Matteo Morotti

Central changes associated with chronic pelvic pain and endometriosis

BACKGROUND Chronic pelvic pain (CPP) is a significant public health problem with 1 million affected women in the UK. Although many pathologies are associated with CPP, the pain experienced is often disproportionate to the extent of disease identified and frequently no pathology is found (chronic pelvic pain syndrome). The central nervous system (CNS) is central to the experience of pain and chronic pain conditions in general are associated with alterations in both the structure and function of the CNS. This review describes the available evidence for central changes in association with conditions presenting with CPP. METHODS A detailed literature search was performed to identify relevant papers, however, this is not a systematic review. RESULTS CPP is associated with central changes similar to those identified in other pain conditions. Specifically these include, alterations in the behavioural and central response to noxious stimulation, changes in brain structure (both increases and decreases in the volume of specific brain regions), altered activity of both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS) and psychological distress. CONCLUSIONS The evidence reviewed in this paper demonstrates that CPP is associated with significant central changes when compared with healthy pain-free women. Moreover, the presence of these changes has the potential to both exacerbate symptoms and to predispose these women to the development of additional chronic conditions. These findings support the use of adjunctive medication targeting the CNS in these women.

Peripheral changes in endometriosis-associated pain

BACKGROUND Pain remains the cardinal symptom of endometriosis. However, to date, the underlying mechanisms are still only poorly understood. Increasing evidence points towards a close interaction between peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing. Recently, studies demonstrating nerve fibres and neurotrophic and angiogenic factors in endometriotic lesions and their vicinity have led to increased interest in peripheral changes in endometriosis-associated pain. This review focuses on the origin and function of these nerves and factors as well as possible peripheral mechanisms that may contribute to the generation and modulation of pain in women with endometriosis. METHODS We conducted a systematic search using several databases (PubMed, MEDLINE, EMBASE and CINAHL) of publications from January 1977 to October 2013 to evaluate the possible roles of the peripheral nervous system in endometriosis pathophysiology and how it can contribute to endometriosis-associated pain. RESULTS Endometriotic lesions and peritoneal fluid from women with endometriosis had pronounced neuroangiogenic properties with increased expression of new nerve fibres, a shift in the distribution of sensory and autonomic fibres in some locations, and up-regulation of several neurotrophins. In women suffering from deep infiltrating endometriosis and bowel endometriosis, in which the anatomical distribution of lesions is generally more closely related to pelvic pain symptoms, endometriotic lesions and surrounding tissues present higher nerve fibre densities compared with peritoneal lesions and endometriomas. More data are needed to fully confirm a direct correlation between fibre density in these locations and the amount of perceived pain. A better correlation between the presence of nerve fibres and pain symptoms seems to exist for eutopic endometrium. However, this appears not to be exclusive to endometriosis. No correlation between elevated neurotrophin levels and pain severity appears to exist, suggesting the involvement of other mediators in the modulation of pain. CONCLUSIONS The increased expression of neurotrophic factors and nerve fibres in endometriotic lesions, eutopic endometrium and the peritoneum imply a role of such peripheral changes in the pathogenesis of endometriosis-associated pain. However, a clear link between these findings and pain in patients with endometriosis has so far not been demonstrated.

Progestogen-only contraceptive pill compared with combined oral contraceptive in the treatment of pain symptoms caused by endometriosis in patients with migraine without aura.

OBJECTIVE Evaluate patient satisfaction at 6-month treatment in women with symptomatic rectovaginal endometriosis and migraine without aura with (progestogen-only contraceptive pill, POP versus sequential combined oral contraceptives, COC) STUDY DESIGN: A patient preference trial including 144 women (82 in the group COC and 62 in the group POP). Main outcome measure was the degree of patient satisfaction by using a Likert scale. Secondary objectives were to evaluate differences in endometriosis-related pain and changes in migraine features during the treatment. RESULTS In group POP, 38/62 women (61.2%) were satisfied or very satisfied after treatment, compared to 31/82 women (37.8%) in group COC (p=0.005). The intensity of chronic pelvic pain and dyspareunia significantly decreased at 6-month treatment in both the groups. At 6-month treatment, the number of migraine attacks was lower than at baseline in group POP (p=0.002), while it was not reduced in group COC (p=0.521). The intensity of migraine attacks was significantly different between baseline and 6-month treatment in group POP (p<0.001) but not in group COC (p=0.078). CONCLUSIONS POP is better tolerated than COC and it seems to ameliorate migraine attacks compared to COC in symptomatic patients with rectovaginal endometriosis and migraine without aura. Both drugs efficaciously relieve endometriosis-related pain symptoms. This study supports the use of the POP in women with rectovaginal endometriosis and coexisting migraine without aura.

Frozen section pathology at time of hysterectomy accurately predicts endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia

OBJECTIVES A significant number of women diagnosed with atypical endometrial hyperplasia (AEH) on endometrial biopsy will be diagnosed with endometrial cancer (EC) on the hysterectomy specimen at permanent section. Surgical treatment for AEH and EC differ substantially. We have assessed the concordance in EC between frozen and permanent sections on patients undergoing hysterectomy for AEH. MATERIALS AND METHODS A retrospective review of 66 frozen sections on patients undergoing hysterectomy for AEH was performed. Frozen and permanent section diagnoses were categorized as negative or positive for malignancy. Permanent section carcinomas were classified as low or high risk based on their histopathology, myometrial invasion and differentiation. Correlation between frozen and permanent section and sensitivity, specificity, PPV, NPV and accuracy of frozen section in predicting EC in permanent section were calculated. Likelihood of diagnosing EC on frozen section was compared based on risk stratification at permanent section. RESULTS Frozen and permanent sections revealed malignancy in 43.9% and 56% of the patients respectively. 94.1% of high risk carcinomas were identified as EC at frozen section as compared to 55% of low risk EC. Concordance was good (κ=0.75). Sensitivity, specificity, NPV, PPV and accuracy in predicting EC at frozen section were 73%, 93.1%, 73% and 93.1% respectively. Carcinomas were detected at frozen section significantly more often if they were at high risk. CONCLUSIONS The substantial agreement between frozen and permanent sections allows minimizing under- and overtreatment of women undergoing hysterectomy for AEH. High risk EC are efficiently identified in frozen section.

Multidetector computerized tomography enteroclysis vs. rectal water contrast transvaginal ultrasonography in determining the presence and extent of bowel endometriosis

To compare the accuracy of multidetector computerized tomography enteroclysis (MDCT‐e) and rectal water contrast transvaginal ultrasonography (RWC‐TVS) in determining the presence and extent of bowel endometriosis.

Lymphedema microsurgical preventive healing approach for primary prevention of lower limb lymphedema after inguinofemoral lymphadenectomy for vulvar cancer

Objective Lower limb lymphedema (LLL) is the most disabling adverse effect of surgical treatment of vulvar cancer. This study describes the use of microsurgical lymphatic venous anastomosis (LVA) to prevent LLL in patients with vulvar cancer undergoing inguinofemoral lymph node dissection (ILND). Methods The study included 8 patients with invasive carcinoma of the vulva who underwent unilateral or bilateral ILND. Before incision of the skin in the inguinal region, blue dye was injected in the thigh muscles to identify the lymphatic vessels draining the leg. Lymphatic venous anastomosis was performed by inserting the blue lymphatics coming from the lower limb into one of the collateral branches of the femoral vein (telescopic end-to-end anastomosis). An historical control group of 7 patients, which underwent ILND without LVA, was used as comparison. After 1 month from the surgery, all patients underwent a lymphoscintigraphy. Results In the study group, 4 patients underwent bilateral ILND, and 4 patients underwent unilateral ILND. Blue-dyed lymphatics and nodes were identified in all patients. It was possible to perform LVA in all the patients. The mean (SD) time required to perform a monolateral LVA was 23.1 (3.6) minutes (range, 17–32 minutes). The mean (SD) follow-up was 16.7 (6.2) months; there was only 1 case of grade 1 lymphedema of the right leg. Lymphoscintigraphic results showed a total mean transport index were 9.08 and 14.54 in the study and the control groups, respectively (P = 0.092). Conclusions This study shows for the first time the feasibility of LVA in patients with vulvar cancer undergoing ILND. Future studies including larger series of patients should clarify whether this microsurgical technique reduces the incidence of LLL after ILND.

The preoperative diagnosis of borderline ovarian tumors: a review of current literature.

PurposeTo evaluate the available information on the preoperative diagnosis of borderline ovarian tumors (BOTs).MethodsArticles were identified through electronic databases (Medline and EMBASE, MEDLINE, PubMed), no date or language restrictions were placed; relevant citations were hand searched.ResultsWomen with BOTs are more likely to have no symptom than women with invasive ovarian cancers; however, the type of symptoms is similar in patients with BOTs and invasive ovarian cancers. Up to 61% of women with BOTs have elevated CA-125; CA 19.9 and endoglin are not useful for diagnosing BOTs. Further studies are required to determine whether the measurements of calprotectin, oviductal glycoprotein 1 and growth differentiation factor-15 are useful for diagnosing BOTs. Ultrasonography and magnetic resonance imaging (MRI) are the mainstay for the diagnosis of BOTs. Combining MRI and positron emission tomography may facilitate the identification of BOTs.ConclusionAfter completion of this article, the reader should be aware of the symptoms of BOTs, the potential role and pitfalls of tumor marker measurement. In addition, the reader will understand the appearance of BOTs at imaging techniques; the reader will be able to compare and combine ultrasonography, MRI and positron emission tomography in diagnosing BOTs. In clinical practice, the reader should be better able to assess whether an ovarian mass is a benign tumor, a BOT or an invasive cancer.

Breast cancer with synchronous massive metastasis in the uterine cervix: a case report and review of the literature.

IntroductionMetastatic breast cancer is rare in the female genital tract, and when present it more commonly tends to involve ovary or endometrium; uterine cervix is only occasionally involved. This condition poses differential diagnostic problems in the settings of clinical and pathological investigations.Case presentationAn asymptomatic 78-year-old woman came to our attention in the context of routine gynecological surveillance; clinical examination disclosed enlarged uterine body and cervix. Our patient then underwent computed tomography and magnetic resonance imaging that outlined the possibility of cervical cancer with parametrial involvement. Moreover, a suspect mass was found on the mammogram in the left breast. Breast surgical excision was performed, which revealed invasive breast carcinoma, while synchronous cervical biopsy discovered distant metastasis in the uterine cervix. On histological examination, both lesions showed non-cohesive architectural pattern consistent with lobular morphology; anyway, to rule out primary poorly differentiated cervical cancer, appropriate immunohistochemical panel was performed, which confirmed the mammary derivation of the tumor. Due to disseminate disease, the patient underwent multisystemic medical treatment including radiotherapy, chemotherapy and hormone therapy, and she is still alive at 30-month follow-up.DiscussionGenital tract metastases in patients with known breast carcinoma can present with abnormal vaginal bleeding, but they often are asymptomatic. Therefore, only strict gynecological surveillance of these patients can permit early detection of these secondary lesions. Aggressive treatment of isolated cervical metastasis should be performed when feasible; otherwise, systemic chemotherapy with taxane could be sufficient in increasing survival. It should be emphasized that, in most cases, only accurate immunohistochemical investigation, particularly if performed on the primary lesion as well, can solve differential diagnostic problems and allow the clinician to establish appropriate treatment.

Targeting tyrosine-kinases in ovarian cancer.

Introduction: Epithelial ovarian cancer (EOC) is the leading cause of gynaecologic cancer death. Although in some cases initial treatment is effective, most of the women diagnosed with EOC will probably need medical treatment for their disease. There is a critical need to develop effective new strategies for the management of patients with advanced or recurrent EOC, and targeted therapy with tyrosine kinase inhibitors (TKIs) has continued to be an area of active research and development in this setting. Areas covered: This review summarises the available evidence on the use of TKIs in the clinical management of women with EOC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches up to March 2013. Expert opinion: Several Phase I/II and III trials evaluated TKIs in EOC; however, it is difficult to draw conclusions on the efficacy of TKI regimens in these patients. TKIs seem to be better tolerated than conventional chemotherapy with a different toxicity profile. A better understanding of the signalling pathways, the toxicity profiles, the potential pharmacokinetic interactions as well as the identification of predictive biomarkers are needed to better identify a targeted patient population before these agents become part of routine treatment.

Pharmacokinetic and toxicity considerations for the use of anthracyclines in ovarian cancer treatment

Introduction: Safe and effective treatments are needed for ovarian cancer. While there are many drugs currently available, there has recently been a renewed novel interest in the use of anthracyclines. Areas covered: This review summarizes the available evidence on pharmacokinetic (PK) and toxicology implications of anthracyclines and pegylated liposomal doxorubicin (PLD) in the clinical management of women with epithelial ovarian cancer. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to September 2010. Expert opinion: PLD is a liposomal formulation of doxorubicin (DXR), with a distinct pharmacokinetic profile, characterized by extended circulation time and a reduced clearance and volume of distribution with respect to the free drug. PLD is effective and well tolerated in relapsed ovarian cancer. The toxicity profile of PLD is characterized by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression and decreased cardiotoxicity compared to free DXR. The good response rate, toxicity profile and pharmacokinetic profile of PLD suggest that PLD could be an option in first-line and second-line treatment in ovarian cancer; especially in those who had experienced taxane-induced toxicity or had a poor performance status.