Management of NFAs: medical treatment

Introduction

Non-functioning pituitary adenomas (NFPAs) are in general large tumors that present with symptoms secondary to local pressure on adjacent structures. Transsphenoidal surgery is the first line of treatment but residual tumor mass is often detected post-operatively. Medical therapy, in any stage of tumor management, is not well established.

Methods

A literature search was performed to review the available data on medical treatment of NFPAs.

Results

Medications investigated for the treatment of NFPAs include dopamine receptor agonists (DA) and somatostatin receptor ligands. Randomized controlled trials are lacking, but available data suggest that DA have a positive effect on tumor remnant stabilization after surgery and could be considered in this setting. Temozolomide is reserved for aggressive tumors, although future studies are required.

Conclusions

NFPA are often not amenable to complete surgical resection. Conservative follow-up after surgery is associated with a high prevalence of tumor remnant progression. DA therapy may prevent residual tumor enlargement in over 85% of these patients, with a substantial consequent reduction in the need for repeat surgery or radiation therapy. It is our view that DA treatment should be routinely considered for the management of NFPA patients with incompletely resected tumors.

     

The combined use of <Emphasis Type="Italic">Camellia sinensis</Emphasis> and metronomic zoledronic acid in a breast cancer-induced osteolysis mouse model

Purpose

In previous studies, we demonstrated that green tea (Camellia sinensis, CS) water extract had potent anti-tumor and anti-metastasis effects in the 4T1 mouse breast cancer xenograft model, and the metronomic regimen (0.0125 mg/kg twice a week for 4 weeks) of zoledronic acid (ZOL) was also effective in decreasing tumor burden and metastasis when compared with the conventional regimen. This study aimed to investigate the combined use of CS water extract and metronomic ZOL against tumor metastasis and bone destruction in MDA-MB-231-TXSA human breast cancer.

Methods

Female nude mice were injected with MDA-MB-231-TXSA cells into the marrow space of tibia and were treated with CS water extract and/or metronomic ZOL for 4 weeks. Tumor growth and metastasis to lungs and livers were assessed by in vivo bioluminescence imaging. Abilities of migration and invasion of MDA-MB-231-TXSA cells were also evaluated in vitro.

Results

Our results demonstrated that combination of CS and ZOL had the most potent effects on tumor burden and metastasis to bone, lung and liver, while treatment with CS or ZOL alone significantly protected the bone from cancer-induced osteolysis. In vitro, the combined use of CS + ZOL significantly inhibited MDA-MB-231-TXSA cell migration and invasion. Mechanistic zymography studies showed that the enzyme activities of MMP-9 and MMP-2 were significantly suppressed by CS and CS + ZOL.

Conclusions

The combination of CS plus metronomic ZOL demonstrated potent anti-tumor, anti-metastasis and anti-osteolysis effects against breast cancer, suggesting the potential clinical application against breast cancer patients.

     

Indications for surgical treatment of intrahepatic cholangiocarcinoma with lymph node metastases

Background/Purpose

The postoperative outcome of patients who have intrahepatic cholangiocarcinoma with lymph node metastases is extremely poor, and the indications for surgery for such patients have yet to be clearly established.

Methods

The demographic and clinical characteristics of 133 patients who underwent lymph node dissection during hepatic resection of intrahepatic cholangiocarcinoma were retrospectively analyzed.

Results

Multivariate analysis identified three independent prognostic factors: intrahepatic metastasis, nodal involvement, and tumor at the margin of resection. Of the patients with tumor-free surgical margins, none of the 24 patients who had both lymph node metastases and intrahepatic metastases survived for 3 years. In contrast, the survival rates for the 23 patients who had lymph node metastases associated with a solitary tumor were 35% at 3 years and 26% at 5 years.

Conclusions

Surgery alone cannot prolong survival when both lymph node metastases and intrahepatic metastases are present, while surgery may provide a chance for long-term survival in some patients who have lymph node metastases associated with a solitary intrahepatic cholangiocarcinoma tumor.

     

Daily Intake of High-Fat Diet with Lysophosphatidic Acid-Rich Soybean Phospholipids Augments Colon Tumorigenesis in Kyoto Apc Delta Rats

Background

Oral administration of lysophosphatidic acid (LPA) was shown to attenuate gastric ulceration in rats and mice but aggravate intestinal tumorigenesis in mice.

Aims

The present study examined whether dietary LPA induces or prevents development of colorectal tumor in rats.

Methods

Kyoto Apc Delta rats fed high-fat diet with or without an LPA-rich soybean phospholipid mixture (LSP, 0.1 or 1%) were treated with azoxymethane and dextran sodium sulfate to induce colorectal tumorigenesis. Rats were killed 15 weeks after azoxymethane treatment, and size, total number, location, and severity of colorectal tumors were assessed. Expression of mRNA of LPA receptors in rat colon tissue was assayed.

Results

Rats fed the diet supplemented with 1% LSP had a higher number of tumors 2–4 mm long compared than those with or without 0.1% LSP. The mean distance of tumors >4 mm long from the anus was significantly higher than those of tumors <2 and 2–4 mm long in rats fed 1% LSP-supplemented diet. Supplementation of the diet with 0.1% LSP decreased mRNA expression of LPA5 in colon tumors of rats.

Conclusions

Dietary supplementation of LPA-rich phospholipids dose-dependently augmented colorectal tumorigenesis. Decreased expression of LPA5 in colon tumors may be relevant to augmented tumorigenesis.

     

Medikamentöse Behandlung gastrointestinaler Tumoren

Background

In gastrointestinal cancer, early diagnosis, multidisciplinary treatment and new therapeutic options result in increased cure rates or survival times. After treatment of gastrointestinal cancer, many patients suffer from treatment-related sequelae that affect the quality of life.

Objectives

This article provides an overview of the most common long-term sequelae after pharmacological therapy of gastrointestinal tumors.

Materials and methods

The results of a literature review, current basic research, and expert recommendations are discussed.

Results

Common sequelae after pharmacological therapy of gastrointestinal tumors are polyneuropathy, fatigue, bone marrow toxicity, and sexual dysfunction/reduced fertility.

Conclusions

With more intensive therapeutic approaches, long-term side effects will increase after treatment of gastrointestinal tumors. Because the quality of life can be significantly affected, the development of long-term side effects should be closely monitored in the follow-up of patients.

     

Arginine vasopressin (AVP): a review of its historical perspectives,current research and multifunctional role in the hypothalamo-hypophysial system

Introduction

This publication reviews the function of arginine vasopressin and focuses on the morphologic and functional correlation between the hormone and its effect on stress, the hypophysial–adrenocortical axis, neuroimmune responses, renal function and corticotroph pituitary tumors.

Materials and methods

A literature review was performed using various search engines for information regarding the morphology and the multifunctional role of arginine vasopressin.

Results

Although a large number of studies were published discussing these interactions, there are several important areas that are still obscure.

Conclusion

The questions of how does arginine vasopressin affect the morphology and function of these various areas, and how does the secretion of ACTH and adrenocortical hormones influence the morphology of arginine vasopressin-producing cells and their hormone secretion requires further investigation.

     

Efficacy of lymph node dissection for each station based on esophageal tumor location

Background

The area of nodal dissection should be modified by the location of the primary tumor in an individual patient. The purpose of this study was to evaluate the efficacy of lymph node dissection based on station by the location of the primary tumor based on a multi-institutional nationwide registry of esophageal cancer.

Methods

The study group comprised 1295 patients who underwent R0 resection and three-field esophagectomy. The Efficacy Index (EI) was calculated by multiplying the incidence of metastases to a station and the 5-year survival rate of patients with metastases to that station, by tumor location.

Results

There were 550 patients without nodal metastases and 745 patients with them. In patients with upper tumors, the EIs of recurrent nerve nodes, cervical paraesophageal nodes and supraclavicular nodes were highest. In patients with middle tumors, the EIs of recurrent nerve nodes, cardiac nodes and lesser curvature nodes were highest, and the EIs of supraclavicular nodes and cervical paraesophageal nodes were not negligible. In patients with lower tumors, the EIs of cardiac nodes, lesser curvature nodes and left gastric artery nodes were highest, and the EIs of recurrent nerve nodes were also high.

Conclusion

The EIs of certain node stations were different by location of the primary tumor. Node stations for dissection should be modified by the location of the primary tumor. For upper and middle esophageal tumors, the three-field approach is recommended. Dissection of the upper mediastinum is recommended for patients with lower esophageal tumors.

     

Endoscopic submucosal resection with an endoscopic variceal ligation device for the treatment of rectal neuroendocrine tumors

Background

Endoscopic resection is recommended for rectal neuroendocrine tumors <?1 cm in diameter; the three techniques (mucosal resection, submucosal dissection, and mucosal resection with variceal ligation device) of endoscopic resection of neuroendocrine tumor were reported; however, the optimal endoscopic technique remains unclear.

Purpose

We compared the efficacy and safety of three endoscopic rectal neuroendocrine tumor resection methods.

Methods

We retrospectively enrolled 52 patients with rectal neuroendocrine tumors treated by endoscopy at Aichi Medical University Hospital and Nagoya City University Hospital between May 2003 and June 2017. We compared clinical outcomes in three groups based on the endoscopic treatment method.

Results

Fifty-two patients underwent endoscopic rectal neuroendocrine tumor treatment (mucosal resection, 14; submucosal dissection, 19; mucosal resection with an endoscopic variceal ligation device, 19). In the endoscopic mucosal resection, submucosal dissection, and mucosal resection with variceal ligation device groups, R0 resection occurred in 50.0, 94.7, and 89.5%, respectively (mucosal resection vs. mucosal resection with variceal ligation device, p <?0.05; mucosal resection vs. submucosal dissection, p <?0.01), while the median procedure times were 6.5, 43, and 6.0 min, respectively (submucosal dissection vs. mucosal resection with variceal ligation device procedure times, p?<?0.01; mucosal resection vs. submucosal resection procedure times, p <?0.01). Postoperative bleeding occurred after endoscopic mucosal resection (1/14) and endoscopic submucosal dissection (4/19), but not after endoscopic mucosal resection with a ligation device.

Conclusion

Endoscopic mucosal resection with an endoscopic variceal ligation device was a safe, effective treatment for rectal neuroendocrine tumors.

     

Gene expression of ceramide kinase, galactosyl ceramide synthase and ganglioside GD3 synthase is associated with prognosis in breast cancer

Purpose

Sphingolipids are bioactive lipids implicated in apoptosis, cell survival and proliferation. We analyzed the prognostic value of enzymes from sphingolipid metabolism in breast cancer.

Methods

Differences in expression of ceramide galactosyl transferase (UGT8), ceramide kinase (CERK), and Ganglioside GD3-Synthase (ST8SIA1) in breast cancer cells were investigated by using microarray data of 1,581 tumor samples.

Results

UGT8, CERK, and ST8SIA1 were associated with poor pathohistological grading (P < 0.001). High CERK expression was correlated with ErbB2 status (P = 0.006). Among ER positive breast cancers a significant worse prognosis for patients with tumors showing low ST8SIA1 and UGT8 expression was observed. In the ER negative subgroup those samples with high CERK expression displayed a worse prognosis. In a multivariate analysis only ST8SIA1 and tumor size remained significant.

Conclusions

Our experiments reveal that expression of enzymes from the sphingolipid metabolism has prognostic implications in breast cancer.

     

Prognostic relevance of glucosylceramide synthase (GCS) expression in breast cancer

Purpose

Multidrug resistance (MDR) has been linked to sphingolipid metabolism and preclinical data ascribe glucosylceramide synthase (GCS) a major role for MDR especially in breast cancer cells but no profound data are available on the expression of this potential therapeutic target in clinical breast cancer specimens.

Methods

We analyzed microarray data of GCS expression in a large cohort of 1,681 breast tumors.

Results

Expression of GCS was associated with a positive estrogen receptor (ER) status, lower histological grading, low Ki67 levels and ErbB2 negativity (P < 0.001 for all). In univariate analysis there was a benefit for disease free survival for patients with tumors displaying low levels of GCS expression but this significance was lost in multivariate Cox regression.

Conclusions

Our results suggest ER positive tumors may be the most promising candidates for a potential therapeutic application of GCS inhibitors.

     

Primary Liver Tumors Other than Hepatocellular Carcinoma: Clinical and Molecular Pearls

Purpose of Review

Liver tumors, excluding hepatocellular carcinoma and metastatic disease, are rare. However, it is important to understand how to distinguish these lesions from hepatocellular carcinoma. They run the spectrum of benign to malignant, some aggressive with relatively few therapeutic options. The goal of this paper is to review the most recent literature to provide current insights into diagnosis, treatment, and pathogenesis of these tumor types.

Recent Findings

Recent literature has focused on oncogenomics and putative targets for therapeutic intervention. Several ongoing studies are elucidating molecular pathways and evaluating novel therapies in these rare tumors and we focus on these findings, particularly in intrahepatic cholangiocarcinoma and fibrolamellar HCC. While these advances are promising, surgical resection continues to be associated with the greatest survival benefit for rare malignant tumors of the liver.

Summary

Clinicians must be aware of rare liver tumors to distinguish them from hepatocellular carcinoma and to develop a differential diagnosis in complicated or atypical presentations. In these rare tumors, advances in understanding tumor biology hold the promise of expanding diagnostic and therapeutic possibilities.

     

Clinicopathological differences between right- and left-sided colonic tumors and impact upon survival

Aim

This study is to analyze the clinicopathological differences between right- and left-sided colonic tumors and to evaluate the impact upon the patient’s survival.

Methods

In a period of 5 years (2004–2009), 453 patients were diagnosed with colorectal cancer.

Results

From a total of 453 patients diagnosed with colon cancer, 56.5% of them were men, while 43.5% of them were women. Right-sided colonic tumors were diagnosed in 54.53% of the patients compared to the 45.47% of patients with left-sided colonic tumors. The size of colonic tumors is statistically significant greater in right-sided colonic tumors compared to left ones (P < 0.001). Left-sided colon cancer patients identified to have a statistically significant better overall 5-year survival rate compared to right-sided ones (P < 0.001).

Conclusion

Based upon our results, there is a different biological profile between right- and left-sided colonic tumors.

     

Treatment of acute hepatitis C: recommendations from an expert panel of the Italian Society of Infectious and Tropical Diseases

Aim

This paper is aimed at providing practical recommendations for the management of acute hepatitis C (AHC).

Methods

This is an expert position paper based on the literature revision. Final recommendations were graded by level of evidence and strength of the recommendations.

Results

Treatment of AHC with direct-acting antivirals (DAA) is safe and effective; it overcomes the limitations of INF-based treatments.

Conclusions

Early treatment with DAA should be offered when available.

     

DNA vaccination with a mutated p53 allele induces specific cytolytic T cells and protects against tumor cell growth and the formation of metastasis

Purpose

Genetic vaccination by expression plasmids that encode mutant p53 was conducted to characterize exogenously induced anti-tumoral immunity in mice.

Methods

Gene transfer was evaluated by reporter gene expression assays. The efficacy of genetic immunization was addressed by analysis of solid tumor outgrowth and the formation of metastases. Cell mediated immunity was determined by ⁵¹Cr-release cytotoxicity assays and adoptive lymphocyte transfer experiments.

Results

Genetic vaccination resulted in a persistent protection against the growth and metastasis of transplanted tumor cells. Immunoprotection was based on the induction of cytolytic T cells (CTLs) able to recognize mutant but not wild type p53. Mice were not protected from tumor cell growth when the tumor cells expressed alternate p53 mutations or overexpressed wild type p53. No p53 specific humoral immune response was detected. T-lymphocyte transfer experiments demonstrated that resistance to tumor growth depended both on tumor size and a time-dependent induction of protective immunity. Small tumors (Ø < 0.4 cm³) went into remission or remained stable upon adoptive transfer of T-lymphocytes from mice immunized with mutant p53 DNA; larger tumors progressed. A time course of immunization was evaluated and showed that DNA vaccination must precede tumor cell inoculation in order to induce an efficient anti-tumoral response.

Conclusion

DNA vaccination against the mutated form of p53 can elicit a specific adaptive immune response and has anti-tumoral activity. Tumor burden and the time necessary to acquire tumor immunity were recognized as critical parameters for immunization; however, tumors may evade specific immunotherapy.

     

Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary

Introduction

Histologic, immunohistochemical and electron microscopic studies have provided conclusive evidence that a marked diversity exists between tumors which secrete growth hormone (GH) in excess. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH—releasing hormone secreting tumors or in familial pituitary tumor syndromes.

Materials and methods

A literature search was performed for information regarding pathology, GH-producing tumors and acromegaly.

Results

This review summarizes the current knowledge on the morphology of GH-producing and silent GH adenomas, as well as GH hyperplasia of the pituitary.

Conclusion

The importance of morphologic classification and identification of different subgroups of patients with GH-producing adenomas and their impact on clinical management is discussed.

     

Cancer Center Volume and Type Impact Stage-Specific Utilization of Neoadjuvant Therapy in Rectal Cancer

Background

Neoadjuvant chemoradiation reduces local recurrence in locally advanced rectal cancer, and adherence to national and societal recommendations remains unknown.

Objective

To determine variability in guideline adherence in rectal cancer treatment and investigate whether hospital volume correlated with variability seen.

Design

We performed a retrospective analysis using the National Cancer Database rectal cancer participant user files from 2005 to 2010. Stage-specific predictors of neoadjuvant chemotherapy and radiation use were determined, and variation in use across hospitals analyzed. Hospitals were ranked based on likelihood of preoperative therapy use by stage, and observed-to-expected ratios for neoadjuvant therapy use calculated. Hospital outliers were identified, and their center characteristics compared.

Results

A total of 23,488 patients were identified at 1183 hospitals. There was substantial variability in the use of neoadjuvant chemoradiation across hospitals. Patients managed outside clinical guidelines for both stage 1 and stage 3 disease tended to receive treatment at lower-volume, community cancer centers.

Conclusions

There is substantial variability in adherence to national guidelines in the use of neoadjuvant chemoradiation for rectal cancer across all stages. Both hospital volume and center type are associated with over-treatment of early-stage tumors and under-treatment of more invasive tumors. These findings identify a clear need for national quality improvement efforts in the treatment of rectal cancer.

     

Risk-adapted,long-term management in childhood-onset craniopharyngioma

Purpose

This report is a review of findings on the diagnosis, treatment, clinical course, follow-up, and prognosis of craniopharyngioma patients with special regard to clinical trials and long-term management.

Methods

Literature search on Pubmed for paper published after 1994.

Results

Craniopharyngiomas are rare, embryonic malformations of the sellar/parasellar region with low histological grade. Clinical manifestations are related to increased intracranial pressure, visual impairment, and hypothalamic/pituitary deficiencies. If the tumor is favorably localized, therapy of choice is complete resection, with care taken to preserve hypothalamic and optic functions. In patients with unfavorable tumor location (i.e. involvement of hypothalamic areas), recommended therapy is limited hypothalamus-sparing surgical strategy followed by irradiation. Irradiation has proven effective in treatment of recurrences and progression. Surgical lesions and/or anatomical involvement of posterior hypothalamic areas can result in serious sequelae, mainly hypothalamic syndrome.

Conclusions

It is crucial that craniopharyngioma be managed as a frequently chronic disease, providing ongoing care of pediatric and adult patients’ by experienced multidisciplinary teams in the context of multicenter trials.

     

Prognosis of Cancer with Synchronous or Metachronous Malignant Pleural Effusion

Purpose

Malignant pleural effusions (MPE) may either coincide with or follow the diagnosis of a primary tumor. Whether this circumstance influences prognosis has not been well substantiated.

Methods

Retrospective review of all consecutive patients who were cared for at a Spanish university hospital during an 11-year period and received a diagnosis of MPE.

Results

Of 401 patients, the MPE was the first evidence of cancer in 265 (66%), and it followed a previously diagnosed neoplasm in 136 (34%). Lung cancer predominated in the former group (131, 50%), and breast cancer in the latter (55, 40%). MPE that were the presenting manifestation of hematological and ovarian tumors had a statistically significant survival advantage as compared to those which developed in patients from a previously known cancer (respective absolute differences of 41 and 20 months; p < 0.005).

Conclusions

In hematological and ovarian malignancies, the synchronous or metachronous diagnosis of MPE may have prognostic implications.

     

Cetuximab enhances the efficacy of bortezomib in squamous cell carcinoma cell lines

Purpose

Proteasome inhibition has been shown to be effective in multiple myeloma and solid tumor models. In this in vitro study, we investigated the antitumor effect of bortezomib (Velcade^®) in combination with cetuximab in squamous cell carcinoma cell lines (SCC).

Methods

Dose-escalation studies were performed in five squamous cell carcinoma cell lines using bortezomib or cetuximab alone or in combination. Cell survival and growth inhibition were measured quantitatively using an MTT and LDH assay.

Results

Bortezomib alone showed a significant antiproliferative activity in all SCC cell lines (P < 0.042), and the activity was further significantly enhanced by the addition of cetuximab (P < 0.043).

Conclusions

Our results indicate that cetuximab increases the cytotoxic activity of bortezomib in SCC cell lines. Combination therapy of SCC with bortezomib and cetuximab might be less toxic than conventional drug regimens used in the treatment of these tumors.

     

Die Rolle der Selbsthilfegruppen in der Onkologie

Background

Little is known about self-help associations and their possibilities. Obstacles often prevent early contacts between affected people.

Objectives

The psychosocial support given by self-help associations in different phases is evaluated.

Materials and methods

Based on the experience of the Deutsche ILCO and from cooperation with other organizations and institutions, various dimensions of self-help groups are investigated.

Results

On the professional side, there is a lack of knowledge and of attitude. Suitable structures are rare.

Conclusions

The removal of barriers and development of effective structures are overdue.