Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes.

BACKGROUND: Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. METHODS: To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation. To define a functional-analysis prioritisation criteria, we used outputs for the known functionally confirmed deleterious and benign RAD51C missense changes from nine pathogenicity prediction algorithms. RESULTS: The p.Arg312Trp variant failed to correct mitomycin and olaparib hypersensitivity and to complement abnormal RAD51C foci formation according to functional assays, which altogether with LOH and segregation data demonstrated deleteriousness. Prioritisation criteria were based on the number of predictors providing a deleterious output, with a minimum of 5 to qualify for testing and a PredictProtein score greater than 33 to assign high-priority indication. CONCLUSIONS: Our study points to a non-negligible number of RAD51C missense variants likely to impair protein function, provides a guideline to prioritise and encourage their selection for functional analysis and anticipates that reference laboratories should have available resources to conduct such assays.

Update on the surgical pathology standards on rectal cancer diagnosis, staging and quality assessment of surgery.

Surgery for rectal cancer continues to develop towards improving local control and overall survival, maintaining quality of life and preserving sphincter, genitourinary and sexual function. The multidisciplinary approach integrated in a team of different specialists ensures an individualised treatment for each patient with rectal cancer. Thus, the role of the pathologist has acquired an important relevance, not only in diagnosis, management and evaluation of the surgical specimen, but also for selection of the best adjuvant treatment. Parameters such as macroscopic quality of the mesorectum, status of the circumferential margin and lymph node harvest are considered basic criteria by current guidelines. Additionally, consistency in reporting based on the histologic classification proposed by the World Health Organization (WHO) is mandatory, along with inclusion into the pathologic report of current criteria for tumour node metastasis (TNM) staging, assessment of response to neoadjuvant chemoradiation therapy and clinically relevant molecular studies. Detection of defects in mismatch repair genes and mutational analysis of specific genes should be included as predictive markers for therapy.

Sparing fertility in young patients with endometrial cancer.

The objective of this review is to recognize the characteristics of endometrial adenocarcinoma in young patients and to evaluate the published experience with conservative approach in patients with endometrial adenocarcinoma. We searched MEDLINE articles describing patients with endometrial adenocarcinoma who were treated with hormonal therapy. The search included articles published between January 1966 and January 2007. Endometrial carcinoma in patients under 45 years of age is an unusual condition that shows a more favorable pattern than in older patients. One hundred thirty three patients were found in the search. The average duration of hormonal therapy was approximately 6 months. The average response time was 12 weeks. Seventy six percent of patients treated with hormonal therapy had a complete response and the other 24% never responded to treatment. Of those who initially responded, 66% didn't show recurrence of disease. The other 34% had a relapse. There have been published 4 deaths of patients conservatively managed. A conservative approach in these patients can offer reasonable oncological security and the opportunity of fulfilling their maternal desires in selected cases. However, consideration should be taken regarding the potential adverse outcomes that have been recently published in the literature.

Role of PET/CT in the evaluation of cervical cancer.

PET imaging utilizes a dedicated camera system with multiple positron detector rings. PET/CT precisely aligns and combines metabolic PET mages with anatomical CT images, and is being increasingly preffered over PET scanning alone. FDG is the most widely used radiotracer in the management of cancer patients, and the prototypical PET/CT protocol used in other cancers can also be applied to the management of cervical carcinoma patients. The applications of PET/CT in cervical cancer patients include: assessing local tumor extension (information on metabolic tumor activity and possible endometrial involvement), evaluating pelvic nodal involvement (even in cases with negative CT or MRI studies), detection of distant metastases (PET/CT should be the first imaging technique used to evaluate extrapelvic disease before pelvic exenteration), radiation therapy planning (in patiens with PET scans positive for lymph nodes), identification of persistent/recurrent disease (especially in assessing response to neoadjuvant therapy and prognosis (with an inverse response-survival relationship.

Surgical treatment of recurrent cervical cancer: state of the art and new achievements.

This article review the current situation of the exenterative procedures as part of the treatment of recurrent cervical cancer after radiation. Pelvic exenteration has been proven the only curative choice of treatment in selected cases of this clinical situation. A review of historical and recent published series have shown an increase of 5-y survival from 30 to 42 %. Almost one out of two patients will suffer complications of some kind, and one out of three will have a severe complication with pelvic exenteration. During the past sixty years, a number of outstanding improvements have been achieved - not only in surgical outcomes, but also in quality of life - owing to new reconstructive approaches. Women facing an exenterative procedure must be counseled carefully about the risks and long-term concerns related to the procedure. Each should undergo a comprehensive evaluation to make sure there is no evidence of unresectable or metastatic disease that would make her an unsuitable candidate for exenteration.

The current role of neoadjuvant chemotherapy in the management of cervical carcinoma.

The role of neoadjuvant chemotherapy (NACT) in cervical cancer has been a matter of investigation over the last 20 years. A systematic review and meta-analysis of individual patient data (IPD) demonstrated that NACT followed by surgery is superior to radiotherapy alone in terms of overall survival. However, in spite of the results of the meta-analysis, NACT has not been adopted as the new standard of care. In the present paper, we review the reasons why NACT is still considered an investigational approach in cervical cancer.