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Genetically engineered T cells are a powerful new modality for cancer immunotherapy. However, their clinical application for solid tumors is challenging, and crucial knowledge on cell functionality in vivo is lacking. Here, we fabricated a nanoprobe composed of dendrimers incorporating a calcium sensor and gold nanoparticles, for dual-modal monitoring of engineered T cells within a solid tumor. T cells engineered to express a melanoma-specific T-cell receptor and loaded with the nanoprobe were longitudinally monitored within melanoma xenografts in mice. Fluorescent imaging of the nanoprobe's calcium sensor revealed increased intra-tumoral activation of the T cells over time, up to 24 h. Computed tomography imaging of the nanoprobe's gold nanoparticles revealed the cells' intra-tumoral distribution pattern. Quantitative analysis revealed the intra-tumoral T cell quantities. Thus, this nanoprobe reveals intra-tumoral persistence, penetration and functional status of genetically engineered T cells, which can advance T cell-based immunotherapy and promote next-generation live cell imaging., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Pregnant women are at increased risk for hospitalization and death with influenza infection. The limited data on safety and effectiveness of influenza immunization in pregnancy emphasizes the importance of developing new and well-designed studies and of enhancing safety surveillance in pregnant women who are vaccinated with licensed influenza vaccines. Pregnancy exposure registries aim to collect and maintain data on the effects of marketed drugs and vaccines, when prescribed in pregnancy or during breastfeeding, on the women themselves and their children. Women who are prescribed a medication or vaccine as part of their routine clinical care can be enrolled directly or through reporting health care providers on a voluntary basis. Such registries generally are established for products that are intended for use by adolescents and adults and are a key component of the safety monitoring of licensed products. This article reviews some of the pregnancy registries that have been established for US-licensed vaccines, which includes influenza vaccines, and other postlicensure safety surveillance efforts for monitoring safety in vaccinated pregnant women., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs)., Methods: We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (≥18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response [TLOVR] algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00543725., Findings: From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3.5% [95% CI -1.7 to 8.8]; p(non-inferiority)<0.0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2-4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p<0.0001), as were rash and dizziness (p<0.0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0.0001)., Interpretation: Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1., Funding: Tibotec., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The optimal management of stage II endometrial cancer remains uncertain. We examined the role of radical hysterectomy and adjuvant radiotherapy for stage II endometrial cancer., Study Design: The Surveillance, Epidemiology, and End Results database was used to identify 1577 women with stage II endometrioid type endometrial adenocarcinoma who underwent surgical staging., Results: The cohort included 1198 women who underwent simple hysterectomy (76%) and 379 who underwent radical hysterectomy (24%). Radical hysterectomy had no effect on survival (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.61-1.23). Patients who did not receive radiation were 48% (HR, 1.48; 95% CI, 1.14-1.93) more likely to die than those who underwent adjuvant radiotherapy. The survival benefit from radiation was most pronounced in women who underwent radical hysterectomy., Conclusion: Adjuvant radiation improves survival. Although the routine performance of radical hysterectomy does not appear to be justified, patients with high-risk stage II tumors appear to benefit from combination therapy with radical hysterectomy and radiotherapy.

Objective: We examined the effect of radiation on survival for early-stage uterine carcinosarcomas and leiomyosarcomas., Study Design: The surveillance, epidemiology, and end results database was used to identify patients with stage I/II carcinosarcomas and leiomyosarcomas. Logistic regression and Cox models were developed to determine radiation use and survival., Results: Among 1819 women with carcinosarcomas and 1088 women with leiomyosarcomas, radiation was administered to 667 of the patients (37%) with carcinosarcomas and to 235 of the patients (22%) with leiomyosarcomas. In a multivariate model, adjuvant radiation reduced the risk of death by 21% in women with carcinosarcomas (hazard ratio, 0.79; 95% CI, 0.7-0.9). Radiation reduced mortality rates in patients with carcinosarcomas who had not undergone node dissection but had only a marginal effect on survival in node-negative women. Adjuvant radiation had no effect on survival for early-stage leiomyosarcomas (hazard ratio, 1.1; 95% CI, 0.9-1.4)., Conclusion: Adjuvant radiotherapy improves survival for select patients with early-stage carcinosarcomas but is of limited value for leiomyosarcomas.

Malignancies arising from retrovirally transduced hematopoietic stem cells have been reported in animal models and human gene therapy trials. Whether mature lymphocytes are susceptible to insertional mutagenesis is unknown. We have characterized a primary human CD8(+) T-cell clone, which exhibited logarithmic ex vivo growth in the absence of exogenous cytokine support for more than 1 year after transduction with a murine leukemia virus-based vector encoding the T-cell growth factor IL-15. Phenotypically, the clone was CD28(-), CD45RA(-), CD45RO(+), and CD62L(-), a profile consistent with effector memory T lymphocytes. After gene transfer with tumor-antigen-specific T-cell receptors, the clone secreted IFN-gamma upon encountering tumor targets, providing further evidence that they derived from mature lymphocytes. Gene-expression analyses revealed no evidence of insertional activation of genes flanking the retroviral insertion sites. The clone exhibited constitutive telomerase activity, and the presence of autocrine loop was suggested by impaired cell proliferation following knockdown of IL-15R alpha expression. The generation of this cell line suggests that nonphysiologic expression of IL-15 can result in the long-term in vitro growth of mature human T lymphocytes. The cytokine-independent growth of this line was a rare event that has not been observed in other IL-15 vector transduction experiments or with any other integrating vector system. It does not appear that the retroviral vector integration sites played a role in the continuous growth of this cell clone, but this remains under investigation.

The recent advent of peptide-MHC tetramers has provided a new and effective tool for studying antigen-specific T cell populations through monitoring tetramer binding to T cells by flow cytometry. Yet information regarding T cell activation induced by the bound tetramers cannot be deduced from binding studies alone; complementary methods are needed to bridge this gap. To this end, we have developed a new approach that now enables monitoring both binding to and activation of T cells by peptide-MHC tetramers at the single-cell level. For this purpose, we have employed the CellScan, a non-flow cytometer designed for repetitive measurements of optical parameters (e.g., fluorescence intensity and polarization) of individual living cells. A melanoma-specific MART1 CTL line and a gp100-specific CTL clone were incubated with specific and control single-chain peptide-MHC tetramers for 45 min. Subsequently, the fluorescence intensity and polarization were measured by the CellScan. Specific binding of fluorescently labeled peptide-MHC tetramers to CTLs, recorded by the CellScan, was comparable to that measured by flow cytometry. CellScan monitoring of the degree of fluorescence polarization of fluorescein diacetate-labeled CTLs that were reacted with tetramers revealed specific activation of the CTLs, which was confirmed by cytokine (INF gamma) production. These results provide a new means of monitoring both the binding to and activation of T lymphocytes by cognate peptide-MHC complexes at the single-cell level, which can now be applied to distinguish between cognate responding and anergic T cells.

This article describes the design, methodology, baseline distributions, and general follow-up characteristics of the American Foundation for AIDS Research (AmFAR) National Observational Database (ODB) Project including the benefits and limitations of collecting information on a large simple cohort in the HIV community setting. The study prospectively followed 15,611 HIV-positive men and women and collected longitudinal and cross-sectional data on demographics, medical conditions, drug therapies, laboratory parameters, and survival. Participants were followed between October 1990 and December 1993 by 252 community-based sites coordinated by 22 centers in the Community-Based Clinical Trials Network (CBCT Network) throughout the United States (including Puerto Rico) and Toronto, Canada. The ODB provided quantitative information on a national level needed to track the HIV epidemic and plan clinical trials conducted through the Network, and to provide sites with local databases to monitor patients and facilitate access to therapies in clinical trials. Overall, the ODB contains information on 1,925 women (12%) and 13,686 men (88%), 60% white, 20% African American, 17% Latino/Hispanic, with 56,254 baseline and follow-up forms, a median follow-up of about 12 months, a 16% loss-to-follow-up, and an 11% mortality rate. AmFAR plans to place the ODB in the public domain.

In spite of diagnostic and therapeutic improvements the Surveillance Epidemiology and End Results Program data suggest that the overall cure rate for patients with ovarian cancer is 39%. Because of the dramatic difference in cure between patients with local disease (80% to 90%) and those with distant disease (15% to 25%), screening to find early ovarian cancer or its precursors is desirable. Transvaginal ultrasonography is the most efficient, accurate, and least expensive of the imaging modalities (transabdominal ultrasonography, computed tomography, magnetic resonance imaging, radioimmunoscintigraphy) for this purpose. To date, 10,000 women have been screened in three large programs; 11 cancers were detected (10 stage I, one occult stage IIIB) and all have apparently been cured. Doppler flow imaging and morphology index values improve the accuracy of transvaginal ultrasonography. A cost analysis suggests that screening costs are not yet less than treatment costs if there is to be universal screening of 27 million women at risk in the United States. However, for a population with a lifetime risk for ovarian cancer of 1%, screening will save five lives per 2000 patients screened.

Leukocyte migration studies with amniotic fluid (AF) were performed in 47 pregnant women and 24 control patients. Previous reports about the enhancing effect of AF on leukocyte migration during pregnancy were confirmed (p less than 0.003). No enhancing effect was observed with first-trimester leukocytes. Maximal enhancement occurred during the second trimester (p less than 0.0001). It decreased during the third trimester (p less than 0.01) and lost significance in the postpartum period (p less than 0.072). Fifteen pregnant and control patients were investigated with autologous plasma. Leukocyte migration enhancement (LME) was significant with pregnancy plasma (PL) (p less than 0.03). Again LME was the largest during the second trimester (p less than 0.006). It is concluded that an immunologically active factor is present in AF and PL which in term induces the enhancing activity of a predetermined effector cell subgroup. This process is absent in conjunction with male leukocytes and is lacking in the majority of patients with toxemia of pregnancy.

Between 1974 and 1982, 273 patients with epithelial cancer of the ovary (International Federation of Gynaecology and Obstetrics Stages III and IV) were randomized in four therapeutic trials. In Trial I Adriamycin plus cisplatin versus cisplatin alone versus thiotepa plus methotrexate was tested. The superiority of Adriamycin plus cisplatin in producing the best response rate led to its use as the reference arm in subsequent trials. All investigational arms included cisplatin plus other drugs (cyclophosphamide, Adriamycin, hexamethylmelamine, and thiotepa) in various combinations. Eligibility for second look required complete clinical remission and completion of at least 10 cycles of chemotherapy. To date, 73 second-look operations have been performed on randomized patients. An additional 43 nonrandomized patients underwent second-look procedures and are analyzed separately. Between 40% and 46% of patients treated with cisplatin regimens had no disease at second look. Cell differentiation and volume of postoperative disease did not influence response.

Leukocyte migration enhancement (LME), a common denominator of pregnancy and malignancy, was investigated in order to determine the immunologic factors and processes involved in this in vitro assay. Reproducibility of results was confirmed by parallel investigations of single patients in an independent laboratory. Preliminary evidence also suggests that the phenomenon of LME is observable not only with the leukocyte migration assay, as performed in the present study, but also with the "indirect" migration inhibitory factor (MIF) assay. Highly significant correlation between results obtained with plasma (PL) and amniotic fluid (AF) was observed (p less than 0.00089). No significant correlation between LME and IgG concentrations as well as complement (C3) concentrations in AF and PL could be detected. C3 concentrations correlated significantly to gravity (p less than 0.007) and parity (p less than 0.003). No immune complexes were detected in either AF or PL samples. An unspecific protein effect as the cause of LME was ruled out in showing no significant correlation between LME and protein concentrations of AF and PL. A highly significant correlation between antigen concentration in PL and migration area was demonstrated (p less than 0.00001). It is suggested that leukocyte migration inhibition (LMI) represents a state of antigen excess, while LME represents antibody excess. Through selective removal of the IgG immunoglobulins LME could be converted into LMI, indicating an IgG subfraction as the responsible immunoglobulin in the phenomenon of LME.

Patients with advanced ovarian carcinoma, Stage III or IV (International Federation of Gynaecology and Obstetrics), were randomized to primary chemotherapy with doxorubicin (Adriamycin) and cisplatin plus or minus hexamethylmelamine, and cyclophosphamide (CHAP). The four-drug CHAP regimen produced a 57% complete clinical response rate and a 26% partial response rate for clinically evaluable patients. The median survival of CHAP patients is 25 months. The two-drug Adriamycin-cisplatin (AP) regimen produced a 43% complete response rate and a 35% partial response rate. The median survival is 18 months. The four-drug regimen produced a significantly longer median survival (28 versus 18 months) for patients with poorly differentiated tumors than for patients with well-differentiated tumors on either treatment. Examination of treatment failure or death by treatment, histology, and size of largest residual tumor and comparison to similar patients treated with AP in this and two preceding controlled trials also suggest that CHAP is superior to AP for patients with poorly differentiated tumors.

A group of patients with squamous cell carcinoma of the cervix were tested for cellular hypersensitivity prior to the initiation of therapy. Fourteen of 15 patients manifested inhibition of leukocyte migration with homologous tumor extracts, and 13 patients showed inhibition with autologous tumor extracts. Lymphocytes from 10 to 11 patients exhibited cytotoxicity for a homologous cell line and lymphocytes from 4 to 5 patients, for autologous cell lines. These results indicate that the absence of cellular hypersensitivity is infrequent in patients with squamous cell carcinoma. A comparison of the degree of sensitivity detected by use of each test showed a good correlation in a group of 10 patients. The efficacy of both autologous and homologus antigens to react with sensitized leukocytes supports the hypothesis that these antigens are tumor related. Although no correlation was found among the immunologic tests, clinical status of the patient, or prognosis based on the evaluation of several histologic parameters, further studies are needed to determine the usefulness of these tests as a prognostic index in individual patients, especially in patients with Stage I carcinoma.

Original histologic slides were reviewed from 87 patients with advanced ovarian carcinoma, all of whom had been treated with cisplatin, alone or in combination. The degree of lymphocyte infiltration in the tumor was not related to histologic or cytologic tumor differentiation. However, the degree of lymphocyte infiltration was related to improved survival.

The original histologic material of 87 patients with Stage III or IV ovarian adenocarcinoma was reviewed. These patients had been treated with cisplatin, alone or in combination. There was a significant association among the morphologic parameters of histologic differentiation, mitotic activity, and cellular pleomorphism. However, none of these was associated either with survival or with maximum response of the tumor among the cisplatin-treated patients. The possible significance of these findings is discussed.

Cellular hypersensitivity was studied in patients with adenomatous hyperplasia and adenocarcinoma of the endometrium with the use of dinitrochlorobenzene (DNCB) skin tests and inhibition of leukocyte migration by homologous and autologous tumor antigen. Inhibition of leukocyte migration by homologous endometrial carcinoma antigen was found in two of five patients with adenomatous hyperplasia and eight of 11 patients with endometrial adenocarcinoma. A comparable degree of inhibition was found with autologous antigen. DNCB skin reactions were found to be strongly positive in patients with adenomatous hyperplasia, and a lesser degree of reactivity was observed in patients with endometrial adenocarcinoma. No correlation was found between leukocyte migration tests and DNCB reactions, and no correlation was observed between these tests and the age of the patient, clinical stage of disease, or histologic grade of the tumor.

Amniotic fluid was found to cause significant leukocyte migration enhancement during the second and third trimester of pregnancy and in the early postpartum period when compared to the migration area obtained with an ovarian tumor homogenate antigen (p less than 0.01), choriocarcinoma spent medium (p less than 0.01), and placental pool homogenate (p less than 0.01). Only borderline significance (p less than 0.1) was obtained when migration enhancement with AF was compared between pregnant and nonpregnant female control patients, indicating minimal unspecific activity of AF. Migration enhancement with autologous amniotic fluid was slightly larger than with homologous amniotic fluid, but the difference did not reach significance (p less than 0.4). None of the control antigens caused migration enhancement; placental pool homogenate in concentrations above 4 mg. per cent caused migration inhibition but did not in lower concentrations. The enhancing effect of AF could be abolished by dilution but not by addition of excessive antibody to estrogen of HCG. It is suggested that a blocking factor is present in AF preventing recognition of fetoplacental antigen by the maternal immune system. Thus in vitro leukocyte migration enhancement may correlate to in vivo graft enhancement.