The use of biomarkers and HPV genotyping to improve diagnostic accuracy in women with a transformation zone type 3.

BACKGROUND: Twenty percent of women referred to colposcopy have a type 3 transformation zone-where colposcopic assessment for high-grade dysplasia (CIN2+) is not possible. This study examines the effectiveness of HPV biomarkers and genotyping in combination with techniques that sample an endocervical TZ. METHODS: A prospective diagnostic accuracy study. Women booked for large-loop excision (LLETZ) with squamous dyskaryosis, high-risk HPV and a TZ3 were recruited. Immediately prior to LLETZ samples were collected for p16/Ki-67 dual-stained cytology, HPV genotyping and H&E, p16- and Ki-67-stained endocervical curettings. RESULTS: In women with low-grade screening (n = 64), 35.9% had CIN2+; dual-stained cytology had the greatest effect on the PPV of routine screening (76.1% vs 35.9%) and perfectly predicted the absence of CIN2+. In women with a high-grade screening result (n = 37); 75.6% had CIN2+ and dual-stained curettings improved the PPV (96.5 vs 75.6%). CONCLUSIONS: With high-grade screening and a TZ3, LLETZ appears safest as three quarters have CIN2+ . Women with low-grade screening and a TZ3 have a twofold increased risk of CIN2+ when compared to women where the TZ is visible. The use of dual-stained cytology may help identify those women who can be safely offered surveillance and those who require treatment.

The multidisciplinary care of a woman presenting with lymphoma in pregnancy whose delivery was also complicated by placenta accreta spectrum.

We report the case of a 44-year-old presenting with breathlessness in her second trimester of pregnancy diagnosed with pulmonary diffuse large B cell lymphoma (DLBCL) which was further complicated by a placenta accreta spectrum (PAS) disorder. In pregnancy, she was treated with rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone, which was associated with neutropenic sepsis requiring admissions to the intensive care unit with respiratory compromise. She safely delivered an infant at 31 weeks but required a hysterectomy at the time for PAS and seven days ventilation on the intensive care unit post-operatively. It is the first case report of DLBCL and PAS in pregnancy.

Case report: Primary bone lymphoma presenting as a painful supraclavicular lump.

Primary bone lymphoma is a rare type of non-Hodgkin's lymphoma. It commonly arises from long bones such as the femur in the appendicular skeleton. The authors present a case of primary bone lymphoma of the clavicle, an uncommon location for this pathology, presenting as a painful supraclavicular lump in a 76-year-old woman. Magnetic resonance imaging and ultrasound examinations showed the typical feature of preservation of the bony cortex, and PET-CT revealed no alternative primary site of malignancy. This case highlights the importance of considering typical imaging characteristics of a lesion, even if it presents in an unusual site, as well as the value of completion imaging in clinical practice to secure a diagnosis.

An open-source, expert-designed decision tree application to support accurate diagnosis of myeloid malignancies.

Accurate, reproducible diagnoses can be difficult to make in haemato-oncology due to multi-parameter clinical data, complex diagnostic criteria and time-pressured environments. We have designed a decision tree application (DTA) that reflects WHO diagnostic criteria to support accurate diagnoses of myeloid malignancies. The DTA returned the correct diagnoses in 94% of clinical cases tested. The DTA maintained a high level of accuracy in a second validation using artificially generated clinical cases. Optimisations have been made to the DTA based on the validations, and the revised version is now publicly available for use at http://bit.do/ADAtool.

Management of Malignant Vulval Melanoma: A Retrospective Case Series and Review of the Literature.

OBJECTIVES: The aims of the study were to evaluate clinicopathologic features, management, and outcomes in vulval melanoma and to review the literature. MATERIALS AND METHODS: Data were collected retrospectively on patients with vulval melanoma from 2001 to 2017 in 5 gynecological oncology cancer centers (Bristol, Taunton, Truro, Plymouth, and Cheltenham). SPSS software was used for univariate and multivariate statistical analysis. Disease-specific median survival was calculated using Kaplan-Meier curves. RESULTS: Forty-four patients with vulval melanoma were included, with a median age of 71 years. Forty-three of 44 had wide local excision with full inguinal lymphadenectomy if abnormal lymph nodes. Seven patients had sentinel lymph nodes. However, 2 patients with negative sentinel lymph nodes had distant recurrences within 16 months.On univariate analysis, presence of ulceration (p = .012), perineural invasion (p = .03), and area of lesion (p = .016) were associated with risk of recurrence but only presence of microsatellites (p = .01) was associated with risk of death.There were 31 deaths (70%): 29 (94%) of 31 from melanoma and 28 (64%) of 44 recurrences: 17 local (10 groin, 7 vulval) and 9 distant. Overall median survival was 32.5 months (95% CI, 17.8-46.5 months) and median recurrence-free survival 12.6 months (95% CI, 7.7-17.4 months). CONCLUSIONS: This retrospective multicenter study highlights the high recurrence rate and poor prognosis of vulval melanoma. Lymph node surgery did not make any difference to recurrence-free survival or overall survival. The presence of microsatellites was associated with a statistically increased risk of death.

Primary cutaneous acral CD8+ T-cell lymphoma of the ear: A case report.

Primary cutaneous acral CD8+ T-cell lymphoma (TCL) is a rare, distinct type of cutaneous TCL. Despite its worrisome histological appearance it has a benign clinical course. It is therefore important to recognize this as a distinct entity from other more aggressive CD8+ lymphomas, for which the management is very different.

Mature teratoma containing carcinoid tumour arising within a fallopian tube.

A 52-year-old woman with a background of vaginal hysterectomy for heavy menstrual bleeding underwent an elective laparoscopic adhesiolysis, left salpingo-oophorectomy for left-sided pelvic pain, and a right salpingectomy. Despite a grossly normal appearance, histology revealed a rare presentation of mature teratoma with insular carcinoid tumour arising from the left fallopian tube. Even though the salpingectomy was thought to be curative, the patient underwent a second operation to remove her remaining right ovary as a precaution against malignant spread. In light of limited information in such rare cases, counselling on best management and discussion of risks to guide patient decision making remains challenging.

The Use of Central Pathology Review With Digital Slide Scanning in Advanced-stage Mycosis Fungoides and Sézary Syndrome: A Multi-institutional and International Pathology Study.

This pathology PILOT study aims to define the role and feasibility of centralized pathology review in a cohort of 75 patients from different centers in the United States and Europe using digital slide scanning. The pathologic material from 75 patients who had been diagnosed with mycosis fungoides/Sézary syndrome and were clinically staged as IIb or above was retrieved from 11 participating centers. Each pathology reviewer was provided with the pathologic diagnosis (by the referring pathologist), and the following list of histopathologic criteria (presence or absence) from the initial report: epidermotropism, folliculotropism (FT), large cell transformation, syringotropism, and granulomas. Patients with advance stage were selected for this study as this is a population where there is significant variability in the diagnosis of pathologic prognostic and predictive biomarkers. The slides were digitally scanned with an Aperio scanner and consensus review of cases occurred when major or minor discrepancies between the referral diagnosis and central pathology review occurred. Among the 75 cases, 70 (93.3%) had a final consensus diagnosis between the 3 central review pathologists. The overall agreement between the consensus review and the referring pathologist was 60%. The overall agreement was also higher between the reviewers and consensus review, compared with the referring pathologist and consensus. 65.3% of cases had some type of discrepancy (major or minor) between the outside and consensus review. Major discrepancies were seen in 34 of 73 cases (46.6%; 73 cases indicated a yes or no response). Minor discrepancies were seen in 32 of 75 (42.7%) of cases. Most of the major discrepancies were accounted by a difference in interpretation in the presence or absence of large cell transformation or FT. Most minor discrepancies were explained by a different interpretation in the expression of CD30. We found digital slide scanning to be a beneficial, reliable, and practical for a methodical approach to perform central pathology review in the context of a large clinical prospective study.

Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro.

BACKGROUND: Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. OBJECTIVES: To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. METHODS: Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. RESULTS: In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of ß-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. CONCLUSION: Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS.

Alemtuzumab-based therapy for Secondary Malignant Histiocytosis arising from Pre-B-ALL.

•Secondary Malignant Histiocytosis (SMH) is an exceedingly rare, life-threatening condition that invariably occurs in the presence of an underlying monoclonal hematologic disorder. Prognosis of SMH remains dismal and there is no established treatment. •We report a case of a patient who developed SMH during induction chemotherapy for his underlying pre-B-ALL, that caused persistently high fevers and was only diagnosed by a marrow while cytopenic in phase 2 induction. He was treated with alemtuzumab-based therapy that reduced the histiocytic infiltration of the bone marrow from 80% to 15% and made him eligible to undergo T-cell replete allogeneic stem transplantation from his sibling. •This report is the first to highlight the role of alemtuzumab, an anti-CD52 monoclonal antibody, in clonal disorders originating from transdifferentiation. •The alemtuzumab-based regimen should be reserved only for carefully selected allogeneic transplant patients.

Traumatic Neuroma After Hysterectomy and Bilateral Salpingo-Oophorectomy: A Rare Cause of Post Hysterectomy Pelvic Pain.

The cause of posthysterectomy pain is frequently undiagnosed, and a presumed diagnosis of adhesions is made. Surgical division of adhesions often fails to alleviate the pain. As a result, posthysterectomy pain is seldom investigated despite being associated with a significant deterioration in the quality of life. We report a case of posthysterectomy bilateral neuroma of the autonomic nerves to the ovary that leads to significant pelvic pain. Excision of these neuromas resulted in complete resolution of pelvic pain and significant improvement in the quality of life. This interesting observation does not support the widespread use of laparoscopy for posthysterectomy pain but should be considered in patients with pain that occurs at an interval after hysterectomy who have had no pelvic pain preceding the hysterectomy.

Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.

IMPORTANCE: The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown. OBJECTIVE: To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period. INTERVENTIONS: The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B, 21 patients), and a combination of ocular and extensive treatment (group C, 23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy. MAIN OUTCOMES AND MEASURES: Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens. RESULTS: Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; P = .003) and was similar among all treatment groups (P = .10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure. CONCLUSIONS AND RELEVANCE: In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment.

Glycogen synthase kinase 3 protein kinase activity is frequently elevated in human non-small cell lung carcinoma and supports tumour cell proliferation.

BACKGROUND: Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC. METHODS: The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture. RESULTS: Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/ß at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes. CONCLUSION: NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.

Expression of the prostaglandin F synthase AKR1B1 and the prostaglandin transporter SLCO2A1 in human fetal membranes in relation to spontaneous term and preterm labor.

BACKGROUND: Human labor is a complex series of cellular and molecular events that occur at the materno-fetal and uterine levels. Many hypotheses have been proposed for the initiation of human labor, one hypothesis suggests that maturation of the fetus releases a signal in the amniotic fluid that will be transmitted to myometrium via the fetal membranes and initiate uterine contractions. There is strong evidence that prostaglandins (PGs) play a central role in initiation and progression of human labor. OBJECTIVES: In this study we intended to investigate the expression of prostaglandin F synthase and the prostaglandin transporter in the human fetal membranes and to explore the relationship between cytokines and PGs in the mechanism of human labor. METHODS: We used fetal membranes obtained before labor at term and after spontaneous labor at term or preterm to identify the changes in prostaglandin F synthase (AKR1B1) and human prostaglandin transporter (SLCO2A1) proteins in relation to parturition. Using fetal membranes explants we tested the effect of cytokines (interleukin-1 and tumor necrosis factor alpha) on PG production and the concomitant changes in cyclooxygenase-2 (PTGS2), AKR1B1 and SLCO2A1 expression. RESULTS: Expression of PTGS2 and AKR1B1 was upregulated in the fetal membranes in association with term labor while SLCO2A1 was downregulated with advancing gestation and during term labor. Before labor, IL-1 increased the expression of PTGS2, however during labor TNF upregulated PTGS2 and AKR1B1 proteins. CONCLUSIONS: The prostaglandin F synthase AKR1B1 is upregulated while prostaglandin transporter is downregulated during term labor. The amnion is more responsive than choriodecidua to stimulation with pro-inflammatory cytokines. The mechanisms of term and preterm labor are different.

Giant thoracic mass: an unusual presentation of primary pulmonary Hodgkin's lymphoma.

Primary pulmonary Hodgkin's lymphoma (PPHL) is rare. PPHL without peripheral lymphadenopathy or hepatosplenomegaly is exceptionally uncommon. We present a 61-year-old woman believed to have a solitary intrapulmonary fibrous tumour on a CT and a CT-guided biopsy, until surgical excision. Histopathology and immunohistochemistry of the excised mass confirmed PPHL. PPHL is a very rare differential diagnosis of large solitary intrapulmonary masses. A CT-guided biopsy is recommended, as it can be diagnostic, reserving excision for cases where the diagnosis remains in doubt.

Solitary mycosis fungoides: a distinct clinicopathologic entity with a good prognosis: a series of 15 cases and literature review.

BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL), accounting for almost 50% of all primary cutaneous lymphomas. The occurrence of solitary lesions, which are clinically and histopathologically indistinguishable from classic MF has been described. OBJECTIVE: We describe 15 cases of solitary MF and discuss the relationship to classic MF, "reactive" processes and to other, rarer forms of CTCL that may present with solitary lesions. METHODS: We conducted a retrospective chart review and a PubMed search to identify all reported cases of solitary MF to date, as well as information about other CTCLs presenting as a solitary lesion. RESULTS: Fifteen patients were identified. Follow-up data were available on 10 patients with a median follow-up of 10 months (range, 1 to 48 months). Clinical, pathological, immunocytochemical, and molecular-genetic features were analyzed. Five cases were diagnosed as folliculotropic MF (FMF). Of the 10 cases with follow-up, 2 were treated with topical steroids, 2 were completely excised, 5 received radiotherapy, and 1 received tacrolimus. One hundred twenty-eight cases of solitary MF were identified in the literature and reviewed for commonalities to and differences with our cases and other CTCLs. LIMITATIONS: This study was retrospective; follow-up data were not available in some cases and were only short term in others. CONCLUSIONS: Solitary MF appears to have a good prognosis. In lesions that are not completely excised, curative radiotherapy can be used. Long-term follow up is advised.

Overexpression of the TXNDC5 protein in non-small cell lung carcinoma.

UNLABELLED: Thioredoxin domain containing protein 5 (TXNDC5) is a member of the thioredoxin (Trx) domain-containing family of proteins that have been implicated in cancer progression. The expression of TXNDC5 in non-small cell lung carcinoma (NSCLC) tumours compared to patient-matched normal lung tissue was determined and cell line models were used to determine if expression was regulated by hypoxia. PATIENTS AND METHODS: Samples of tumour and normal lung tissue were taken during surgery and immediately frozen. The expression of TXNDC5 was determined by Western blotting and immunohistochemistry. To analyse the effect of hypoxia on TXNDC5 expression NSCLC cell lines were used. RESULTS: Tumours from 18/29 (62%) individuals exhibited an increase in TXNDC5 expression compared to normal lung tissue (p<0.05). TXNDC5 expression was not elevated by hypoxia. CONCLUSION: TXNDC5 is up-regulated in the majority of resected human NSCLC. Cell line data indicates that the expression of TXNDC5 in tumour cells is not regulated by hypoxia.