The effect of visceral reception activation (water load test) on autonomic activity and gastric myoelectric activity in gastrointestinal malignancies.

OBJECTIVES: The aim of this study was to analyze the effect of water load test (WLT) on heart rate variability (HRV), blood pressure variability (BPV), hemodynamic parameters and gastric myoelectric activity in gastrointestinal (GI) cancer patients. BACKGROUND: WLT activates gastrointestinal mechanoreception and osmoreception, and hence, can indirectly modulate autonomic activity. METHODS: Eighty patients (mean age 61.2 years) were enrolled, along with the group of healthy controls. HRV, BPV and electrogastrography (EGG) were recorded at rest (in a fasted state) and after water uptake at 100 ml/min. RESULTS: WLT contributed to an increase in the percentages of normogastria time, from 37.3 % to 50.0 % (p=0.02) and from 42.3 % to 47.7 % (p=0.01), respectively in colon and rectal cancer. Cancer patients presented lower values of HRV indices determined on linear analysis at rest and after WLT. CONCLUSIONS: A slight predominance of the sympathetic component was observed in response to WLT, which was reflected by changes in hemodynamic parameters. The response to WLT is a consequence of GI mechanoreception and osmoreception activation and resultant pressure reaction. This effect was disrupted by the neoplastic process within the GI tract, especially in gastric and colon malignancies, but not in rectal cancer (Tab. 2, Fig. 12, Ref. 40). Text in PDF www.elis.sk Keywords: autonomic nervous system, gastric myoelectric activity, water uptake, heart rate variability, blood pressure variability, gastrointestinal cancer.

Hippo pathway - brief overview of its relevance in cancer.

The Hippo pathway is the major regulator of organ growth and proliferation. Described initially in Drosophila, it is now recognized as one of the most conserved molecular pathways in all metazoan. Recent studies have revealed the Hippo signalling pathway might contribute to tumorigenesis and cancer development. The core components of the Hippo pathway include the mammalian sterile 20-like kinases (MSTs), large tumour suppressor kinases (LATSs), the adaptor proteins Salvador homologue 1 (SAV1, also called WW45) and Mps One Binder kinase activator proteins. The major target of the Hippo core kinases is the mammalian transcriptional activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). In cancer, the Hippo signalling is inactivated and YAP and TAZ are activated and free to translocate into the nucleus to promote cell proliferation. Nuclear YAP/TAZ activate or suppress transcription factors that regulate target genes involved in cell proliferation, tissue growth, control of organ size and shape or metastasis. The Hippo signalling pathway that controls the most important cellular processes like growth and division appears to be a very promising research subject in the field of cell biology and tissue engineering. It consists of elements that in the cell play the roles of tumour suppressors as well as oncogenes. This 'Janus like' - an opposite activity hidden within one and the same signalling pathway represents a significant obstacle for studying it. This property of the Hippo pathway is worth remembering, as it will appear several times during the discussion of its properties. Here, we will review certain data regarding biology of the Hippo signalling and its interplay with other prominent signalling pathways in the cell, its relevance in cancer development and therapies that might target elements of the Hippo pathway in most human cancers.

Enterohormonal disturbances in colorectal cancer patients.

Gastrointestinal (GI) hormonal peptides play a role in the development of gastrointestinal malignancies, and their abnormal levels may contribute to dysmotility. The aim of this study was to analyze plasma concentrations of enterohormones (motilin, ghrelin, gastrin and pancreatic polypeptide) and to verify if their abnormal levels may contribute to the severity of dyspeptic symptoms in colorectal cancer patients. The study included 60 patients with colorectal malignancies (22 men and 38 women), among them 30 individuals with colon cancers (group A) and 30 subjects with rectal tumors (group B). Fasting plasma levels of pancreatic polypeptide (PP), motilin, gastrin and ghrelin were determined by means of ELISA. The results were compared with the respective parameters of healthy volunteers. Colon cancer patients presented with significantly lower concentrations of ghrelin than the subjects with rectal tumors and healthy controls (156.8±86.7 vs. 260.2±87.6 vs. 258.4±94.2 pg/ml, p=0.02), as well as with significantly higher levels of PP (265.5±66.3 vs. 154.1±54.6 vs. 148.3±64.3 pg/ml, p=0.005). Also the levels of motilin turned out to be lower in colon cancer patients than in the subjects with rectal malignancies and healthy controls. No statistically significant intergroups differences were found in plasma levels of gastrin (388.2±98.6 vs. 475.6±88.7 vs. 428.2±91.2 pg/ml, p>0.05). Epigastric bloating was the most frequent dyspeptic symptom, reported by 63.3% and 40% of patients with colon and rectal tumors, respectively. Our findings imply that colon cancer patients may present with abnormal plasma levels of enterohormones significantly more often than individuals with rectal malignancies. Dysmotility observed in colon cancer patients may result not only from anticancer surgery, but also from abnormal release of enterohormones, induced either by neoplastic process or by changes within the autonomic nervous system.

Electroneurography in the evaluation of oxaliplatin-induced neuropathy in colorectal cancer patients.

Cold-induced neuropathy is the most observed side effect of oxaliplatin. Presence of neuropathy is routinely assessed by electroneurographical examination. The use of electroneurography has not been a part of typical oncological monitoring and treatment protocols, leading to untreated, irreversible damage to patients' peripheral nerves, undiagnosed for long periods of time. 36 colorectal cancer patients followed FOLFOX4 with/without bevacizumab or XELOX were enrolled between February 2013 and January 2015 in the study at the University Hospital Oncological Department, Krakow, Poland. Electroneurography was performed prior to the first cycle of chemotherapy and after the 4th cycle. 32 out of 36 enrolled patients completed neurological evaluation. Pre-treatment neurographic examination revealed presence of peripheral neuropathy in 10 (31.25%) patients; 6 (18.75%) had sensory neuropathy and 4 (12.5%) had mixed, sensorimotor neuropathy. After treatment examination revealed significant increase in the number of neuropathic patients; presence of peripheral neuropathy was observed in 19 patients (59%), sensory polyneuropathy was diagnosed in10 patients (31.25%) and mixed neuropathy was diagnosed in 9 patients (28.13%). Early electrophysiological monitoring followed by a symptom dependent oxaliplatin regimen would be highly beneficial for patients undergoing oxaliplatin treatment, improving their well-being and positively affecting their life quality.

Salvage chemotherapy in metastatic colorectal cancer with the combination of capecitabine and mitomycin C.

A significant proportion of heavily pretreated patients with metastatic colorectal cancer maintain good performance status (PS) and are eligible for further systemic treatment. Mitomycin C (MMC) combined with capecitabine can be considered as salvage treatment in this group of patients. To evaluate the efficacy and toxicity of mitomycin C and capecitabine as at least third-line systemic therapy (after failure of 5Fu, irinotecan, oxaliplatin-based chemotherapy regimens and targeted therapies) in patients with metastatic colorectal cancer. A total of 31 patients with a median age of 55.2 years with metastatic colorectal cancer received salvage chemotherapy at the Oncological Department of University Hospital in Krakow, Poland, between July 2011 and July 2014. Chemotherapy consisted of intravenous MMC 6 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1-14 followed by a 7-day treatment-free interval. Each cycle was repeated every 3 weeks unless there was evidence of disease progression or unacceptable toxicity. All the31 patients were evaluable for response and toxicity. A total of 113 cycles were administered. Five of the 31 (16.1%) patients had stable disease after three cycles of chemotherapy, 24 (77.4%) patients progressed and 1 (3.2%) patient is still undergoing treatment. One patient (3.2%) died due to cardiac infarct 5 days after starting treatment. Median progression free survival (PFS) was 2.5 months. Median overall survival (OS) was 4.9 months. Toxicity was mild and easily manageable. Mitomycin C and capecitabine can be considered as salvage therapy in heavily pretreated patients with metastatic colorectal cancer and with good performance status. Toxicity of these drugs combination is moderate and easily manageable.

Neutropenia management and granulocyte colony-stimulating factor use in patients with solid tumours receiving myelotoxic chemotherapy--findings from clinical practice.

PURPOSE: Clinical practice adherence to current guidelines that recommend primary prophylaxis (PP) with granulocyte colony-stimulating factors (G-CSFs) for patients at high (≥20 %) overall risk of febrile neutropenia (FN) was evaluated. METHODS: Adult patients with breast cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), or ovarian cancer were enrolled if myelotoxic chemotherapy was planned, and they had an investigator-assessed overall FN risk ≥20 %. The primary outcome was FN incidence. RESULTS: In total, 1,347 patients were analysed (breast cancer, n = 829; NSCLC, n = 224; SCLC, n = 137; ovarian cancer, n = 157). Patients with breast cancer exhibited fewer individual FN risk factors than patients with other cancers and were far more likely to have received a high-FN-risk chemotherapy regimen. However, a substantial proportion of all patients (45-80 % across tumour types) did not receive G-CSF PP in alignment with investigator risk assessment and guideline recommendations. FN occurred in 127 patients overall (9 %, 95% confidence interval (CI) 8-11 %), and incidence was higher in SCLC (15 %) than other tumour types (8 % in ovarian and NSCLC, 9 % in breast cancer). A post hoc analysis of G-CSF use indicated that G-CSF prophylaxis was not given within the recommended timeframe after chemotherapy (within 1-3 days) or was not continued across all cycles in 39 % of patients. CONCLUSIONS: FN risk assessment was predominantly based on clinical judgement and individual risk factors, and guidelines regarding G-CSF PP for patients at high FN risk were not consistently followed. Improved education of physicians may enable more fully informed neutropenia management in patients with solid tumours.

Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper.

BACKGROUND: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first-line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly patients are at increased risk of this event and measures to reduce it should be considered. METHODS: A committee of experts in breast cancer and NHL met under the auspices of the International Society for Geriatric Oncology to review the literature and make recommendations, based on level of evidence, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines. RESULTS AND RECOMMENDATIONS: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative dose of anthracyclines and short infusion duration. The fact that cumulative and irreversible cardiotoxicity is likely to be greater in this population than among younger patients calls for effective pretreatment screening for risk factors, rigorous monitoring of cardiac function and early intervention. Use of liposomal anthracycline formulations, prolonging the infusion time for conventional anthracyclines and cardioprotective measures should be considered. However, when treatment is being given with curative intent, care should be taken to ensure reduced cardiotoxicity is not achieved at the expense of efficacy.

Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients.

The aim of this phase II study was to evaluate the efficacy and toxicity of two regimens of ifosfamide in metastatic soft tissue sarcoma patients given as first- and second-line chemotherapy. Two different schedules of ifosfamide were investigated in a randomised manner: Ifosfamide was given either at a dose of 5 g/m(2) over 24 h (5 g/m(2)/1 day), every 3 weeks or at a dose of 3 g/m(2) per day, administered over 4 h on three consecutive days (3 g/m(2)/3 days), every 3 weeks. Both schedules were given as first-line or second-line chemotherapy. A total of 182 patients was entered, 103 in first- and 79 in second-line, of whom 8 patients were ineligible, 5 in the first- and 3 in the second-line study. Most patients had a leiomyosarcoma, 46 of the 98 in the first-line and 34 of the 76 in the second-line. The two study arms were well balanced in both the first- and second-lines with respect to sex, age and performance status. In first-line treatment, 5 g/m(2)/1 day yielded five partial responses (PR) (Response Rate (RR) 10%), versus 12 PR (RR 25%) for the 3 g/m(2)/3 days. As second-line treatment, the 24-h infusion yielded: one CR and one PR (RR 6%) and the 3-day schedule one CR and two PR (RR 8%). Survival did not differ between the two regimens. The major World Health Organization (WHO) grade 3 and 4 toxicities encountered were: leucopenia in 19% of all courses in the first-line and 32% in the second-line with the 5 g/m(2)/1 day, while for the 3 g/m(2)/3 days schedule the rates were 57 and 63% respectively. Grade 3 or 4 infections were seen in 4% of patients treated with 5 g/m(2)/1 day first-line and 10% of patients given 3 g/m(2)/3 days, both as first- and second-lines. No such infections were seen in patients receiving 5 g/m(2)/1 day as second line treatment. In advanced soft-tissue sarcomas in the first-line, ifosfamide 3 g/m(2), given over 4 h on three consecutive days, is an active regimen with acceptable toxicity while the 5 g/m(2) over 24 hours schedule resulted in a disappointing response rate.

Multimodality treatment of noninflammatory stage IIIb breast cancer.

BACKGROUND AND OBJECTIVES: The 1990s have established the contribution of multimodality therapy in the management of IIIb noninflammatory breast cancer (IIIb NIBC), by reducing the odds of recurrence and death. METHODS: A total of 300 women with IIIb NIBC received a multimodality therapy. The treatment consisted of neoadjuvant chemotherapy [FAC (5-fluorouracil, Adriamycin, cyclophosphamide) regimen], radical (Halsted) mastectomy or modified (Patey mastectomy), postoperative radiotherapy, and adjuvant chemohormone therapy [FAC regimen + cyclophosphamide, 5-fluorouracil and methotrexate (CMF) regimen or Tamoxifen]. RESULTS: Complete or partial clinical response (CR or PR) after neoadjuvant chemotherapy was obtained in 83% patients. Ninety-nine patients (33%) survived 5 years without evidence of disease (NED). The uni- and multivariate analyses factors that had significant influence on the treatment results were: clinical response to neoadjuvant chemotherapy, pathological tumor size, and microscopical status of the axillary lymph nodes. CONCLUSIONS: We conclude that neoadjuvant FAC regimen chemotherapy is very effective in producing objective tumor regression and offers the benefit of radical mastectomy to patients with previously unresectable IIIb NIBC.

[Use of ifosfamide in multidrug therapy of small cell lung carcinoma]. / Zastosowanie ifosfamidu w wielolekowej chemioterapii drobnokomórkowego raka pluca.

Own concept of small cell lung carcinoma (SCLC) chemotherapy with multidrug regimen including ifosfamide, adriamycin, and etoposide is presented. In the pilot trial, 67% of remissions in patients with localized, and 33% in patients with disseminated neoplastic process were achieved. Proposed therapy has moderate toxicity, markedly lower than that of the regimen including cis-platin. No nephrotoxicity is worth emphasizing. The authors suggest that proposed regimen may be of value in patients in whom combined chemo- and radiotherapy is foreseen.

[Results of adjuvant therapy with the preparation Poly-a Poly-u in patients with malignant melanoma during a 10-year observation]. / Wyniki adjuwantnej terapii preparatem Poly-A Poly-U u chorych na czerniaka zlosliwego w 10-letniej obserwacji.

During 10 years patients with malignant melanoma were followed up after radical removal of primary tumour and metastatic regional lymph nodes, the half of whom was given immunomodulation with the preparation Poly-A Poly-U in a controlled clinical trial. It was found that the performed immunomodulation exerted slight effect on the course of malignant melanoma causing later development of recurrence, less dynamic course of the disease, longer asymptomatic periods in relation to the control group. No effect of the drug administration was observed on longterm survival.

[Diagnostic difficulties in a 32-year old patient with cardiac tamponade]. / Trudnosci diagnostyczne u 32-letniego chorego z tamponada serca.

At present the most frequent cause of cardiac tamponade is neoplasma. A case of a 32-year-old male with recurrent cardiac tamponade caused by pericardium mesothelioma is described. Despite advanced neoplastic process in the pericardium, pleura and mediastinum, neither radiologic examinations of the chest, echocardiography, nor repeated cytologic examination of the pericardial exudate, could establish the etiology of the tamponade. Only after a pericardial window had been performed was it possible to: 1) establish the diagnosis and introduce causal treatment; 2) prevent recurrence of the tamponade; 3) perform cytoreduction of the tumor. It seems that in cases of chronic exudative pericarditis of unknown cause it is proper to perform an early pericardial window as a diagnostic and therapeutic procedure.

Phase II study of miltefosine (hexadecylphosphocholine) in advanced soft tissue sarcomas of the adult--an EORTC Soft Tissue and Bone Sarcoma Group Study.

The EORTC Soft Tissue and Bone Sarcoma Group conducted a phase II study with oral miltefosine at a dose of 50 mg thrice daily in patients with metastatic soft tissue sarcomas. No responses were seen in 18 evaluable patients. Toxicity consisted mainly of nausea/vomiting. It is concluded that oral miltefosine has no activity in soft tissue sarcoma.