Clinical validation of a tissue-agnostic genome-wide methylome enrichment molecular residual disease assay for head and neck malignancies.

BACKGROUND: Outcomes for patients with locally advanced head and neck cancer (HNC) treated with curative intent remain disappointing, with 5-year survival rates at 50%. Most recurrences occur within the first 2 years after treatment, providing a window of opportunity to identify patients with molecular residual disease (MRD). A tissue-agnostic test for MRD detection in patients with human papillomavirus (HPV) positive and negative HNC, where tissue is often scarce, is needed. PATIENTS AND METHODS: Patients with stage I-IVB HNC, including patients positive and negative for HPV, were enrolled and peripheral blood plasma was collected longitudinally at diagnosis and ∼3, 12, and 24 months after curative intent treatment. The full cohort includes 325 patients with 1155 samples. Samples were split into distinct sets to train and validate a classifier capable of identifying MRD using a tissue-agnostic genome-wide methylome enrichment platform. The primary endpoint was recurrence-free survival (RFS). RESULTS: With a median follow-up of 60 months, patients in the blinded validation set with MRD positivity experienced significantly worse RFS with a hazard ratio (HR) of 35.7 [95% confidence interval (CI) 10.8-117.8; P < 0.0001]. For patients with HPV negativity, HR was 42.3 (95% CI 9.8-182.3; P < 0.0001); for patients with HPV-positive oropharyngeal cancer, HR was 24.1 (95% CI 3.0-196.8; P < 0.0001). Moreover, the lead time between MRD positivity and clinical recurrence was up to 14.9 months, with a mean lead time of 4.1 months. Surveillance sensitivity was 91% (95% CI 77% to 97%) and specificity was 88% (95% CI 80% to 93%). CONCLUSIONS: Here we validate the clinical performance characteristics of a tissue-agnostic genome-wide methylome enrichment assay for MRD detection in patients with HNC. The MRD detection test showed high sensitivity for identifying recurrence at high specificity across different anatomical sites, HPV status, and treatment regimens, highlighting the broad applicability for MRD detection in patients with HNC.

The role of surgical navigation in computer-assisted mandibular reconstruction: is it necessary?

BACKGROUND: Accurate mandibular reconstruction following tumor ablation is important yet challenging. While computer-assisted surgery and surgical navigation have been applied widely in maxillofacial reconstruction, the accuracy and the efficacy remain debatable due to the native mobile nature. This study aimed to evaluate the surgical outcomes and accuracy of mandibular reconstruction aided by different types of adjunctive computer-assisted techniques with or without intraoperative navigation. MATERIAL AND METHODS: Patients with anterior and/or lateral mandibular defects who underwent microvascular mandibular reconstruction aided by adjunct computer-assisted techniques, with or without intraoperative navigation were assessed. The deviations in spatial alignment of the bony segments between the pre-operative and post-operative datasets were measured to evaluate the overall surgical outcomes and accuracy. Independent t-test was performed and p-value less than 0.05 was statistically significant. RESULTS: A total of 93 patients with L/LC or LCL defects who underwent microvascular mandibular reconstruction aided by adjunct computer-assisted techniques with or without surgical navigation were assessed. No significant difference was observed when comparing the mean differences between the preoperative and postoperative intercondylar and intergonial distance in both navigation-assisted and computer-aided design/computer-aided manufacturing (CAD/CAM) groups. There were also no significant differences noted among the different mandibular defects, osteosynthesis plates and types of free flap. CONCLUSIONS: Accurate mandibular reconstruction following tumor resection can be achieved by incorporating intraoperative navigation and adjunctive methods such as computer-assisted techniques and our innovative device, mandibular fixation device.

[Development of a quality of life questionnaire for adults with anisometropic amblyopia].

Objective: To develop and validate the health-related quality of life (HRQOL) questionnaire for adult patients with anisometropic amblyopia. Methods: Cross-sectional study. A total of 170 adult patients with anisometropic amblyopia, 100 adult patients with other eye diseases and 80 healthy adults with normal vision were recruited at the First Affiliated Hospital of Nanjing Medical University, and 20 healthy adults with normal vision were recruited at Qinhuai Medical District of Easter Theater General Hospital of PLA from December 2019 to February 2020. Individual interviews of 30 adult patients with anisometropic amblyopia generated 80 questionnaire items. For item reduction, 40 adult patients with anisometropic amblyopia were asked to complete the 80-item questionnaire and responses were analyzed. Then factor analyses were performed to identify prominent factors (subscales). The reliability of the questionnaire was evaluated by Cronbach's α coefficient. The overall and sub-scale scores were the average scores of all included items, ranging from 0 (worst HRQOL) to 100 (best HRQOL). The final 20-item questionnaire was administered to additional 100 adult patients with anisometropic amblyopia, 100 adult patients with other eye diseases and 100 visually normal adults. Mean overall and subscale scores were compared across groups using one-way analysis of variance. Results: The final adult anisometropic amblyopia questionnaire (AAAQ) consisted of a function subscale and a psychosocial subscale, each containing 10 items. The Cronbach's α coefficients of the overall, function subscale and psychosocial subscale were 0.88, 0.78 and 0.78. There were 55 males and 45 females in 100 adult anisometropic amblyopia patients, with a median age of 26 years (range, 18 to 43 years). The age and gender distribution were matched with 100 adult patients with other eye diseases and 100 healthy adults with normal vision (all P>0.05). The mean overall score (28.63±9.18), function subscale score (27.69±9.88) and psychosocial subscale score (29.53±9.90) for adult patients with anisometropic amblyopia were significantly lower compared to adult patients with other eye diseases (71.28±8.14, P<0.01; 65.56±7.81, P<0.01; 76.85±10.76, P<0.01) and visually normal adults (84.54±9.13, P<0.01; 81.70±9.27, P<0.01; 87.38±10.06, P<0.01). Conclusion: The AAAQ meets the requirements for validity and reliability of a HRQOL questionnaire, and can be used to assess the HRQOL of adult patients with anisometropic amblyopia. (Chin J Ophthalmol, 2021, 57: 341-347).

Maxillary Reconstruction Using Submental Artery Island Flap and Sagittal Mandibular Ramus/Coronoid Process Graft Pedicled With Temporalis Muscle.

PURPOSE: The purpose of this study is to describe maxillary reconstruction using the submental artery island flap and the sagittal mandibular ramus and coronoid process graft pedicled with the temporalis muscle through the modified lateral lip and submandibular approach. MATERIALS AND METHODS: From May 2013 to September 2016, 11 patients with maxillary defects secondary to maxillary cancer ablation who underwent maxillary reconstruction using a submental artery island flap and a sagittal mandibular ramus and coronoid process graft pedicled with the temporalis muscle through the modified lateral lip and submandibular approach were enrolled in this prospective study. RESULTS: All submental artery island flaps and sagittal mandibular ramus and coronoid process grafts were successful, with satisfactory functional and esthetic outcomes. No functional impairment at the donor site occurred in any case. CONCLUSION: The submental artery island flap combined with the sagittal mandibular ramus and coronoid process graft is a feasible and acceptable technique for maxillary reconstruction in older patients because it is safe, quick, and straightforward to harvest and it offers a very acceptable esthetic and satisfactory outcome, with the advantage of low morbidity of the donor site. When combined with the 3-dimensional virtual operative method, the technique can improve postoperative outcomes.

GluR1 protects hypoxic ischemic brain damage via activating Akt signaling pathway in neonatal rats.

OBJECTIVE: To investigate the role of glutamic acid receptor 1 (GluR1) in hypoxic-ischemic brain damage (HIBD) in neonatal rats and its underlying mechanism. MATERIALS AND METHODS: 7-day-old neonatal rats received right common carotid artery (CCA) ligation for the establishment of HIBD. After the operation, rats were sacrificed at different time points (0, 4, 6, 12, 24, 48, and 72 h), respectively. Meanwhile, rats in Sham group underwent similar procedures without ligation. Lentivirus-GLUR1-shRNA (LV-GLUR1 shRNA group) was constructed and then transfected into the right lateral ventricles of rats to inhibit GluR1 in vivo. Rats received LV-control injection were selected in the control group (LV-control group). After injection of Lentivirus-GLUR1-shRNA, CCA ligation was performed in rats for HIBD construction. Western blot was performed to detect the protein levels of GLUR1, Akt, p-Akt, and vascular endothelial growth factor (VEGF) in brain tissues. Cell apoptosis was measured by TUNEL staining assay. RESULTS: After hypoxic ischemia (HI), GLUR1 expression increased gradually and reached a peak at 24 h. Meanwhile, p-Akt expression increased immediately and then gradually decreased. 24 h later, p-Akt expression increased again and peaked at 48 h. VEGF expression increased at 4 h after HI and reached a peak at 12 h. The expression levels of GLUR1, p-Akt, and VEGF in the brain tissues derived from rats transfected with LV-GLUR1 shRNA significantly decreased at both 4 h and 24 h after HI. In addition, results indicated that cell apoptosis was enhanced after LV-GLUR1 shRNA administration, suggesting the role of GLUR1 in protecting against HIBD. CONCLUSIONS: GLUR1 exhibits a remarkable protective role in HIBD, which may be related to the activation of the Akt signaling pathway and the upregulation of VEGF after HI.

Clinicopathologic analysis of 2736 salivary gland cases over a 11-year period in Southwest China.

OBJECTIVE: To investigate the epidemiological and clinicopathological characteristics of salivary gland tumors in southwest China in order to provide data for clinical diagnosis and other similar research. METHODS: Between March 2007 and December 2017, 2736 patients with salivary gland tumors were recruited, the clinical and pathological data were retrospectively analyzed. RESULTS: A total of 2736 patients had a ratio of males to females of about 1.02:1. The ratio of benign to malignant tumors was 3.46:1. Pleomorphic adenoma and adenoid cystic carcinoma had 50.8% and 7.2%, respectively. About 65.4% tumors occurred in the parotid gland. There was no significant difference between the tumor in the left or right parotid and the use of cell phones. There were significant differences between gender and both the characteristics and locations of salivary gland tumors (p < .05). There were also significant differences between the pathological characteristics and location of the salivary gland (p < .05). CONCLUSIONS: The salivary gland benign and malignant tumors were more common in pleomorphic adenoma and adenoid cystic carcinoma, most occurred in the parotid gland. The minor gland tumors are lower than other parts of China. The incidence of parotid gland tumors is not related to the use of cell phones.

PacBio SMRT assembly of a complex multi-replicon genome reveals chlorocatechol degradative operon in a region of genome plasticity.

We have sequenced a Burkholderia genome that contains multiple replicons and large repetitive elements that would make it inherently difficult to assemble by short read sequencing technologies. We illustrate how the integrated long read correction algorithms implemented through the PacBio Single Molecule Real-Time (SMRT) sequencing technology successfully provided a de novo assembly that is a reasonable estimate of both the gene content and genome organization without making any further modifications. This assembly is comparable to related organisms assembled by more labour intensive methods. Our assembled genome revealed regions of genome plasticity for further investigation, one of which harbours a chlorocatechol degradative operon highly homologous to those previously identified on globally ubiquitous plasmids. In an ideal world, this assembly would still require experimental validation to confirm gene order and copy number of repeated elements. However, we submit that particularly in instances where a polished genome is not the primary goal of the sequencing project, PacBio SMRT sequencing provides a financially viable option for generating a biologically relevant genome estimate that can be utilized by other researchers for comparative studies.

[Clinical application and accuracy of the genioplasty surgical templates system for osseous genioplasty].

Objective: To develop and validate a new genioplasty templates system for monoblock osseous genioplasty. Methods: Thirty-six patients with chin deformities were enrolled in this study. The chin template system included a cutting guide and a repositioning guide for a genioplasty. Chin templates were designed in a computer and fabricated using a three-dimensional printing technique. The accuracy of the genioplasty templates were assessed by comparing the actual postoperative outcomes with the virtual plan. Results: All genioplasty was successfully completed by the template system. The largest linear root-mean-square deviation(RMSD) between the planned and the postoperative chin segments was 1.16 mm and the largest angular RMSD was 3.06°. Conclusions: The results showed that the chin template system provides a reliable method for transfer of genioplasty planning. The operation precision of the genioplasty can be improved by using the surgical templates system.

[Comparison between computer aided simulation and dental model orthognathic surgery for the treatment of patients with mandibular excess and facial asymmetries].

Objective: To evaluate the results of the orthognathic surgery with computer aided simulation-three-dimensional(3D) printed surgical guide and dental model surgery in the treatmemt of patients with mandibular excess and facial asymmetries. Methods: The coordinate system was built in ProPlan CMF 2.0 software, and the horizontal plane consisted of PoL, PoR, OrL, middle sagittal plane through nasion point and basion point and the plane perpendicular to the horizontal plane, coronoid plane through nasion point and the plane perpendicular to the horizontal plane and middle sagittal plane. The orientation of maxilla and mandibular distal segment was calculated by each triangle(U1-U6L-U6R, L1-L6L-L6R, Me-M5L-M5R) before and after orthognathic surgery. A total of 60 mandibular excess patients with facial asymmetries were enrolled in this retrospective study. They were divided into two groups, group Ⅰ with computer aided simulation, group Ⅱ with dental model surgery. The difference of maxillary occlusal plane roll and yaw angle, mandibular occlusal plane roll and yaw angle, and mandibular body plane roll and yaw angle were calculated. Statistical analysis was performed with SPSS 17.0 software. Results: The yaw angle of mandibular occlusal plane of the dental model surgery and computer aided simulation was 0.36°± 0.48° and 0.84° ± 0.36° (P=0.043), respectively. The roll angle of mandibular occlusal plane of the dental model surgery and computer aided simulation was 0.26°±0.79° and 0.54°±0.40°(P=0.032), respectively. The yaw angle of mandibular body plane of the dental model surgery and computer aided simulation was 0.60°± 1.04° and 0.23°±0.52°(P=0.008), respectively. The roll angle of mandibular body plane of the dental model surgery and computer aided simulation was 0.82° ± 0.72° and 0.53° ± 0.37° (P=0.028), respectively. The changes in computer aided simulation group were more obvious than that in the dental model surgery group, but the difference was not significant in the yaw angle of maxillary occlusal plane and the roll angle of maxillary occlusal plane between the two groups(P >0.05). Conclusions: It was more effective to correct mandibular asymmetry by computer aided simulation than dental model surgery.

[The influence of urothelial carcinoembryonic antigen 1 on invasion and migration of oral carcinoma cell lines].

OBJECTIVE: To investigate the effects of long chain non-coding RNA urothelial carcinoembryonic antigen 1(UCA1) on invasion, migration and proliferation abilities in oral squamous cell carcinoma cell lines SCC15 and CAL27. METHODS: Small interfering RNA of UCA1(UCA1-siRNA) was transfected into SCC15 and CAL27 cell lines by Lipofectamine(TM) 3000 to silence UCA1 , and transfected negtive control si-RNA served as a control. The effect of UCA1-siRNA was detected by quantitative real time-polymerase chain reaction(qRT-PCR) to confirm the successful inhibition of UCA1 by siRNA. The matrix metalloproteinase 9(MMP-9) protein level was detected by Western blotting analysis. The effect of siRNA on cell proliferation and invasion was assessed by transwell migration assay and wound healing assay. Cell counting kit-8(CCK-8) assay was carried out to estimate the proliferation of two cell lines with different expression levels of UCA1. RESULTS: Expressions of UCA1 of SCC15 and CAL27 were successfully suppressed after transfected with siRNA which verified by qRT-PCR, and the efficiency of downregulation of SCC15 and CAL27 was 86.45%(P<0.001)and 78.24%(P<0.001), respectively. The migration, invasion and proliferation of SCC15 and CAL27 cell lines after transfected with siRNA were obviously restrained. The number of migration and invasion of CAL27 cells were 719.20±92.36 versus 208.00±25.58 (P=0.000 7) and 363.40 ± 45.96 versus 164.80 ± 24.68(P= 0.005 2), respectively, the number of migration and invasion of SCC15 cells were 437.20±54.75 vs 145.80±23.31(P=0.001 1) and 249.80±38.41 vs 63.80±11.11 (P=0.001 6), respectively (UCA1-si compare to negtive control), the relative proliferation rates of SCC15 and CAL27 were SCC15: R24 h=0.870, R48 h=0.863, R72 h=0.64, R96 h=0.732; CAL27: R24 h=0.913, R48 h=0.829, R72 h=0.756, R96 h= 0.705(P<0.05), and MMP-9 expression level was decreased by UCA1-siRNA compared with negative control. CONCLUSIONS: UCA1 could enhance the ability of invasion and migration of SCC15 and CAL27 cell lines via regulating MMP-9 protein expression, which suggests that UCA1 might play a pivotal role in oral squamous cell carcinoma invasion and progression.

Effect of rhCSF-1 on human hemopoiesis in long-term cultures from patients with acute myelogenous leukemia.

Bone marrow and/or peripheral blood cells from seven patients with acute myelogenous leukemia (AML) were maintained for 7 weeks in Dexter-type long-term culture (LTC) in order to study the effect of exogenous recombinant human colony-stimulating factor-1 (rhCSF-1) and to quantitate endogenous levels of CSF-1. rhCSF-1 was added every 2 days during the first 3 weeks of culture at 15 ng/ml. In all but one culture, adding rhCSF-1 inhibited putative leukemic hemopoiesis [i.e. decreased numbers of abnormal (blast) colony-forming cells and blasts] and stimulated putative normal hemopoiesis (increased numbers of CFU-GM and macrophages). Our data, however, do not distinguish direct effects of rhCSF-1 on normal or leukemic cells from indirect effects mediated by accessory cells. In cultures with a poorly formed adherent layer (all derived from patients classified as M5), the endogenous levels of CSF-1 were lower than those in cultures with a good (confluent) adherent layer, indicating that the levels of CSF-1 in LTC from AML patients positively correlate with the formation of the adherent layer. Our data indicate that CSF-1 is an important modulator of human hemopoiesis in LTC established from AML bone marrow or peripheral blood, and that rhCSF-1 might be valuable for purging leukemic cells in LTC established from AML patients' bone marrow or peripheral blood for autologous transplantation.

Recurrent sarcoid granulomatous nephritis and reactive tuberculin skin test in a renal transplant recipient.

End-stage renal failure developed in a patient with systemic sarcoidosis and granulomatous nephritis. She received a successful cadaveric renal transplant and was doing well for about six years before graft impairment occurred. At that time, her mother was found to have active open pulmonary tuberculosis, and she had a strongly reactive result on tuberculin skin testing. No clinical evidence of tuberculosis or systemic sarcoidosis was noted, but a renal graft biopsy specimen revealed the recurrence of an unusual sarcoid lesion identical to that which had occurred in her native kidney. Her condition responded to high-dose prednisone with improvement in graft function.

Renal allograft biopsy and conversion of cyclosporine to azathioprine.

A prospective nonrandomized study was conducted to evaluate the results of two conversion protocols on two similar groups of renal graft recipients totaling 54 patients who were converted from CsA to AZA at 6-12 months posttransplant. With protocol I, 24 patients (3 haploidentical, 21 cadaveric recipients) were converted with a graft biopsy followed by a 14-day overlap of CsA and AZA before the CsA dose was tapered and discontinued in 6 days. Of the 24 patients, 8 were found to have occult rejection in biopsy and received methylprednisolone 500 mg boluses for three days before overlap started. Thirty patients (2 haploidentical, 28 cadaveric recipients) were converted with protocol II, which had CsA and AZA overlap and tapering schedules identical to those of protocol I without a preconversion biopsy. Follow-up extended as far as 3 years posttransplant. There was a substantial incidence of chronic rejection and graft loss after conversion in protocol II patients. We also found that there was a possible link between postconversion acute rejection and late graft loss from chronic rejection. The incidence of acute rejection after conversion was significantly lower among protocol I patients as compared with that of protocol II (4% vs. 37%, P less than 0.001). However, if 8 patients with occult rejection in the preconversion biopsy were added to the total number of postconversion rejection in protocol I, the incidence of postconversion rejection in this group (38%) would be similar to that of protocol II. Using the time of conversion as the onset of the risk, protocol I patients had better graft survival than protocol II (100% vs. 80%, P less than 0.005) at 3 years posttransplant. If conversion becomes necessary, we recommend a preconversion graft biopsy to identify and treat patients with occult rejection before the beginning of CsA and AZA overlap, especially for those patients whose creatinine is higher than 2 mg/dl without obvious cause before conversion.

The prognostic value of the eosinophil in acute renal allograft rejection.

A case report of marked peripheral blood eosinophilia and eosinophilic infiltration of a rejected renal allograft in a transplant recipient stimulated our review of the clinical course of 132 consecutive renal transplant recipients. A total of 187 acute rejections occurred in 112 patients. Diagnosis was made by renal biopsy in 124 cases. The percentage of eosinophils in the leukocyte differential of patients with irreversible rejection was 5.2 +/- 5.7 (mean +/- SD) versus that seen in patients with reversible rejection, 2.9 +/- 3.5 (P less than .05). The difference in the total eosinophil counts in each group was not statistically significant. Patients with peripheral blood eosinophil percentages greater than or equal to 4% had a 37.9% irreversible rejection rate, whereas those who had less than 4%, had a 22.4% loss rate (P less than .01). Six of seven patients with greater than or equal to 2% eosinophils in the inflammatory infiltrate of their renal allograft lost their kidney, whereas grafts with less than 2% eosinophils had a 36.8% loss rate (P less than .02). We conclude that the increased presence of eosinophils in the peripheral blood and/or renal allograft biopsy specimen is an adverse prognostic factor for acute rejection outcome.

Reevaluation of T cell subset monitoring in cyclosporine-treated renal allograft recipients.

The predictive value of peripheral blood T cell subset monitoring in renal allograft recipients has been questionable, and there has been no information concerning the correlation of T cell subset changes with the clinical event related to cyclosporine nephrotoxicity. This study was conducted to investigate the clinical usefulness of serial T cell subset monitoring in 34 consecutive renal transplant patients treated with cyclosporine by determining the total peripheral lymphocyte count and T cell subset counts using Leu-4, Leu-3ab, and Leu-2a monoclonal antibodies and flow cytometry up to 6 months after transplantation. The absolute counts of all cells were lower in transplanted patients than those of normal controls, but were not different from those of hemodialysis patients. During infection, the helper/suppressor (H/S) ratio and the cell counts, except for suppressor cells, decreased significantly. Within one week prior to rejection, all cell counts also decreased significantly. Furthermore, cell counts before steroid-resistant rejection were significantly lower than those before steroid-responsive rejection. In contrast, lymphocyte and T cell counts were increased significantly within one week prior to cyclosporine nephrotoxicity being diagnosed; the H/S ratio was not correlated with rejection or toxicity. These results indicate that H/S ratio is not associated with clinical events of renal allograft recipients, but serial lymphocyte and T cell subset counts can provide valuable information for the differentiation of rejection from cyclosporine nephrotoxicity, and also for predicting the outcome of the allograft rejection.

Enzyme-linked immunosorbent assay for serum renal tubular antigen in kidney transplant patients.

A mouse monoclonal antibody, specific for binding with the epithelial surface antigen in human renal proximal tubules, was produced by hybridoma culture. Using this antibody, an enzyme-linked immunosorbent assay was developed to measure the human renal tubular epithelial antigen (HRTE) concentrations in serum samples from 25 normal subjects and 66 consecutive renal allograft recipients. In 46 patients treated with azathioprine and prednisone, serum HRTE was elevated more than two-fold in 56 of 62 rejection episodes 2-5 days before the clinical diagnosis was made. Of the 56 rejection episodes, the antigen level fell to baseline after treatment in 44 steroid-responsive episodes, but it remained elevated in 8 steroid-resistant rejections, and it became undetectable 3-4 days after the initial elevation in 4 episodes in which allografts were lost to rejection. In 20 patients treated with cyclosporine and prednisone, all 25 rejection episodes demonstrated a greater than two-fold increase of serum HRTE 1-6 days prior to the diagnosis of rejection. The antigen level fell to baseline in 23 reversible rejection episodes, however serum HRTE remained elevated in 2 steroid-resistant patients whose grafts were lost to rejection. Cyclosporine nephrotoxicity without rejection was confirmed in 6 episodes, each of which demonstrated a more than two-fold increase in HRTE 2-4 days before toxicity was diagnosed. When the cyclosporine dose was reduced, the antigen level decreased as the serum creatinine declined. Serial determinations of serum HRTE in renal transplant recipients can provide valuable information for the early diagnosis and management of allograft rejection and cyclosporine nephrotoxicity.

Incidence of cytomegalovirus disease in cyclosporine-treated renal transplant recipients based on donor/recipient pretransplant immunity.

We retrospectively reviewed the clinical data of all renal transplant patients treated with cyclosporine as their main chronic immunosuppressive agent between 12/83 and 11/85 to identify cytomegalovirus-negative patients at our institutions who received cytomegalovirus (CMV)-positive kidneys. Using a latex agglutination test, twenty-two such patients were identified, of whom 2 were excluded due to early death and lack of posttransplant follow-up serology. Of the remaining 20 patients, 12 developed CMV antibody in the first 4 months posttransplant, and of these, 11 were hospitalized with complications related to primary CMV disease. Two of these seroconverting patients eventually died, and one lost her kidney. Of the 8 persistantly CMV-negative patients, 1 lost his kidney soon after transplantation, and one had a febrile illness 4 months posttransplant caused by a bacterial pneumonia. Concomitantly, 145 renal transplants (CMV-negative recipient receiving a CMV-negative kidney or CMV-positive recipient receiving either positive or negative kidneys) given to 142 patients functioned for at least 4 weeks. Only 3 cases of CMV reactivation disease occurred in previously antibody-positive patients. We conclude that the transplantation of a cytomegalovirus-positive kidney into a CMV-negative recipient carries a high risk of mortality/morbidity from primary cytomegalovirus disease. On the other hand, reactivation of CMV disease was uncommon early in the posttransplant course of cyclosporine-treated patients.

Acute effects of intravenous cyclosporine on blood pressure, renal hemodynamics, and urine prostaglandin production of healthy humans.

The acute renal failure associated with cyclosporine may result from vasoconstriction of intrarenal arterioles. To evaluate the mechanism of cyclosporine-induced nephrotoxicity, we acutely administered cyclosporine to eight healthy female volunteers with normal blood pressure and renal function. Cyclosporine (4 mg/kg) in 250 ml of 5% dextrose in water (D5W) was administered as a steady intravenous infusion over 6 hr. Glomerular filtration rate and renal plasma flow were measured by serum disappearance of 99m TcDTPA and 131I hippuran, respectively, during the last 3 hr of the infusion. D5W was given to the patients on separate days before the cyclosporine infusion to obtain control data. Systolic and diastolic blood pressure measured every hour during the infusions and renal vascular resistance were slightly higher during cyclosporine administration, but the increases were not statistically significant. Renal plasma flow was not affected by cyclosporine, being 479.6 +/- 24.9 ml/min during the control infusion and 463.3 +/- 12.7 ml/min during the cyclosporine infusion. However, glomerular filtration rate was reduced by cyclosporine in all patients (control, 108.8 +/- 2.5 ml/min, vs. cyclosporine, 91.1 +/- 2.2 ml/min, P less than .01), except one who demonstrated no significant change. Urinary excretion of thromboxane B2 during cyclosporine administration was markedly increased in all patients, being 39.9 +/- 8.2 ng/hr in the control period and 85.8 +/- 22.3 ng/hr during cyclosporine infusion (P less than .05), except for the one patient in whom no decrease in GFR was noted. There was no significant change in the urinary excretion rate for 6-keto-prostaglandin F1a or prostaglandin E during cyclosporine infusion. Serum averaged levels of peripheral renin activity, angiotensin II, and aldosterone did not change during with the cyclosporine administration compared with the control. All patients demonstrated a decrease in 24-h urinary excretion of sodium and potassium on the day of the cyclosporine infusion. Verapamil SR (240 mg daily for 7 days prior to cyclosporine infusion) did not reverse the reduction in glomerular filtration rate induced by cyclosporine; however, a significant reduction in renal vascular resistance and an increase in renal plasma flow (P less than .05) were noted when the volunteers were treated with both verapamil and cyclosporine compared with cyclosporine alone. Intravenous infusion of Cremophor EL, the vehicle to dissolve cyclosporine, demonstrated no significant effects on blood pressure, renal hemodynamics or urinary prostaglandin excretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Patient profile and effect of dietary therapy on post-transplant hyperlipidemia.

The effect of dietary therapy on the serum lipid profile was examined in 32 post-transplant patients. Patients were transplanted more than 4 months before the study and had stable renal function and no other condition affecting lipid metabolism. Serum lipid profiles were determined on two serum samples obtained after a 12-hour fast. Seventeen patients who had pre-transplant hyperlipidemia (HLP) had similar HLP after transplantation. Of the 14 patients with normal pre-transplant profiles, 9 remained normal and 5 developed HLP. Twelve patients with HLP received out-patient dietary therapy providing less than 500 mg of cholesterol, less than 35% of calories from fat, less than 50% of calories from carbohydrate, and a P:S ratio greater than 1. Maintenance calories were based on the Harris-Benedict standard except for 9 overweight patients who were given less. After 3 months of therapy, serum cholesterol and triglycerides decreased to normal in 8 of 9 patients in whom both were elevated before dietary treatment and were unchanged in one patient. In 3 patients who had normal triglyceride but elevated cholesterol levels before therapy, cholesterol decreased but remained above normal; triglyceride increased in one patient and remained normal in two. High-density lipoprotein cholesterol (HDL-C) increased in all 12 patients and became normal in 11. Body weight fell in 11 of 12 patients receiving dietary therapy. Cholesterol, triglyceride, and HDL-C remained unchanged in 11 patients who did not undergo dietary treatment. Dietary therapy is a safe and effective way to treat post-transplant HLP.

Antitumor effect of VNP20009, an attenuated Salmonella, in murine tumor models.

VNP20009, a genetically modified strain of Salmonella typhimurium with deletions in the msbB and purI loci, exhibited antitumor activities when given systemically to tumor-bearing mice. VNP20009 inhibited the growth of subcutaneously implanted B16F10 murine melanoma, and the human tumor xenografts Lox, DLD-1, A549, WiDr, HTB177, and MDA-MB-231. A single intravenous injection of VNP20009, at doses ranging from 1 x 10(4) to 3 x 10(6) cfu/mouse, produced tumor growth inhibitions of 57-95%. Tumor volume doubling time, another indicator for tumor growth inhibition, also significantly increased in mice treated with VNP20009. Using mice with immune system deficiencies, we also demonstrated that the antitumor effects of VNP20009 did not depend on the presence of T and B cells. In addition, VNP20009, given intravenously, inhibited the growth of lung metastases in mice. Only live bacteria showed the antitumor effect.