Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes

Epithelial tissues have sparse stroma, in contrast to their corresponding tumours. The effect of cancer cells on stromal cells is well recognized. Increasingly, stromal components, such as endothelial and immune cells, are considered indispensable for cancer progression. The role of desmoplastic stroma, in contrast, is poorly understood. Targeting such cellular components within the tumour is attractive. Recent evidence strongly points towards a dynamic stromal cell participation in cancer progression that impacts patient prognosis. The role of specific desmoplastic stromal cells, such as stellate cells and myofibroblasts in pancreatic, oesophageal and skin cancers, was studied in bio‐engineered, physiomimetic organotypic cultures and by regression analysis. For pancreatic cancer, the maximal effect on increasing cancer cell proliferation and invasion, as well as decreasing cancer cell apoptosis, occurs when stromal (pancreatic stellate cells) cells constitute the majority of the cellular population (maximal effect at a stromal cell proportion of 0.66–0.83), accompanied by change in expression of key molecules such as E‐cadherin and β‐catenin. Gene‐expression microarrays, across three tumour types, indicate that stromal cells consistently and significantly alter global cancer cell functions such as cell cycle, cell–cell signalling, cell movement, cell death and inflammatory response. However, these changes are mediated through cancer type‐specific alteration of expression, with very few common targets across tumour types. As highlighted by these in vitro data, the reciprocal relationship of E‐cadherin and polymeric immunoglobulin receptor (PIGR) expression in cancer cells could be shown, in vivo, to be dependent on the stromal content of human pancreatic cancer. These studies demonstrate that context‐specific cancer–stroma crosstalk requires to be precisely defined for effective therapeutic targeting. These data may be relevant to non‐malignant processes where epithelial cells interact with stromal cells, such as chronic inflammatory and fibrotic conditions. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Oral manifestations of secondary syphilis in the elderly – a timely reminder for dentists

Syphilis is a sexually transmitted infectious disease caused by Treponema pallidum. Cases of syphilis have increased in frequency and are challenging when affecting the elderly. The main causes of increased prevalence of syphilis are sexual promiscuity, lack of knowledge about the disease and decreasing use of barrier protection. Clinically, the oral manifestation of syphilis may resemble other entities, which hampers the correct diagnosis. We report a case of a 79‐year‐old male with weight loss and feeding difficulties. In the oral cavity there were ulcerative lesions in the hard palate and bilaterally in the buccal mucosa. The incisional biopsy revealed only a non‐specific ulceration of the oral mucosa. After 20 days, the patient was re‐evaluated and presented maculopapular lesions in the palmar and plantar areas. Positive serological venereal disease reference laboratory (VDRL) tests confirmed the diagnosis of secondary syphilis. The patient was treated with Benzathine penicillin G. After two weeks of treatment the oral lesion disappeared and the patient returned to normal feeding and gained weight. This case report reinforces the need to alert physicians and dentists to include sexually transmitted infections such as syphilis in the differential diagnosis of oral ulcerative lesions in elderly sexually active patients.     

Biomarkers and Their Relation to Cardiac Function Late After Peripartum Cardiomyopathy

BackgroundAngiogenic imbalance involving the placental protein soluble Fms-like tyrosine kinase-1 (sFlt-1) and cleavage of the nursing-hormone prolactin by the enzyme cathepsin D (CD) both play a role in the pathogenesis of peripartum cardiomyopathy (PPCM). We hypothesized that angiogenic imbalance and increased activity of CD have a long-lasting impact in women with PPCM.Methods and ResultsA nationwide Danish cohort of women with PPCM (PPCM group, n = 28), age matched women with previous preeclampsia (n = 28) and uncomplicated pregnancies (n = 28) participated in a follow-up study including biomarker analysis, exercise testing and cardiac magnetic resonance imaging. The median time to follow-up was 91 months (range 27–137 months) for the PPCM group. Levels of sFlt-1, placental growth factor, N-terminal pro-natriuretic brain peptide, and copeptin were all significantly higher in the PPCM group. More women in the PPCM group had detectable CD activity (68%) compared with the preeclampsia group (29%) and uncomplicated pregnancies group (36%) (P = .0002). Levels of angiogenic factors and biomarkers correlated inversely with maximal exercise capacity and cardiac functional parameters assessed with cardiac magnetic resonance imaging.ConclusionsWomen with PPCM had higher biomarker levels and CD activity up to 7 years after diagnosis. Higher biomarker levels correlated inversely with maximal exercise capacity and markers of cardiac dysfunction suggesting that persistent angiogenic imbalance and increased CD activity is associated with residual cardiac dysfunction.     

GPs’ views on managing advanced chronic kidney disease in primary care: a qualitative study

BackgroundChronic kidney disease (CKD) has become a significant part of the GP’s workload since the introduction of the National Institute for Health and Care Excellence guidelines in 2008. Patients with advanced CKD (stages G4 and G5) often have comorbidities, varied disease progression, and are likely to be older. GPs may experience difficulties with management decisions for patients with advanced CKD, including when to refer to nephrology.AimTo explore GPs’ views of managing patients with advanced CKD and referral to secondary care.MethodSemi-structured interviews with 19 GPs. Transcribed interviews were thematically analysed.ResultsGPs had little experience of managing patients with advanced CKD, including those on dialysis or having conservative care (treatment without dialysis or a transplant), and welcomed guidance. Some GPs referred patients based on renal function alone and some used wider criteria including age and multimorbidity. GPs reported a tension between national guidance and local advice, and some had learnt from experience that patients were discharged back to primary care. GPs with more experience of managing CKD referred patients later, or sometimes not at all, if there were no additional problems and if dialysis was seen as not in the patient’s interests.ConclusionGPs want guidance on managing older patients with advanced CKD and comorbidities, which better incorporates agreement between local and national recommendations to clarify referral criteria. GPs are not generally aware of conservative care programmes provided by renal units, however, they appear happy to contribute to such care or alternatively, lead conservative management with input from renal teams.     

Leukopenic chronic T cell leukemia mimicking hairy cell leukemia: association with human retroviruses

We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's "prolymphocytic" leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.     

Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD,McKay RR,Werner L,Atkins MB,Van Allen EM,Olivier KM,Song J,Signoretti S,McDermott DF,Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.

Background

Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC.