESULTS: Labeling yields for the direct and N2S4 "regular" preparations averaged 73% +/- 2.8% and 91% +/- 2%, for the "specific" preparations, 60% +/- 3.5% and 75% +/- 2% and for the "nonspecific" preparations 13% +/- 1.0% and 16% +/- 1% respectively. All preparations were evaluated in tumor-bearing mice. The control and specific preparations permitted excellent scintigraphic visualization of tumors; the percentages of specific preparations in the tumors being 2.1% +/- 0.5% and 3.1% +/- 0.4%, respectively. With nonspecific preparations, tumors were not visualized and the percentages of administered radioactivity per gram of tumor were only 0.9% +/- 0.2% and 0.9% +/- 0.3%, respectively. CONCLUSIONS: In these 99mTc labeling procedures, the amino group-mediated nonspecific binding of 99mTc to Mabs can be as high as 16% and contributes to increased liver uptake and decreased tumor uptake of radioactivity.

Blocking catabolism with eniluracil enhances PET studies of 5-[18F]fluorouracil pharmacokinetics.

UNLABELLED: Noninvasive methods for measuring the pharmacokinetics of chemotherapeutic drugs such as 5-fluorouracil (FU) are needed for individualized optimization of treatment regimens. PET imaging of [18F]FU (PET/[18F]FU) is potentially useful in this context, but PET/[18F]FU is severely hampered by low tumor uptake of radiolabel and rapid catabolism of FU in vivo. Pretreatment with eniluracil (5-ethynyluracil) prevents catabolism of FU. Hypothesizing that suppression of catabolism would enhance PET/[18F]FU, we examined the effects of eniluracil on the short-term pharmacokinetics of the radiotracer. METHODS: Anesthetized rats bearing a subcutaneous rat colorectal tumor were given eniluracil or placebo and injected intravenously 1 h later with [18F]FU or [3H]FU. In the 18F studies, dynamic PET image sequences were obtained 0-2 h after injection. Tumors were excised and frozen at 2 h and then analyzed for labeled metabolites by high-performance liquid chromatography. Biodistribution of radiolabel was determined by direct tissue assay. RESULTS: Eniluracil improved tumor visualization in PET images. With eniluracil, tumor standardized uptake values ([activity/g]/[injected activity/g body weight]) increased from 0.72 +/- 0.06 (mean +/- SEM; n = 6) to 1.57 +/- 0.20 (n = 12; P < 0.01), and tumor uptake increased by factors of 2 or more relative to plasma (P < 0.05) and bone, liver, and kidney (P < 0.01). Without eniluracil (n = 5), 57% +/- 4% of recovered radiolabel in tumor at 2 h was on catabolites, with the rest divided among FU (2% +/- 1%), anabolites of FU (38% +/- 7%), and unidentified peaks (4% +/- 2%). With eniluracil (n = 8), catabolites, FU, and anabolites comprised 2% +/- 1%, 41% +/- 5%, and 57% +/- 4%, respectively, of the recovered radiolabel in tumors. CONCLUSION: Eniluracil increased tumor accumulation of 18F relative to host tissues and fundamentally changed the biochemical significance of that accumulation. With catabolism suppressed, tumor radioactivity reflected the therapeutically relevant aspect of FU pharmacokinetics--namely, uptake and anabolic activation of the drug. With this approach, it may be feasible to measure the transport and anabolism of [18F]FU in tumors by kinetic modeling and PET. Such information may be useful in predicting and increasing tumor response to FU.

Single amino acid substitution in the Fc region of chimeric TNT-3 antibody accelerates clearance and improves immunoscintigraphy of solid tumors.

UNLABELLED: Recent studies in antibody catabolism have identified residues at the CH2-CH3 interface of the IgG heavy chain critical for serum persistence of immunoglobulins. Amino acid substitutions in the Fc region of murine IgG1 were shown to drastically accelerate antibody clearance in mice. Our laboratory has previously described a human-mouse chimeric TNT-3 (chTNT-3) monoclonal antibody directed against a universal nuclear antigen that has potential for the radioimmunotherapy of many solid tumors. In the current study, we engineered a chTNT-3 mutant containing a single amino acid substitution, to determine whether a more rapid clearance profile would make the antibody suitable for diagnostic imaging. METHODS: A single amino acid substitution in the CH2 domain of the human gamma1 constant region was made by polymerase chain reaction mutagenesis. High-level expression was achieved using the Glutamine Synthetase Gene Amplification System, and the chTNT-3 mutant was purified by protein A affinity and ion-exchange chromatography. A radioimmunoassay was performed to examine antigen binding, and in vivo studies were undertaken to evaluate clearance and tumor targeting in human tumor xenograft models. RESULTS: The chTNT-3 mutant retained the high affinity of chTNT-3, with a binding constant of 1.5 x 10(-9) mol/L. The mutant was eliminated rapidly from BALB/c mice, with a beta-phase half-life of 33.8 h, compared to 134.2 h for chTNT-3. Moreover, biodistribution studies in human colon tumor-bearing nude mice reflected this accelerated clearance. Tumor levels of the mutant were, respectively, 65%, 39%, and 36% of the tumor levels achieved with the parental chTNT-3 6, 12, and 24 h postinjection. The rapid clearance of the chTNT-3 mutant from the blood resulted in higher tumor-to-normal organ ratios for many normal tissues. Imaging of tumor-bearing mice with 99mTc-labeled chTNT-3 mutant demonstrated early visualization of tumors in 3 different solid tumor xenograft models. CONCLUSION: The accelerated clearance produced by a single amino acid substitution in the Fc region of chTNT-3 leads to improved imaging in tumor-bearing mice. These studies suggest that a rapidly clearing antibody generated by this approach may be useful for the immunoscintigraphy of human tumors.

Synthesis and preliminary evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG): a new potential imaging agent for viral infection and gene therapy using PET.

Synthesis and preliminary biological evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)-guanine ([18F]FHBG) is reported. 9-(4-Hydroxy-3-hydroxymethylbutyl)-guanine (penciclovir) 4 was converted to 9-[N2, O-bis-(methoxytrityl)-3-(tosylmethybutyl)]guanine 7 by treatment with methoxytrityl chloride followed by tosylation. The tosylate 7 was reacted with either tetrabutylammonium fluoride or KF in the presence of kryptofix 2.2.2. to produce the 4-fluoro-N2-O-bis-(methoxytrityl) derivative 8. Removal of the methoxytrityl groups by acidic hydrolysis produced FHBG 5. Radiolabeled product [18F]FHBG was prepared by fluorination of the tosylate 7 with [18F]KF and kryptofix 2.2.2. The labeled product was isolated by HPLC purification on a reverse-phase C18 column, and eluted at 12 min with 15% acetonitrile in water at a flow rate of 2.25 mL/min. Radiochemical yield was 8.0-22.3% with an average of 12% in 7 runs (corrected for decay). Synthesis time was 90 to 100 min including HPLC purification with radiochemical purity >99%, and average specific activity of 320 mCi/micromol. In vitro studies of the compound in HT-29 colon cancer cells revealed 18.2-fold higher uptake into transduced cells compared to control in 3 h. The agent may be useful for imaging viral infection or transfected cells in gene therapy.

Synthesis of [11C-methyl]-alpha-aminoisobutyric acid (AIB).

Alpha-aminoisobutyric acid (AIB) labeled with the cyclotron-produced, positron-emitting radionuclide 11C has been synthesized with the label in the alpha-methyl group. Our previously published synthesis of [11C] AIB in the carboxyl position from [11C] HCN requires a rigorous quality assurance program to ensure that the concentration of cyanide in the final product is below certain levels. This can be avoided using the method described here with [11C] CH3I. The radiochemical yield calculated to end of bombardment (EOB) was 45-55% from [11C] CO2 with radiochemical purity of [11C-methyl] AIB exceeding 99%. Synthesis times from [11C] CO2 were about 55 min. Specific activities of 1 Ci/mumol were achieved on average. It has been shown that [11C-carboxyl] AIB is a useful imaging agent in patients with soft tissue cancers and melanoma, and it demonstrates tumor uptake in a spectrum of other animal tumor models. Because AIB is a nonmetabolized amino acid, [11C-methyl] AIB should be equally as useful. Either agent can be employed for the quantification of the A-type amino acid transport system in vivo with PET.

Evaluation of 9-[(3-18F-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]-FHPG) in vitro and in vivo as a probe for PET imaging of gene incorporation and expression in tumors.

Preparation of 9-[(3-18F-fluoro-1-hydroxy-2-propoxy)methyl]-guanine ([18F]-FHPG) for clinical use, and its evaluation as a positron emission tomography (PET) imaging agent for gene incorporation and expression in tumors are reported. In vitro studies in human colon cancer cells, HT-29, transduced with the retroviral vector G1Tk1SvNa and nontransduced (wild type) showed 4, 8, 12, and 15 times higher uptake of the probe in 1, 3, 5, and 7 h, respectively, in transduced cells compared with the controls. In vivo studies in tumor-bearing nude mice demonstrated that the tumor uptake of the radiotracer is three and six-fold higher in 2 and 5 h, respectively, in transduced cells compared with the control cells. These results suggest that [18F]-FHPG is a potential in vivo PET imaging agent for monitoring gene incorporation and expression in gene therapy of cancer.

9-[(3-[18F]-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]-FHPG): a potential imaging agent of viral infection and gene therapy using PET.

A no-carrier-added synthesis of 9-[(3-[18F]-fluoro-1-hydroxy-2-propoxy)methyl]-guanine ([18F]-FHPG) is reported. The 9-[(1,3-dihydroxy-2-propoxy)methyl)guanine (DHPG) was converted to 9-[N2,O-bis(methoxytrityl)-3-(tosyl)-2-propoxy-methyl]guanine by treatment with methoxytrityl chloride followed by tosylation. The tosylate was reacted with [18F]-KF in the presence of kryptofix 2.2.2. to produce the 3-fluoro-N2-O-bis-(methoxytrityl) derivative. Removal of the methoxytrityl protecting groups by acid hydrolysis produced [18F]-FHPG. The labeled product was purified by HPLC on a reverse-phase C18 column, and eluted in 9 min with a mobile phase of 5% acetonitrile in water. The radiochemical yield was 7-17%, with an average of 10% in 10 runs (corrected for decay to EOB). The radiochemical purity was > 99%, and specific activities with an average of 526 mCi/mumol were obtained. The synthesis time was 70-80 min, including HPLC purification and determination of radiochemical purity and specific activity.