Follow-up of women with cervical adenocarcinoma in situ treated by conization: A single centre clinical experience.

OBJECTIVE: Hysterectomy has been the historical gold standard final step in the treatment algorithm of adenocarcinoma in situ (AIS) recommended by most North American colposcopy guidelines. AIS disproportionately affects young childbearing age women, therefore a fertility sparing treatment option is desirable. Our study examines the impact of conservative treatment of AIS with conization followed by serial surveillance. METHODS: A retrospective chart review was completed of patients treated for AIS from 2006 to 2020. Charts were identified by pathologic diagnosis of AIS on cervical and uterine specimens. Charts were excluded if AIS was not treated with conization, if AIS was not confirmed on initial conization specimen, or if invasive disease was found at initial conization. RESULTS: 121 patient charts were analyzed. Median age of patients at first conization and hysterectomy was 34.8 and 40.9, respectively. First conization was by Cold Knife Cone in 58% of patients, and by Loop Electrosurgical Excisional Procedure in 42% of patients. Median follow-up period in our study was 609 days. 5% of patients had recurrence, with only one patient who recurred as cancer. One case of recurrence had a positive initial conization margin. Median time to recurrence was 700 days. 47% of patients underwent eventual hysterectomy. Residual AIS was found in 23% of hysterectomy specimens. Adenocarcinoma was diagnosed on hysterectomy specimen in four patients. CONCLUSION: Our study demonstrates the oncologic safety of treating AIS with conization and serial surveillance. Routine hysterectomy completed as a part of the AIS treatment algorithm, as in current clinical guidelines, is unnecessary.

Enhanced recovery after surgery (ERAS®) society guidelines for gynecologic oncology: Addressing implementation challenges - 2023 update.

BACKGROUND: Despite evidence supporting its use, many Enhanced Recovery After Surgery (ERAS) recommendations remain poorly adhered to and barriers to ERAS implementation persist. In this second updated ERAS® Society guideline, a consensus for optimal perioperative care in gynecologic oncology surgery is presented, with a specific emphasis on implementation challenges. METHODS: Based on the gaps identified by clinician stakeholder groups, nine implementation challenge topics were prioritized for review. A database search of publications using Embase and PubMed was performed (2018-2023). Studies on each topic were selected with emphasis on meta-analyses, randomized controlled trials, and large prospective cohort studies. These studies were then reviewed and graded by an international panel according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: All recommendations on ERAS implementation challenge topics are based on best available evidence. The level of evidence for each item is presented accordingly. CONCLUSIONS: The updated evidence base and recommendations for stakeholder derived ERAS implementation challenges in gynecologic oncology are presented by the ERAS® Society in this consensus review.

Quality-of-life implications of risk-reducing cancer surgery.

BACKGROUND: Modern advances in genetic sequencing techniques have allowed for increased availability of genetic testing for hereditary cancer syndromes. Consequently, more people are being identified as mutation carriers and becoming aware of their increased risk of malignancy. Testing is commonplace for many inheritable cancer syndromes, and with that comes the knowledge of being a gene carrier for some patients. With increased risk of malignancy, many guidelines recommend that gene carriers partake in risk reduction strategies, including risk-reducing surgery for some syndromes. This review explores the quality-of-life consequences of genetic testing and risk-reducing surgery. METHODS: A narrative review of PubMed/MEDLINE was performed, focusing on the health-related quality-of-life implications of surgery for hereditary breast and ovarian cancer, familial adenomatous polyposis and hereditary diffuse gastric cancer. RESULTS: Risk-reducing surgery almost uniformly decreases cancer anxiety and affects patients' quality of life. CONCLUSION: Although the overwhelming quality-of-life implications of surgery are neutral to positive, risk-reducing surgery is irreversible and can be associated with short- and long-term side-effects.

Development of small particle speciation for nuclear forensics by soft X-ray scanning transmission spectromicroscopy.

Synchrotron radiation spectromicroscopy provides a combination of submicron spatial resolution and chemical sensitivity that is well-suited to analysis of heterogeneous nuclear materials. The chemical and physical characteristics determined by scanning transmission X-ray microscopy (STXM) are complementary to information obtained from standard radiochemical analysis methods. In addition, microscopic quantities of radioactive material can be characterized rapidly by STXM with minimal sample handling and intrusion, especially in the case of particulate materials. The STXM can accommodate a diverse range of samples including wet materials, complex mixtures, and small quantities of material contained in a larger matrix. In these cases, the inventory of species present in a sample is likely to carry information on its process history; STXM has the demonstrated capability to identify contaminants and sample matrices. Operating in the soft X-ray regime provides particular sensitivity to the chemical state of specimens containing low-Z materials, via the K-edges of light elements. Here, recent developments in forensics-themed spectromicroscopy, sample preparation, and data acquisition methods at the Molecular Environmental Science Beamline 11.0.2 of the Advanced Light Source are described. Results from several initial studies are presented, demonstrating the capability to identify the distribution of the species present in heterogeneous uranium-bearing materials. Future opportunities for STXM forensic studies and potential methodology development are discussed.

Ovarian cancer in Manitoba: trends in incidence and survival, 1992-2011.

BACKGROUND: Because the International Cancer Benchmarking Partnership, in a study of diagnosis years between 1995 and 2007, showed lower-than-expected survival for Manitoba's ovarian cancer patients, we undertook an analysis to describe the features of ovarian cancer diagnosed in Manitoba during a 20-year period. We also determined the most recent trends in survival to see if the previous results were sustained. METHODS: In this retrospective cohort study, ovarian cancer cases diagnosed during 1992-2011 were extracted from the Manitoba Cancer Registry. The incidence of ovarian cancer was calculated for the overall group and for age, morphology, residence, treatment, and stage. Trends over time, with a particular focus on changes that might correlate with poor survival, were analyzed. The 1- and 3-year relative survival rates were also calculated. RESULTS: The incidence of ovarian cancer did not vary over time (p = 0.640), even when stratified by age or morphology groups. Use of adjuvant chemotherapy decreased (p = 0.005) and use of neoadjuvant chemotherapy increased over time (p = 0.002). Diagnoses of stage iv cancers declined over time (p < 0.020). Trends in incidence did not coincide with previously observed decreases in relative survival. CONCLUSIONS: A decline in diagnoses of stage iv ovarian cancer could be responsible for a recent increase in relative survival. However, sample size might have limited power in some analyses, and the previously reported decrease in relative survival might have been due to a random fluctuation in the data. Future efforts will focus on continued monitoring of the patterns of ovarian cancer presentation and outcomes in Manitoba.

Malignant transformation of mature cystic teratoma of the ovary: 30-year experience of a single tertiary care center.

OBJECTIVE: To review the authors' experience with this rare disease and describe their management modality and the outcome. MATERIAL AND METHODS: From January 1983 to December 2013, 13 patients with malignant transformation arising in ovarian MCT were treated at the Division of Gynecologic Oncology in the University of Manitoba. Demographic characteristics, symptoms, signs, stage, mode of therapy, and results of follow-up were reviewed retrospectively. RESULTS: Median age at diagnosis was 53 years (range 25-65). The most common presenting symptom was a palpable mass in nine cases. Squamous cell carcinoma (SCC) was found in 38% (five cases), adenocarcinoma in 15% (two cases), anaplastic carcinoma in 8% (one case), and papillary thyroid carcinoma in 38% (five cases). Eight cases were Stage I, two cases were Stage II, and three cases were Stage III. All patients underwent surgery. Five patients received adjuvant treatment with platinum-based chemotherapy + pelvic radiation. Four patients had recurrent disease (two SCC and two adenocarcinoma). Three patients died of disease after recurrence. The median follow up period of the entire patient population was 60 months, with a three-year overall survival of 76%. CONCLUSION: Malignant transformation of MCT is large ovarian tumors that mainly occur in patients in their fifth and sixth decades of life. They often present as incidental pathologic findings after surgery for MCT. SCC has traditionally been the most common pathology, however in the present series, the authors found that papillary thyroid carcinoma was equally common. Platinum-based chemotherapy with pelvic radiation in early stage (including Stage IA) and locally recurrent dis- ease should be offered. Advanced stages and mucinous adenocarcinoma represent a poorer prognosis despite adjuvant treatment. In patients with papillary thyroid carcinoma, conservative surveillance in early stage and adjuvant total thyroidectomy with radioactive iodine treatment in advanced stage disease appears to be an effective treatment.

Informal caregiving to older cancer patients: preliminary research outcomes and implications.

BACKGROUND: The population of the Western world is aging while cancer survival rates are rising. Older patients with cancer will increasingly be taken care of by informal family caregivers. The current study describes levels of psychological distress, social support and coping abilities reported by partners who are caregivers to older patients with cancer (60+ years), comparing them to a control group of spouses of similarly aged people not suffering from life-threatening illness. PATIENTS AND METHODS: Two hundred sixteen partners who are primary caregivers of cancer patients aged 60+ were compared with 76 partners of healthy people aged 60+ and never diagnosed with any terminal illness. Participants completed self-reporting measures on psychological distress, coping ability and social support. RESULTS: Caregivers to cancer patients reported high levels of distress, low levels of social support and low levels of coping abilities which are negatively correlated to distress. Increased patient age was found to accentuate these processes. CONCLUSION: Age and the progression of cancer as a chronic illness present the physician with the reality that focus of care should be on the dyad (patient and caregiver), with high priority given to partners who are informal caregivers.

Superior vena cava syndrome - changing etiology in the third millennium.

Superior vena cava syndrome (SVCS), is diagnosed following different degrees of central venous system obstruction, which traditionally was caused by infections, tumors or fibrosing mediastinitis. Recently the role of SVC thrombosis secondary to indwelling central venous devices or pacemaker leads as well as different hypercoagulable states have drawn much attention. In the current review we present a 58-year-old female patient who underwent recurrent pacemaker replacements due to recurrent infections. The patient was hospitalized with superior vena cava syndrome and multiple thrombi in the upper body circulation. Additionally the evaluation was conducted for thrombophilia, which revealed the presence of high titers of antiphospholipid antibodies, suggesting the concurrent diagnosis of the antiphospholipid syndrome (APS). This case reflects the changes in the etiology of SVCS, and the need for a comprehensive evaluation of patients, in the search for additional factors that may complicate a pacemaker insertion, such as the presence of antiphospholipid antibodies. We review the relevant literature and highlight the importance for an interdisciplinary approach in the treatment of SVCS nowadays.

Heterogeneity in the development of cytotoxic T lymphocytes in vitro revealed by sensitivity to hydrocortisone.

In the present study we used hydrocortisone (HC) treatment in vivo as a probe to analyze two different in vitro systems for the regeneration of cytotoxic T lymphocyte (CTL), namely the antifibroblast reaction (AFR) and the mixed lymphocyte culture (MLC) system. We found that cells remaining in the thymus after HC treatment had increased reactivity in these two systems. However, the same treatment in the spleen severely depressed the MLC reactivity in both the proliferative and the cytolytic phases, while markedly increasing the AFR reactivity. These findings demonstrate heterogeneity of CTL precursors and/or their pathways of differentiation into effector cells. In addition, MLC-reactive cells in the thymus appear to be distinct from such cells in the spleen, as judged from their differential sensitivity to HC.

Construction of T cell hybridomas secreting allogeneic effect factor.

T cell hybridoma lines were constructed by fusion of DBA/2 alloantigen-activated T cell blasts with the AKR thymoma line BW5147. Certain of the hybridomas prepared in this manner secreted spontaneously into their culture supernates biologically active molecules that displayed B cell- and T cell-activating properties characteristic of allogeneic effect factor (AEF). Cell surface phenotype analysis documented that the hybridomas were, indeed, somatic cell hybrids between the two respective partner cells used for fusion. The B cell-activating properties of these hybridoma supernates was demonstrated by their capacity to stimulate T cell-depleted spleen cells to respond in vitro to T-dependent antigens. The T cell-activating properties of these hybridoma supernates was verified by their capacity to stimulate autonomous development of self-specific cytotoxic T lymphocytes and by their capacity to exert mitogenic effects on unprimed T cells. The biologically active molecules secreted by these hybridomas were, like conventional AEF, inhibitable by specific anti-Ia antibodies thus indicating the presence of Ia determinants on the relevant hybridoma products. Finally, these AEF-secreting hybridomas could be stimulated to proliferate and to secrete increased quantities of AEF when exposed to the specific alloantigen-bearing target cells to which the T cell blasts had been originally sensitized.

Identification of a T cell hybridoma that produces large quantities of macrophage-activating factor.

A murine T cell hybridoma, constructed by fusion of alloantigen-activated T cells with the BW5147 T cell lymphoma, which produces a lymphokine capable of inducing tumoricidal activity in macrophages, has been identified. Lymphokine release could be detected only after mitogen stimulation of the T cell hybridoma culture. Upon cloning of the parental hybridoma, 24 out of 27 clones produced tumoricidal-inducing activity. Seven clones produced more cytocidal-inducing activity than did conventional supernatants, generated by concanavalin A stimulation of normal murine spleen cell cultures, which contained macrophage-activating factor (MAF). The supernatant of hybridoma clone 24/G1 was 25 times more active than conventional MAF preparations. Using supernatants from a variety of clones, the levels of macrophage-activating activity and interleukin 2 were found to vary independently of one another. The lymphokine produced by hybridoma clone 24/G1 appeared to be identical to conventional MAF by a variety of criteria including: (a) a requirement for a second signal for induction of tumoricidal activity in macrophages, (b) inactivation after incubation for 1 h at 65 degrees C, and (c) loss of activity after treatment at pH 4.0 but not at pH 5.0. Like conventional MAF, the hybridoma MAF eluted as a single peak after molecular sieve chromatography on Sephadex G100 and exhibited an apparent molecular weight of 55,000. Although somewhat heterogeneous, the majority of hybridoma 24/G1 MAF displayed an isoelectric point of 5.4 as determined using the chromatofocusing technique. These results thus illustrate the usefulness of T cell hybridomas in distinguishing between various lymphokine activities and indicate that the T cell hybridoma clone 24/G1 will be of particular usefulness in achieving the biochemical purification of substantial quantities of murine MAF.

Analysis of T cell function in autoimmune murine strains. Defects in production and responsiveness to interleukin 2.

In the studies reported here, we have analyzed the production and consumption of T cell growth factor, more recently termed interleukin 2 (IL-2), as well as some cell-mediated immune functions, in murine strains [MRL, BXSB, NZB, and (NZB x NZWF1] manifesting systemic lupus erythematosus (SLE)-like syndromes. Young (4-6 wk) or old (4-8 mo) autoimmune or normal mice were studied and compared with regard to the following T cell functions in vitro after stimulation with concanavalin A (Con A): (a) mitogenic response; (b) IL-2 levels in culture supernates; and (c) the ability to respond to and adsorb IL-2. In addition, proliferative activity in the allogeneic mixed leukocyte culture and frequency of alloreactive cytotoxic T lymphocyte precursors (CTLp) were analyzed in some of these strains. Reduced Con A-induced mitogenic responses and IL-2 production appeared at 3-6 wk of age in the early, severe SLE developing strains MRL-Mp-lpr/lpr (MRL/l) and male BXSB and progressed thereafter. Similar defects appeared at a later stage in MRL/Mp-+/+ and (NZB x NZW)F1 hybrid mice, which develop late disease. Detailed analysis of cells from the enlarged lymph nodes and spleens of older MRL/l mice demonstrated that such cells: (a) responded poorly to Con A or allogeneic stimulator cells, even in the presence of exogenous IL-2; (b) did not suppress IL-2 production by normal spleen cells; (c) were relatively incapable of adsorbing or inactivating IL-2; and (d) had a markedly reduced anti-H-2b CTLp frequency in the mesenteric lymph nodes but a normal one in spleen. These results indicate that the proliferating Thy-1.2+, Lyt-1+ T cells in MRL/l mice are defective in their responses to mitogenic stimuli, in IL-2 production, and in expression of acceptor sites for IL-2. The relevance of these defects to the MRL/l disease as well as to the role of IL-2 in autoimmunity in general remains to be determined.

Long-term survival in a stage IV small cell carcinoma of the endometrium.

•Small cell carcinoma of the endometrium is a rare malignancy with poor survival.•A patient was diagnosed with stage IV small cell carcinoma of the endometrium.•She was treated with surgery, chemotherapy (cisplatin/etoposide) and radiotherapy.•She remains disease free 5 years after completion of her treatments.

Vav1/Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells.

Formation of the immunological synapse (IS) in T cells involves large scale molecular movements that are mediated, at least in part, by reorganization of the actin cytoskeleton. Various signaling proteins accumulate at the IS and are localized in specialized membrane microdomains, known as lipid rafts. We have shown previously that lipid rafts cluster and localize at the IS in antigen-stimulated T cells. Here, we provide evidence that lipid raft polarization to the IS depends on an intracellular pathway that involves Vav1, Rac, and actin cytoskeleton reorganization. Thus, lipid rafts did not translocate to the IS in Vav1-deficient (Vav1-/-) T cells upon antigen stimulation. Similarly, T cell receptor transgenic Jurkat T cells also failed to translocate lipid rafts to the IS when transfected with dominant negative Vav1 mutants. Raft polarization induced by membrane-bound cholera toxin cross-linking was also abolished in Jurkat T cells expressing dominant negative Vav1 or Rac mutants and in cells treated with inhibitors of actin polymerization. However, Vav overexpression that induced F-actin polymerization failed to induce lipid rafts clustering. Therefore, Vav is necessary, but not sufficient, to regulate lipid rafts clustering and polarization at the IS, suggesting that additional signals are required.

Differentiation of murine bone marrow stem cells in vitro: long-term growth promoted by a lymphocyte-derived mediator.

In attempts to induce differentiation of lymphoid cells from hematopoietic stem cells in vitro, the effects of allogeneic effect factor on the growth of murine bone marrow cultures were studied. Allogeneic effect factor is a soluble mediator derived from mixed secondary murine leukocyte cultures. For several weeks it supported the growth of bone marrow cultures, as indicated by the maintenance of stem cell activity, cellular proliferation, and heterogeneity. Another lymphokine, T cell growth factor, did not, Pre-T lymphocytes could be detected in these cultures for several weeks.

T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation.

Triggering of the antigen-specific T cell receptor-CD3 complex (TCR-CD3) stimulates a rapid phospholipase C-mediated hydrolysis of inositol phospholipids, resulting in the production of second messengers and in T cell activation and proliferation. The role of tyrosine phosphorylation in these events was investigated with a tyrosine protein kinase (TPK) inhibitor, genistein. At doses that inhibited TPK activity and tyrosine phosphorylation of the TCR zeta subunit, but not phospholipase C activity, genistein prevented TCR-CD3-mediated phospholipase C activation, interleukin-2 receptor expression, and T cell proliferation. These findings indicate that tyrosine phosphorylation is an early and critical event that most likely precedes, and is a prerequisite for, inositol phospholipid breakdown during receptor-mediated T cell activation.

Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation.

The hematopoietically expressed product of the vav proto-oncogene, Vav, shared homology with guanine nucleotide releasing factors (GRFs) [also called guanosine diphosphate-dissociation stimulators (GDSs)] that activate Ras-related small guanosine triphosphate (GTP)-binding proteins. Human T cell lysates or Vav immunoprecipitates possessed GRF activity that increased after T cell antigen receptor (TCR)-CD3 triggering; an in vitro-translated Vav fragment that contained the putative GRF domain was also active. Vav-associated GRF stimulation after TCR-CD3 ligation paralleled its tyrosine phosphorylation; both were blocked by a protein tyrosine kinase (PTK) inhibitor. Vav also was a substrate for the p56lck PTK. Thus, Vav is a PTK-regulated GRF that may be important in TCR-CD3-initiated signal transduction through the activation of Ras.

Direct resorption of bone by human monocytes.

Cultured human peripheral blood monocytes stimulate the release of bone mineral and matrix from killed long bones of fetal rats. These effects were inhibited by cortisol but were not altered by hormones that normally stimulate osteoclastic bone resorption. There was no evidence of morphologic differentiation of the monocytes into osteoclasts during bone resorption.