The alternative complement component factor B regulates UV-induced oedema, systemic suppression of contact and delayed hypersensitivity, and mast cell infiltration into the skin.

Ultraviolet (UV) wavelengths in sunlight are the prime cause of skin cancer in humans with both the UVA and UVB wavebands making a contribution to photocarcinogenesis. UV has many different biological effects on the skin that contribute to carcinogenesis, including suppression of adaptive immunity, sunburn and altering the migration of mast cells into and away from irradiated skin. Many molecular mechanisms have been identified as contributing to skin responses to UV. Recently, using gene set enrichment analysis of microarray data, we identified the alternative complement pathway with a central role for factor B (fB) in UVA-induced immunosuppression. In the current study we used mice genetically deficient in fB (fB-/- mice) to study the functional role of the alternative complement pathway in skin responses to UV. We found that fB is required for not only UVA but also UVB-induced immunosuppression and solar-simulated UV induction of the oedemal component of sunburn. Factor B-/- mice had a larger number of resident skin mast cells than control mice, but unlike the controls did not respond to UV by increasing mast cell infiltration into the skin. This study provides evidence for a function role for fB in skin responses to UV radiation. Factor B regulates UVA and UVB induced immunosuppression, UV induced oedema and mast cell infiltration into the skin. The alternative complement pathway is therefore an important regulator of skin responses to UV.

An omics approach to delineating the molecular mechanisms that underlie the biological effects of physical plasma.

The use of physical plasma to treat cancer is an emerging field, and interest in its applications in oncology is increasing rapidly. Physical plasma can be used directly by aiming the plasma jet onto cells or tissue, or indirectly, where a plasma-treated solution is applied. A key scientific question is the mechanism by which physical plasma achieves selective killing of cancer over normal cells. Many studies have focused on specific pathways and mechanisms, such as apoptosis and oxidative stress, and the role of redox biology. However, over the past two decades, there has been a rise in omics, the systematic analysis of entire collections of molecules in a biological entity, enabling the discovery of the so-called "unknown unknowns." For example, transcriptomics, epigenomics, proteomics, and metabolomics have helped to uncover molecular mechanisms behind the action of physical plasma, revealing critical pathways beyond those traditionally associated with cancer treatments. This review showcases a selection of omics and then summarizes the insights gained from these studies toward understanding the biological pathways and molecular mechanisms implicated in physical plasma treatment. Omics studies have revealed how reactive species generated by plasma treatment preferentially affect several critical cellular pathways in cancer cells, resulting in epigenetic, transcriptional, and post-translational changes that promote cell death. Finally, this review considers the outlook for omics in uncovering both synergies and antagonisms with other common cancer therapies, as well as in overcoming challenges in the clinical translation of physical plasma.

Management of Advanced Squamous Cell Carcinoma of the Vulva.

Vulvar cancer is a rare gynaecological malignancy, accounting for 2-5% of cancers of the female genital tract. Squamous cell carcinoma is the most frequently occurring subtype and, historically, has been a disease of older post-menopausal women, occurring with a background of lichen sclerosus and other epithelial conditions of the vulvar skin that may be associated with well-differentiated vulvar intra-epithelial neoplasia (dVIN). An increase in human papillomavirus (HPV) infections worldwide has led to an increase in vulvar squamous carcinomas in younger women, resulting from HPV-associated high-grade vulvar squamous intra-epithelial lesions (vHSIL). Surgical resection is the gold standard for the treatment of vulvar cancer. However, as approximately 30% of patients present with locally advanced disease, which is either irresectable or will require radical surgical resection, possibly with a stoma, there has been a need to investigate alternative forms of treatment such as chemoradiation and targeted therapies, which may minimise the psychosexual morbidity of radical surgery. This review aims to provide an update on management strategies for women with advanced vulvar cancer. It is hoped that investigation of the molecular biologies of the two different pathways to vulvar squamous cell carcinoma (HPV-associated and non-HPV-associated) will lead to the development of targeted therapeutic agents.

Cancer of the vagina: 2021 update.

Diagnosis of a primary vaginal cancer is rare, as most vaginal tumors are metastatic from another primary site. Although cancer of the vagina is more common in postmenopausal women, an increase in young women being diagnosed with primary vaginal cancer has been reported, especially in countries with a high HIV prevalence. This is associated with persistence of high-risk HPV infection. The emphasis should be on primary prevention with prophylactic HPV vaccination. Once there is a suspicion of a primary vaginal cancer, this should be confirmed histologically with biopsy. Staging has been done clinically, as with cervical cancer; however, there is a role for imaging in assisting with staging as this is often a difficult assessment. Treatment should be individualized and depends on stage as well as histologic subtype. It is prudent to refer cases to centers of excellence with experience in dealing with this rare gynecological cancer.

Cancer of the vulva: 2021 update.

Vulvar cancer is an uncommon gynecological malignancy primarily affecting postmenopausal women. There is no specific screening and the most effective strategy to reduce vulvar cancer incidence is the opportune treatment of predisposing and preneoplastic lesions associated with its development. While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer. Therefore, any suspicious vulvar lesion should be biopsied to exclude invasion. Once established, the most common subtype is squamous cell carcinoma. Treatment of vulvar cancer depends primarily on histology and surgical staging. Treatment is predominantly surgical, particularly for squamous cell carcinoma, although concurrent chemoradiation is an effective alternative, particularly for advanced tumors. Management should be individualized and carried out by a multidisciplinary team in a cancer center experienced in the treatment of these tumors.

Immunosuppressive ultraviolet-A radiation inhibits the development of skin memory CD8 T cells.

Ultraviolet A (UVA) radiation can have dual affects on the immune system depending on dose. At doses of approximately 1.8 J cm(-2), UVA acts in an immunosuppressive manner, whilst at higher doses UVA can promote recovery and protection against UVB-induced immunosuppression in mice. We utilised a model of contact hypersensitivity (CHS) to investigate how different doses of UVA modulates CD8 T cell immunity against a hapten in vivo. Only 1.8 J cm(-2) UVA decreased the CHS response compared to unirradiated mice, but this did not correlate with an inhibition of primary effector CD8 T cells. A similar expansion of effector CD8 T cells in skin-draining lymph nodes and accumulation of IFN-gamma-producing CD8 T cells in the ear skin was observed between unirradiated and UVA-irradiated mice. However, dermal memory CD8 T cells examined 9 weeks post challenge showed decreased numbers in mice irradiated with 1.8 J cm(-2) UVA compared with unirradiated, 1.3 J cm(-2) and 3.4 J cm(-2) UVA-irradiated mice. Therefore, UVA does not inhibit the expansion, migration or IFN-gamma secretion of CD8 T cells during a primary immune response. However, exposure to immunosuppressive UVA causes a defect in CD8 T cell development that impairs the ability of cells to become long-term memory cells.

Stage IA2 cervical carcinoma: how much treatment is enough?

OBJECTIVE: The current guidance for the management of women with stage IA2 cervical carcinoma is that whatever the primary surgical intervention, pelvic lymphadenectomy should be included. The role of lymphadenectomy in the management of cervical carcinoma remains somewhat confused, as the procedure has not been proven to be therapeutic, although it is claimed that the information gained is valuable in determining the need for adjuvant therapy. For lymphadenectomy to have clinical utility in the care of women with stage IA2 cervical carcinoma, a sufficiently high incidence of node positivity would be required to justify the morbidity of the procedure for the whole group. The objective of this paper was to establish the incidence of pelvic lymph node positivity in stage IA2 cervical carcinoma. METHODS: A PubMed search using the words "stage IA2 cervical carcinoma," "microinvasive cervical carcinoma," "stage IA cervical carcinoma," "stage I cervical carcinoma," and "lymphadenectomy in cervical carcinoma" was performed; the articles were divided into those that adhered to the International Federation of Gynecology and Obstetrics (FIGO) definition of a stage IA2 tumor and those that did not. Sentinel node studies were not included, as this procedure does not form part of the FIGO guidelines. RESULTS: Studies adhering to the FIGO definition showed a 0.5% incidence of lymph node metastases in stage IA2 cervical carcinomas, which is not as high as was previously believed (7.3%). CONCLUSIONS: The very low rate of positive lymph nodes in correctly staged IA2 cases cannot justify the inclusion of lymphadenectomy as part of standardized care for these patients.

Chemoradiation in advanced vulval carcinoma.

INTRODUCTION: Vulval carcinoma is uncommon, affecting approximately 2 per 100,000 women annually. The treatment of choice is radical vulvectomy and inguinal lymph node dissection. Advanced vulval carcinomas involve midline structures (such as clitoris, urethra, or anus) and/or adjacent pelvic organs or bone, and adequate excision may require urinary diversion, colostomy, or pelvic exenteration. Less morbid and less mutilating therapeutic alternatives have been investigated, particularly chemoradiation, which has shown success in the management of anal carcinomas. Chemoradiation has been used, instead of primary radical surgery, to treat advanced vulval carcinomas at Groote Schuur Hospital (GSH) since 1982. This is a retrospective study of the GSH's experience of the use of chemoradiation as primary therapy for women with advanced vulval carcinoma. METHODS: Data from patients' medical records were transcribed onto a standardized pro forma, computerized, and analyzed. RESULTS: Between 1982 and 2001, 50 women with advanced vulval carcinomas were treated with chemoradiation at GSH. Fourteen women (28%) who had a complete response to chemoradiation had significantly improved survival compared with 29 (58%) who had a partial response (P = 0.000218). Partial responders who had surgery had significantly better survival than those who did not (P = 0.0064). Other prognostic factors for survival were performance status and tumor stage. CONCLUSIONS: Less than a third of the women treated with primary chemoradiation had a complete response. Survival was improved in women who responded partially but had residual disease surgically excised. Performance status, age, and tumor stage were also associated with survival.

Vaccines against cervical cancer.

PURPOSE OF REVIEW: The purpose of this review is to give an overview of recent developments relating to human papillomavirus vaccines and their effect on cervical cancer. Original research publications from the last year (2007) have been reviewed and summarized to present an up to date synopsis of relevant trials, and the impact they will have on clinical practice. Comparisons of the two vaccines on the market are made, and details of each are given. The effect of vaccination on men and those in the developing world is explored. RECENT FINDINGS: Recent findings include results of the Females United to Unilaterally Reduce Endo/Ectocervical Disease II (FUTURE II) and PApilloma TRIal against Cancer In young Adults (PATRICIA) trials that show a significant reduction in human papillomavirus-associated anogenital disease with both quadrivalent and bivalent vaccines. The effect is greatest in women who are not yet exposed to the human papillomavirus. The international community recognizes the potential impact of this, particularly in the developing world, and strategies are being developed to try and deliver care effectively. SUMMARY: In summary, research published in the last year has continued the initial optimistic outlook for human papillomavirus vaccination and it is likely that its effect on cervical cancer will be as promising as initially appeared.

Cancer of the vulva.

Vulvar cancer is an uncommon gynecological malignancy primarily affecting postmenopausal women. There is no specific screening and the most effective strategy to reduce vulvar cancer incidence is the opportune treatment of predisposing and preneoplastic lesions associated with its development. While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer. Therefore, any suspicious vulvar lesion should be biopsied to exclude invasion. Once established, the most common subtype is squamous cell carcinoma. Treatment of vulvar cancer depends primarily on histology and surgical staging. Treatment is predominantly surgical, particularly for squamous cell carcinoma, although concurrent chemoradiation is an effective alternative, particularly for advanced tumors. Management should be individualized, and carried out by a multidisciplinary team in a cancer center experienced in the treatment of these tumors.

Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.

PURPOSE: We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. PATIENTS AND METHODS: Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL) -2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m(2)). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. RESULTS: Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 +/- 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. CONCLUSION: Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.

Anterior hippocampal volume reduction in male patients with schizophrenia.

Quantitative high resolution magnetic resonance imaging (MRI) was utilized to measure anterior, posterior, and total hippocampal volumes in 27 male patients with chronic schizophrenia and 24 male controls. To optimize measurement techniques, hippocampal volumes were: (1) acquired with 1.4-mm slices; (2) excluded with the amygdala; (3) normalized for position; and (4) corrected for total intracranial volume (ICV). The results of a linear mixed effects regression analysis, which made it possible to analyze total anterior and total posterior hippocampal volumes separately, indicated that the anterior hippocampus was significantly smaller in the schizophrenic group relative to the control group. There were no significant group differences with respect to posterior hippocampal volumes, and no significant correlations between hippocampal volumes and illness duration. A significant lateralized asymmetry was also noted in both groups with the right hippocampal volume being larger than the left. These preliminary findings support a significant anterior hippocampal volume reduction in men with schizophrenia as well as a similar hippocampal volume asymmetry in both male controls and schizophrenics.

Fine temporal resolution of analytic phase reveals episodic synchronization by state transitions in gamma EEGs.

The analytic signal given by the Hilbert transform applied to an electroencephalographic (EEG) trace is a vector of instantaneous amplitude and phase at the temporal resolution of the digitizing interval (here 2 ms). The transform was applied after band-pass filtering for extracting the gamma band (20-80 Hz in rabbits) to time series from up to 64 EEG channels recorded simultaneously from high-density arrays giving spatial "windows" of 4 x 4 to 6 x 6 mm onto the visual, auditory, or somatosensory cortical surface. The time series of the analytic phase revealed phase locking for brief time segments in spatial patterns of nonzero phase values from multiple EEG that was punctuated by episodic phase decoherence. The derivative of the analytic phase revealed spikes occurring not quite simultaneously (within +/- 4 ms) across arrays aperiodically at mean rates in and below the theta range (3-7 Hz). Two measures of global synchronization over a group of channels were derived from analytic phase differences between pairs of channels on the same area of cortex. One was a synchronization index expressing phase locking. The other was a decoherence index estimating the variance in phase among multiple channels. Spectral analyses of the indices indicated that decoherence events recurred aperiodically at rates in and below the theta range of the EEGs. The results provide support for the hypothesis that neurons in mesoscopic neighborhoods in sensory cortices self-organize their activity by synaptic interactions into wave packets that have spatial patterns of amplitude (AM) and phase (PM) modulation of their spatially coherent carrier waves in the gamma range and that form and dissolve aperiodically at rates in and below the theta range. Each AM pattern is formed by a nonlinear state transition in the cortical dynamics, as shown by spikes in the derivative. Phase locking within each PM pattern is not at zero phase lag but over a fixed distribution of phase values that is consistent with the radially symmetric phase gradients already reported called "phase cones" detected by Fourier-based methods. The insight is suggested that sensory cortices are bistable comparably to cardiac dynamics, with a diastolic state that accepts sensory input and an abrupt transition to a systolic state that transmits perceptual output. Further support for this inference will require improvements in methods for temporal resolution of the times of onset of spatial patterns of phase modulation.