The liver: another organ involved in Muir Torre syndrome?

Muir Torre syndrome is a rare autosomal dominant cancer-predisposing syndrome characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that belong to the spectrum of hereditary non polyposis colorectal cancer (HNPCC), i.e., tumors of gastrointestinal and genitourinary tracts. Hepatobiliary malignancy in association with Muir Torre syndrome has rarely been reported. Here, we describe a case of Muir Torre syndrome associated with an hepatocellular-carcinoma in a patient with a non-cirrhotic liver and an HNPCC-family with multiple cases of hepatocellular carcinoma.     

The prognostic value of the tumor–stroma ratio is most discriminative in patients with grade III or triple-negative breast cancer

The tumor–stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin-stained tissue slides of 1,794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence-free survival (RFS; HR 1.35, 95% CI 1.10–1.66, p = 0.004). The interaction term was statistically significant for grade and triple-negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43–2.51, p < 0.001) and triple-negative tumors (HR 1.86, 95% CI 1.10–3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple-negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma-high tumor had a worse prognosis compared to patients with a stroma-low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple-negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.     

Appendectomy or right hemicolectomy in the treatment of appendiceal carcinoid tumors?

AIMS AND BACKGROUND: Carcinoids of the appendix continue to be of interest, despite their low incidence. There is still considerable controversy surrounding these tumors, especially with regard to the role of right hemicolectomy in the surgical management. The aim of this work was to explicate the current therapeutic knowledge and to review the criteria for the indications of appendectomy or hemicolectomy. METHODS: The records of patients who underwent appendectomies from 1990 to 2000 were analyzed. Seven patients were included in the study. The clinical data were reviewed for demographic details, tumor size, localization in the appendix, histological patterns and surgical procedures. All patients underwent appendectomy including removal of the mesenteriolum, and in one of them a right hemicolectomy was performed 3 weeks later. The mean follow-up was 7 years (range, 4-14). Follow-up data included symptoms, urinary 5-hydroxyindoleacetic acid, ultrasound examination, computerized tomography, and octreotide scanning. RESULTS: Seven patients (0.9% of all appendectomies) were reported to have carcinoid tumors of the appendix. They were 3 men and 4 women with a mean age of 29 years. All patients were admitted for appendicitis. None suffered from the carcinoid syndrome. The site of the tumor was the apex of the appendix in 4 cases, the body in 2 cases and the base in 1 case. Mean tumor diameter was 8 mm (range, 5-29 mm); in 6 patients it was <2 cm. Treatment was appendectomy in all cases; additional right hemicolectomy was necessary in one case because of a tumor of more than 2 cm with invasion of the mesoappendix and lymph nodes. The 7-year survival rate is 100%. Six patients are without disease, while 1 patient (the one who underwent a right hemicolectomy) developed metastases in the liver 6 years after the operation. This patient, who was treated with a liver resection, is still alive. CONCLUSIONS: According to current guidelines, an appendectomy may be performed for small carcinoid tumors (<1 cm). Reasons for more extensive surgery than appendectomy are tumor size >2 cm, lymphatic invasion, lymph node involvement, spread to the mesoappendix, tumor-positive resection margins, and cellular pleomorphism with a high mitotic index. The criteria that direct us towards major (hemicolectomy) or minor surgery (appendectomy) are controversial. Tumor size is still considered the most important prognostic factor, with a presumed increase in the risk of metastasis for tumors greater than 2.0 cm. The accepted treatment of such tumors is a right hemicolectomy. However, there is no evidence demonstrating a survival benefit for right hemicolectomy over simple appendectomy in patients with carcinoids greater than 2.0 cm in diameter.     

Clinical value of β2-MG and LDH determination in the patients with myelodysplastic syndrome

目的:探讨骨髓增生异常综合征(myelodysplastic syndrome,MDS)患者血清β 2-微球蛋白(β 2-microglobulin,β 2-MG)和乳酸脱氢酶(lactic dehydrogenase,LDH)检测的临床价值.方法:采用放射免疫法测定血清β2-MG,速率法检测LDH,比较两者在30例健康体检者和45例不同亚型MDS患者中的水平,并对两者均增高和均正常的MDS患者进行生存分析.结果:各组MDS患者血清β 2-MG水平均明显高于正常对照组(P＜0.01),其中难治性贫血伴原始细胞过多-Ⅱ(refractory anemia with excessive blasts Ⅱ,RAEB-Ⅱ)组明显高于难治性贫血(refractory anemia,RA)、难治性血细胞减少伴有多系发育异常(refractory cytopenia with multilineage dysplasia,RCMD)和难治性贫血伴原始细胞过多-Ⅰ(refractory anemia with excessive blasts Ⅰ,RAEB-Ⅰ)组,差异均有统计学意义(P均＜0.0 1);RAEB-Ⅰ、RAEB-Ⅱ组血清LDH水平明显高于RA、RCMD组(P＜0.0 1);血清LDH、β 2-MG均增高的患者中位生存期明显短于两者均正常者(P＜0.01).结论:联合检测血清β2-MG和LDH水平,对于MDS的诊断、分型及预后分析具有重要的临床价值.     

Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: are all mutations equal?

Background

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline mutations in MisMatch Repair (MMR) genes, particularly in MLH1, MSH2 and MSH6. Patients with LS seem to have a more favourable prognosis than those with sporadic CRC, although the prognostic impact of different mutation types is unknown.Aim of our study is to compare survival outcomes of different types of MMR mutations in patients with LS-related CRC.

Methods

302 CRC patients were prospectively selected on the basis of Amsterdam or Revised Bethesda criteria to undergo genetic testing: direct sequencing of DNA and MLPA were used to examine the entire MLH1, MSH2 and MSH6 coding sequence.Patients were classified as mutation-positive or negative according to the genetic testing result.

Results

A deleterious MMR mutation was found in 38/302 patients. Median overall survival (OS) was significantly higher in mutation-positive vs mutation-negative patients (102.6 vs 77.7 months, HR:0.63, 95%CI:0.46–0.89, p = 0.0083). Different types of mutation were significantly related with OS: missense or splicing-site mutations were associated with better OS compared with rearrangement, frameshift or non-sense mutations (132.5 vs 82.5 months, HR:0.46, 95%CI:0.16–0.82, p = 0.0153).

Conclusions

Our study confirms improved OS for LS-patients compared with mutation-negative CRC patients. In addition, not all mutations could be considered equal: the better prognosis in CRC patients with MMR pathogenic missense or splicing site mutation could be due to different functional activity of the encoded MMR protein. This matter should be investigated by use of functional assays in the future.     

Prognostic value of tumor–stroma ratio combined with the immune status of tumors in invasive breast carcinoma

Purpose

Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor–stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated.

Methods

A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs).

Results

TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles.

Conclusions

Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients.

     

The value of magnetic resonance imaging in esophageal carcinoma: Tool or toy?

Currently, the use of magnetic resonance imaging (MRI) in patients with esophageal carcinoma is limited. However, the quality of MRI for esophageal carcinoma continues to improve and the importance of MRI in patients with esophageal carcinoma has been gradually recognized. Compared with endoscopic ultrasound and computed tomography applied in T and N staging, MRI has now achieved excellent results after the imaging technique has been optimized. We review the literature on MRI and discuss the future of MRI in esophageal carcinoma. While the role of MRI in staging, tumor volume target delineation and evaluation for preoperative chemoradiotherapy, prognosis and recurrence is still evolving. The application of MRI in esophageal carcinoma has a bright future and potential to improve precision of T and N staging as well as treatment delivery.     

Papillary microcarcinoma of the thyroid gland: is the immunohistochemical expression of cyclin D1 or galectin-3 in primary tumour an indicator of metastatic disease?

Introduction. Papillary microcarcinomas (PMC) of the thyroid gland are defined according to The WHO Committee as papillary carcinomas measuring 10 mm or less in diameter. A large proportion of these tumours are found coincidentally in the treatment of symptomatic goitre and most cases follow an indolent course with an excellent prognosis. However, a more aggressive behaviour with regional and distant metastases does occur. The aim of this study was to evaluate if the immunohistochemical markers cyclin D1 or galectin-3 might indicate the presence of metastatic disease in patients with PMC at the time of diagnosis. Material and methods. From the 1^st of January 1996 to 31^st of December 2002 a total of 169 PMC patients were diagnosed and registered in the national Danish thyroid cancer database DATHYRCA and 131 of these were eligible for the study. Forty-three (33%) had histologically verified regional or distant metastases. Slides were cut from the primary tumour and immunostaining and quantification was subsequently performed. Results. The percentage of positive cells was examined for patients with and without metastases. For cyclin D1 the median values were 31% (range: 0-59) and 21% (range: 0-75), respectively, showing a statistically significant difference (p=0.02). For galectin-3 the medians were 87% (range: 6-96) and 85% (range: 0-99) and no significant difference was found. Conclusion. Cyclin D1 showed significantly higher median expression in patients with metastases compared to those without, indicating a correlation to tumour aggressiveness. However, both groups showed large variation in expression, which disqualify the marker as a discriminator for the detection of metastases. Galectin-3 was without any significant correlation to the presence of metastases from PMC.     

Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel

Purpose

While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood–brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed.

Methods

Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing’s sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing’s sarcoma DM101) xenografts. The activity of cabazitaxel–cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51.

Results

Cabazitaxel penetrated rapidly in the brain, with a similar brain–blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence.

Conclusions

These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.     

The role and its mechanism of intermittent fasting in tumors:friend or foe?

Intermittent fasting(IF)is becoming a prevailing topic worldwide,as it can cause changes in the body’s energy metabolism processes,improve health,and affect the progression of many diseases,particularly in the circumstance of oncology.Recent research has shown that IF can alter the energy metabolism of tumor cells,thereby inhibiting tumor growth and improving antitumor immune responses.Furthermore,IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments.IF is therefore emerging as a promising approach to clinical cancer treatment.However,the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood.In this article,we review the role of IF in tumorigenesis and tumor therapy,and discuss some scientific problems that remain to be clarified,which might provide some assistance in the application of IF in clinical tumor therapy.     

The continuum model of selection in human tumors: general paradigm or niche product?

Berger and colleagues recently proposed a continuum model of how somatic mutations cause tumors to grow, thus supplementing the established binary models, such as oncogene activation and "two hits" at tumor suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the fail-safe model, envisaged an optimum level of gene derangement for tumor growth, but proposed that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: In part, it restates the existing "just right" of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell should avoid becoming cancerous only when it is some way down the road to that state. In contrast, the basic continuum model is a very useful addition to the other genetic models of tumorigenesis, especially in certain scenarios. Fittingly for a quantitative model, we propose that the continuum model is most likely to apply where multiple, cancer-promoting mutations have relatively small, additive effects, either through the well-established case of additive germline predisposition alleles or in a largely hypothetical situation where cancers may have acquired several somatic "mini-driver" mutations, each with weaker effects than classical tumor suppressors or fully activated oncogenes.     

Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte,mismatch repair,and Epstein–Barr virus status in a large cohort of gastric cancer patients

Background

Antibodies against programmed death 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) have recently demonstrated promising results in gastric cancer (GC). PD-L1 expression, the presence of tumor-infiltrating lymphocytes (TILs), and mismatch repair (MMR) deficiency have been proposed as predictive biomarkers for anti-PD-1/PD-L1 antibodies. The aim of this study was to investigate the clinical relevance of PD-L1 expression with TIL, MMR, and Epstein–Barr virus (EBV) status in GC.

Methods

We performed a tissue microarray analysis in 487 advanced GC patients who underwent gastrectomy. PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (TIICs), the densities of TILs, and MMR status were evaluated by immunohistochemistry. EBV was detected by in situ hybridization.

Results

PD-L1 expression on TCs and TIICs, MMR deficiency, and EBV positivity were identified in 22.8, 61.4, 5.1, and 5.1 % cases respectively. PD-L1 expression was more frequently observed in the elderly (TCs P = 0.002), in males (TCs P = 0.029; TIICs P = 0.043), in patients with poorly differentiated adenocarcinoma with solid-type histological features (TCs P < 0.001; TIICs P < 0.001), in patients with MMR deficiency (TCs P < 0.001; TIICs P < 0.001), and in patients with EBV positivity (TCs P = 0.001; TIICs P = 0.050). Strong association was observed between PD-L1 expression and high densities of CD3-positive, CD8-positive, or forkhead box P3 positive TILs (TCs P < 0.001; TIICs P < 0.001). Neither PD-L1 expression on TCs nor that on TIICs was an independent prognostic factor in multivariate analysis.

Conclusions

In GC, PD-L1 expression was associated with distinct clinicopathological features, including high densities of TILs, MMR deficiency, and EBV positivity, but was not a prognostic factor.

     

Is the prevalence of colonic neuroendocrine tumors increased in patients with inflammatory bowel disease?

Inflammatory bowel disease (IBD) patients may bear an increased neuroendocrine tumor (NET) risk. These tumors are mostly reported as coincidental findings during surgery. We aimed to determine the prevalence of colonic NET in a Dutch nationwide IBD cohort and calculate the prevalence rate ratios (PRR) compared with the general Dutch population. Our second aim was to investigate whether a high bowel surgery rate in IBD could result in a high PRR for NET. The Dutch Pathology Registry (PALGA) was searched to identify all IBD patients with colonic NET in The Netherlands between 1991 and 2011. We determined the prevalence and PRR of colonic NET in a 20‐year period. For our second aim, we compared NET prevalence in colonic resection specimens between IBD cases and non‐IBD controls (diverticulitis and ischemia). We identified 51 IBD patients who developed colonic NET resulting in a prevalence of 60.4–89.3 per 100,000 patients in a 20‐year period with a PRR of 2.8–4.1. However, adjusted for resection type, sex and age, a higher NET prevalence was shown in diverticulitis (OR 5.52, 95% CI 3.47–8.78) and ischemia (OR 1.97, 95% CI 1.09–3.58) compared with IBD. Our key finding is that NET are more prevalent in IBD patients compared with the general population (PRR 2.8–4.1). This might be attributed to a high rate of incidental NET as IBD patients frequently undergo intestinal surgery. A lower adjusted NET prevalence in colonic resection specimens for IBD compared to ischemia and diverticulitis supports this hypothesis.     

Are prophylactic haematopoietic growth factors of value in the management of patients with aggressive non-Hodgkin's lymphoma?

Combination chemotherapy used to treat patients with aggressive non-Hodgkin's lymphoma is associated with neutropenia and subsequent infection, hospital admission and treatment delays. Haematopoietic growth factors (HGF) can prevent neutropenia and improve quality of life. We undertook a meta-analysis of six randomised and one nonrandomised trials to quantify the effect in previously untreated patients, and a simple cost-effectiveness analysis. The trials compared HGF plus chemotherapy with chemotherapy alone. In total, there were 779 patients aged between 15 and 82 years. Haematopoietic growth factors was associated with a statistically significant 44% reduction in the incidence of severe neutropenia (neutrophil count <0.5 x 10(9) l(-1)), a 60% reduction in the number of hospital admissions due to infection, an 80% reduction in the number of patients who had a treatment delay due to neutropenia and a 50% reduction in hospital stay. These data together with UK G-CSF drug costs were combined to develop a simple cost-effectiveness model, based on direct costs. Given the current cost of G-CSF, it would only be cost-effective among patients in which high rates of hospital stay due to neutropenia or infection are expected. Alternatively, if the cost could be reduced then all patients may be able to obtain the benefits. However, the evidence that prophylactic HGFs are clinically worthwhile is clear.     

Homeopathy: what is it and is it of value in the care of patients with cancer?

The underlying principles of homeopathy include treating 'like with like' by remedies which are potentized by serial dilution and succussion. These distinguish homeopathy from other forms of alternative or complementary therapy. Conventional scientific wisdom dictates that homeopathy should have no effect above and beyond placebo but experiments on ultra-high dilutions of solutes together with some clinical data suggest the intriguing possibility that it might do in some circumstances. However, most clinical evidence comes from treating relatively minor self-limiting diseases and little comes from treating life-threatening disorders such as cancer. This paper explains the principles of homeopathy and reviews the data on its use in cancer care.