The role of carboplatin in combination with paclitaxel in patients with castration-resistant prostate cancer.

Background: The aim of the present study was to examine the efficacy of carboplatin in combination with paclitaxel in patients with metastatic castration-resistant prostate cancer pretreated with multiple regimens including docetaxel and androgen receptor-targeted agents. Methods: Clinical data from patients treated with carboplatin plus paclitaxel were collected retrospectively from a single institution. Results: 43 patients with metastatic castration-resistant prostate cancer were identified. Median number of cycles was ten (range: 1 to 23), prostate-specific antigen response was observed in 18 (42%) patients, median progression-free survival was 115 days and median overall survival was 8.1 months. Conclusion: Combination chemotherapy using taxane with carboplatin is an effective and well-tolerated therapy in heavily pretreated patients with metastatic castration-resistant prostate cancer.

The prognosis of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel is poor, with only limited guidance on the optimal treatment strategy. We reviewed patients with mCRPC treated with weekly carboplatin/paclitaxel in a single institution, analyzing their prostate-specific antigen (PSA) response, progression-free survival, treatment duration and overall survival (OS). Potential predictive biomarkers and tolerability were evaluated. 43 patients treated between 2012 and 2020 were identified, including 40 refractory to docetaxel. 19 (44%) had received two prior chemotherapy regimens and 38 (88%) were pretreated with androgen receptor-targeted agents; 18 patients (42%) had bone-only disease and 16 (37%) had visceral disease. Median number of cycles was ten (range: 1 to 23), PSA response (>50% decline) was observed in 18 patients (42%), median progression-free survival was 115 days and median OS was 8.36 months. 11 patients (26%) experienced reversible grade 3 or 4 toxicity, two (5%) had febrile neutropenia, and no lethal adverse events were observed. The prognostic role for OS was confirmed for PSA response, higher line of therapy, pretreatment with enzalutamide, longer response to androgen-deprivation therapy and response to docetaxel. In conclusion, combination chemotherapy with carboplatin/paclitaxel is a viable, effective and well-tolerated therapy in heavily pretreated patients with mCRPC, but should be validated in a prospective trial.

Intestinal permeability in patients with metastatic colon cancer treated with patupilone.

BACKGROUND: Only a limited number of cytotoxic drugs have shown activity in metastatic colorectal carcinoma. Patupilone is a novel agent with promising activity in this common cancer. Diarrhea represents the dose-limiting toxicity of patupilone. Measurement of intestinal permeability is one of the potential methods of non-invasive laboratory assessment of gastrointestinal toxicity. METHODS: We have assessed intestinal permeability by measuring absorption of lactulose, mannitol and xylose in 27 previously treated patients with metastatic colorectal cancer enrolled in a phase I trial of patupilone. RESULTS: Lactulose/mannitol and lactulose/xylose ratios increased after the treatment. Significantly higher lactulose/mannitol ratio was observed in patients who had severe diarrhea. Moreover, patients who subsequently had an adverse event of grade 3 or higher had significantly higher baseline lactulose/mannitol or lactulose/xylose ratios. CONCLUSIONS: Measurement of intestinal permeability using the lactulose/mannitol test may represent a biomarker for the monitoring, or even prediction of toxicity of cytotoxic drugs, including patupilone.

Distinguishing Healthy and Carcinoma Cell Cultures Using Fluorescence Spectra Decomposition with a Genetic-Algorithm-Based Code.

In this paper, we analysed the steady state fluorescence spectra of cell suspensions containing healthy and carcinoma fibroblast mouse cells, using a genetic-algorithm-spectra-decomposition software (GASpeD). In contrast to other deconvolution algorithms, such as polynomial or linear unmixing software, GASpeD takes into account light scatter. In cell suspensions, light scatter plays an important role as it depends on the number of cells, their size, shape, and coagulation. The measured fluorescence spectra were normalized, smoothed and deconvoluted into four peaks and background. The wavelengths of intensities' maxima of lipopigments (LR), FAD, and free/bound NAD(P)H (AF/AB) of the deconvoluted spectra matched published data. In deconvoluted spectra at pH = 7, the fluorescence intensities of the AF/AB ratio in healthy cells was always higher in comparison to carcinoma cells. In addition, the AF/AB ratio in healthy and carcinoma cells were influenced differently by changes in pH. In mixtures of healthy and carcinoma cells, AF/AB decreases when more than 13% of carcinoma cells are present. Expensive instrumentation is not required, and the software is user friendly. Due to these attributes, we hope that this study will be a first step in the development of new cancer biosensors and treatments with the use of optical fibers.

Hypomagnesaemia in patients with metastatic colorectal carcinoma treated with cetuximab.

BACKGROUND/AIMS: Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma. Among the side-effects of cetuximab hypomagnesaemia has been described, but the information is still limited. METHODOLOGY: We have evaluated retrospectively serum magnesium, potassium, calcium, creatinine and albumin in 51 consecutive patients with metastatic colorectal carcinoma treated with cetuximab, mostly combined with irinotecan-based combination chemotherapy. RESULTS: A significant decrease of serum magnesium, potassium, calcium and corrected serum calcium, creatinine and albumin concentrations was already evident one week after the start of treatment. Hypomagnesaemia of any grade was detected in 56% of evaluable patients, but grade 3 or grade 4 hypomagnesaemia was observed in 6% and 4% of patients, respectively. Grade 1 hypokalemia was detected in 47%, grade 3 in 17% and grade 4 hypokalemia was detected in 6% of the patients. Among evaluable patients grade 1 hypocalcaemia was detected in (36%), grade 2 hypocalcaemia in 42%, grade 3 in 4% and grade 4 in 13% of patients. Baseline hypocalcaemia of grade 1 or higher was associated with significantly inferior survival. CONCLUSIONS: Asymptomatic hypomagnesaemia, hypokalemia and hypocalcaemia are common in metastatic colorectal carcinoma patients treated with cetuximab. Hypocalcaemia is a predictor of poor prognosis.

Prognostic significance of serum retinol, serum alpha-tocopherol, and urinary neopterin in patients with head and neck carcinoma treated with external beam radiation.

High serum or urinary neopterin concentrations are associated with poor prognosis in patients with tumors of different primary locations, but reports on neopterin in patients with head and neck carcinoma are relatively less numerous. It has been established that decreased circulating concentrations of retinol and alpha-tocopherol are common in this population. We have evaluated the prognostic significance of urinary neopterin, serum retinol, and alpha-tocopherol in 44 patients with head and neck carcinoma. Urinary neopterin, serum retinol, and alpha-tocopherol were determined with high-performance liquid chromatography. High urinary neopterin and low serum retinol were predictive of poor prognosis, while the prognostic significance of low alpha-tocopherol was of borderline significance. Serum retinol significantly decreased during external beam radiation, but a less marked decrease of alpha-tocopherol during therapy did not reach statistical significance. An increase of urinary neopterin was evident late during the course of treatment. In conclusion, high urinary neopterin and low serum retinol are predictive of poor prognosis in patients with head and neck carcinoma.

Low Concentrated Fractionalized Nanofibers as Suitable Fillers for Optimization of Structural-Functional Parameters of Dead Space Gel Implants after Rectal Extirpation.

Dead space after rectal resection in colorectal surgery is an area with a high risk of complications. In this study, our goal was to develop a novel 3D implant based on composite hydrogels enriched with fractionalized nanofibers. We employed, as a novel approach in abdominal surgery, the application of agarose gels functionalized with fractionalized nanofibers on pieces dozens of microns large with a well-preserved nano-substructure. This retained excellent cell accommodation and proliferation, while nanofiber structures in separated islets allowed cells a free migration throughout the gel. We found these low-concentrated fractionalized nanofibers to be a good tool for structural and biomechanical optimization of the 3D hydrogel implants. In addition, this nano-structuralized system can serve as a convenient drug delivery system for a controlled release of encapsulated bioactive substances from the nanofiber core. Thus, we present novel 3D nanofiber-based gels for controlled release, with a possibility to modify both their biomechanical properties and drug release intended for 3D lesions healing after a rectal extirpation, hysterectomy, or pelvic exenteration.

Gastroduodenal, intestinal and colonic permeability during anticancer therapy.

BACKGROUND/AIMS: Measurement of the permeability of gut mucosa may offer a method for objective assessment of mucosal dysfunction during cancer therapy. METHODOLOGY: Gastroduodenal, intestinal and colonic permeability was studied by using capillary gas chromatography and measuring urinary sucralose, sucrose, lactulose, xylose and mannitol levels. A total of 41 patients with metastatic colorectal carcinoma or epithelial ovarian carcinoma were studied before and during chemotherapy with the combinations of cetuximab, irinotecan, 5-fluorouracil and leucovorin; bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin; or paclitaxel/ platinum. RESULTS: Compared to pretreatment values, a significant increase was observed during the first cycle of therapy in the percentage of sucrose, sucrose/mannitol ratio, lactulose and lactulose/ mannitol ratio in patients treated with the combination of bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin. No changes were observed in patients treated with cetuximab, irinotecan, 5-fluorouracil and leucovorin, but these patients had significantly higher baseline percentage of lactulose excretion and sucrose/mannitol and lactulose/ mannitol ratios. CONCLUSIONS: An increase in gastroduodenal and intestinal permeability was observed in patients treated with bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin, but not in patients treated with cetuximab, irinotecan, 5-fluorouracil and leucovorin. No significant increase in colonic permeability was observed, but the present method was insufficient to detect colonic permeability in a significant proportion of patients.

Intestinal permeability, vitamin A absorption and serum alpha-tocopherol during therapy with gefitinib.

Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal toxicity of anticancer therapy. We have assessed intestinal permeability (by measuring absorption of lactulose, mannitol, and xylose), vitamin A absorption and serum alpha-tocopherol in patients with non-small cell lung carcinoma or head and neck carcinomas treated with gefitinib. Lactulose, mannitol and xylose were determined by capillary gas chromatography, and retinol, alpha-tocopherol, retinyl stearate and retinyl palmitate were determined by high-performance liquid chromatography. Compared to healthy controls, patients had significantly increased lactulose/mannitol ratio and lower postprandial retinyl palmitate and retinyl stearate concentrations. Compared with pre-treatment values, xylose absorption was decreased and lactulose/mannitol and lactulose/xylose ratios were increased during the therapy. A significant decrease of serum alpha-tocopherol was evident throughout the course of therapy. In contrast, only minor alterations of vitamin A absorption were observed. In conclusion, an alteration in intestinal permeability reflected in increased lactulose/mannitol and lactulose/xylose ratios was observed during gefitinib therapy. Potential association between decreased serum alpha-tocopherol concentrations and the toxicity of gefitinib therapy should be further investigated.

Urinary neopterin, hemoglobin and peripheral blood cell counts in breast carcinoma patients treated with dose-dense chemotherapy.

BACKGROUND: Among other actions, chemotherapy may induce an activation of systemic inflammatory and immune response. PATIENTS AND METHODS: Urinary neopterin was evaluated, using high-performance liquid chromatography, before and during dose-dense combination chemotherapy with doxorubicin, cyclophosphamide and sequential paclitaxel (neoadjuvant or adjuvant) in 194 patients with breast carcinoma. Hemoglobin, peripheral blood cell count and, in a subgroup of patients, iron metabolism were also evaluated. RESULTS: Urinary neopterin increased significantly during the chemotherapy. The increase in urinary neopterin was accompanied by a gradual decrease of hemoglobin. A marked increase in serum ferritin concentration was observed during the chemotherapy, along with fluctuations of iron concentrations. Among 161 patients treated with primary chemotherapy, the pathological response was evaluable in 150. Pathological complete response was observed in 37 cases (25%). In patients with pathological complete response, significantly lower serum ferritin concentrations were observed. CONCLUSION: Present data demonstrate the presence of systemic immune activation, reflected in increased urinary neopterin concentrations, in breast carcinoma patients treated with dose-dense chemotherapy. Lower ferritin concentrations were predictive of pathological complete response.

Immunotherapy in mucosal melanoma: a case report and review of the literature.

BACKGROUND: Mucosal melanoma is a rare form of melanoma presenting variably as sores or unexplained bleeding located mainly in the head and neck region, anorectal region or female genital tract. Mucosal melanoma is usually diagnosed at an advanced stage and is characterized by an aggressive behavior. Surgery represents the mainstay of treatment for early stage melanomas, but for advanced disease there have been until recently very limited treatment options. Ipilimumab, a human monoclonal antibody directed against the cytotoxic T lymphocyte antigen 4, was the first treatment modality to demonstrate survival benefit in advanced malignant melanoma. METHOD: Description of a new case and review of the literature. RESULTS: We present here a patient with mucosal melanoma with aggressive biological behavior and documented late response to ipilimumab. CONCLUSIONS: Ipilimumab represents an effective treatment option in selected patients with mucosal melanoma.

Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum.

BACKGROUND: Combination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum. METHODS: Intestinal permeability was assessed in 36 breast and ovarian cancer patients treated with paclitaxel/platinum combination by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose and mannitol after oral challenge. The significance of differences during the therapy compared to pre-treatment values was studied by Wilcoxon paired test. The differences between groups of patient were studied by Mann-Whitney U test. Fisher exact test was used to compare the frequency in different subgroups. RESULTS: After administration of the first dose, a significant (p < 0.05) decrease in xylose absorption and increased lactulose/mannitol, sucrose/mannitol, lactulose/xylose and sucrose/xylose ratios were observed, but these parameters returned subsequently to pre-treatment levels. Patients who experienced serious (grade 3 or 4) toxicity had at baseline significantly lower percentages of xylose, mannitol and sucrose, and higher lactulose/mannitol ratio. Nine of 13 (69%) patients with baseline lactulose/mannitol ratio 0.070 or above experienced serious toxicity compared to 4 out of 23 patients (17%) with the ratio below 0.070 (p = 0.002). Post-treatment lactulose, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were significantly increased in patients with serious toxicity. CONCLUSION: A transient significant increase in lactulose/monosaccharide and sucrose/monosaccharide ratios was observed in ovarian and breast cancer patients treated with paclitaxel and platinum. Increased lactulose absorption, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were evident in patients with grade 3 or 4 toxicity, and increased baseline lactulose/mannitol ratio predicted serious toxicity.

Serum alpha-tocopherol, retinol and neopterin during paclitaxel/carboplatin chemotherapy.

BACKGROUND: Disorders of antioxidant balance are considered to be involved in the toxicity associated with radiotherapy or chemotherapy. PATIENTS AND METHODS: Serum alpha-tocopherol and retinol were determined, by high performance liquid chromatography, before and during therapy with a combination of paclitaxel and carboplatin in 28 patients with breast and ovarian cancer. Serum neopterin and cholesterol were measured using a radioimmunoassay and enzymatic colorimetric method, respectively. RESULTS: Compared to pretreatment concentrations, a significant increase was observed in serum alpha-tocopherol and retinol concentrations during therapy that was associated with decreased serum neopterin concentrations. Serum alpha-tocopherol concentrations were significantly higher during therapy in patients who did not experience serious toxicity. CONCLUSION: An increase in alpha-tocopherol and retinol during therapy with combination paclitaxel/carboplatin may be explained by inhibition of systemic immune activation secondary to control of the tumor with effective chemotherapy. Lower alpha-tocopherol concentrations were associated with the toxicity of therapy.

Risk factors of atherosclerosis during systemic therapy targeting vascular endothelial growth factor.

The aim of the present study was to examine the changes in intima-media thickness (IMT) and myocardial perfusion in association with other laboratory risk factors for atherosclerosis in patients treated with therapy that targeted vascular endothelial growth factor (VEGF). IMT, myocardial perfusion and laboratory risk factors of atherosclerosis were studied in 58 patients with metastatic colorectal carcinoma or metastatic renal cell carcinoma prior to and at 3-monthly intervals during anti-VEGF treatment. Compared with the pretreatment IMT, the results indicated that the IMT was consistently increased during therapy in the two patient groups. Patient blood pressure and concentration of troponin T increased transiently. An increase in the concentration of high-density lipoprotein cholesterol and decrease in the concentrations of C-reactive protein and homocysteine were also observed. Novel myocardial ischemia was evident in individual patients. In conclusion, anti-VEGF therapy affects the laboratory risk factors of atherosclerosis and results in an acceleration of atherosclerosis, as demonstrated by increased IMT.

Role of subcutaneous formulation of trastuzumab in the treatment of patients with HER2-positive breast cancer.

Tumors in about 15% of patients with breast cancer overexpress HER2. Trastuzumab (Herceptin(®); F. Hoffmann-La Roche, Basel, Switzerland) is a humanized monoclonal antibody against HER2. While the introduction of trastuzumab has changed the natural course of HER2-positive breast cancer, the need for repeated administration of the drug over a prolonged period of time represents a challenge. Similarly to other chronic disorders, subcutaneous administration of monoclonal antibodies may be of advantage in this setting. The results of a prospective randomized Phase III study have demonstrated that subcutaneous trastuzumab is noninferior compared with the intravenous administration of the drug in terms of efficacy (assessed as pathological complete response rate) as well as in pharmacokinetic parameters. Moreover, another prospective randomized study showed that an overwhelming majority of patients prefer subcutaneous over intravenous trastuzumab. The advent of subcutaneous trastuzumab represents an important progress in the concept of cancer management that is based also on patient choice and preferences.

Predictive and prognostic significance of tumor-infiltrating lymphocytes in patients with breast cancer treated with neoadjuvant systemic therapy.

Despite the progress of tailored therapeutic strategies in patients with breast cancer, there is an unmet medical need for additional biomarkers that would guide therapy, including the administration of targeted agents. It has been demonstrated that the presence of tumor-infiltrating lymphocytes (TILs) is associated with prognosis in patients with early breast cancer. Moreover, TIL counts were shown to predict outcome of neoadjuvant chemotherapy. The neoadjuvant setting is increasingly used to assess the efficacy of new systemic therapies, and TILs are promising as a biomarker reflecting the immune response to tumor. Future studies should investigate on the integration of TILs as predictive biomarkers in patients treated with targeted- agents.

Prognostic significance of CD3+ tumor-infiltrating lymphocytes in patients with endometrial carcinoma.

AIM: The aim of the present study was to investigate tumor-infiltrating leukocytes in patients with endometrial carcinoma. PATIENTS AND METHODS: Cluster of differentiation (CD)3(+), CD8(+) and C20(+) tumor-infiltrating lymphocytes (TILs) and CD68(+) tumor-associated macrophages (TAMs) were evaluated retrospectively by immunohistochemistry in tumor specimen from 124 patients with endometrial carcinoma. RESULTS: A significant decrease of CD3(+) TILs and an increase of CD68(+) TAM count was associated with higher tumor stage. In patients with early-stage, high-risk tumors, low intraepithelial CD3(+) TIL counts were associated with significantly inferior survival. In multivariate analysis of patients with early-stage tumors, intraepithelial CD3(+) TIL counts were an independent predictor of survival. CONCLUSION: In patients with endometrial carcinoma a decrease of intraepithelial CD3(+) TIL counts is associated with advanced stage and high risk group. Intraepithelial CD3(+) TIL counts are an independent predictor of survival in patients with early tumors.

Urinary neopterin concentrations during combination therapy with cetuximab in previously treated patients with metastatic colorectal carcinoma.

BACKGROUND/AIM: Increased concentrations of neopterin, a biomarker of systemic immune response, have been reported after administration of cytokines, cytotoxic chemotherapy or external-beam radiation, but little is known about the effects of targeted-agents on neopterin. PATIENTS AND METHODS: Urinary neopterin was studied in pre-treated patients with metastatic colorectal carcinoma during therapy with cetuximab, administered mostly in combination with irinotecan, 5-fluorouracil and leucovorin. Urinary neopterin was determined by high-performance liquid chromatography. RESULTS: High initial urinary neopterin concentrations predicted poor prognosis. A significant correlation was observed between urinary neopterin and peripheral blood leukocyte count, hemoglobin and carcinoembryonic antigen concentrations. Urinary neopterin concentrations significantly increased during therapy only in patients with initially low neopterin concentrations. CONCLUSION: Urinary neopterin concentrations predict prognosis in patients with metastatic colorectal carcinoma treated with cetuximab. Rising neopterin concentrations indicate an activation of systemic immune response that could be responsible for the antitumor activity of cetuximab.

Prevalence of perfusion defects detected by stress 99mtechnetium sestamibi myocardial perfusion single-photon emission computed tomography in asymptomatic patients with breast cancer.

AIM: The aim of the present study was to investigate myocardial perfusion in relation to disease history and laboratory parameters of atherosclerosis risk in asymptomatic patients with breast carcinoma. PATIENTS AND METHODS: One-hundred and eighty-one patients with breast carcinoma were studied. Myocardial perfusion was assessed using single-photon emission computed tomography (SPECT) with 99mtechnetium sestamibi. RESULTS: Perfusion defects were detected in 12 patients (7%). Higher body-mass index, increased concentrations of D-dimers, C-reactive protein, fibrinogen, glucose, triglycerides, and urinary albumin, a history of hypertension and of radiotherapy to the left chest wall were all associated with increased risk of perfusion defects. In a multivariate stepwise selection logistic regression model, body mass index, albuminuria and radiotherapy to the left hemithorax were significantly associated with the presence of perfusion defects. CONCLUSION: In addition to other factors, treatment history may be associated with the presence of perfusion defects in patients with breast cancer.

Urinary neopterin concentration and toxicity of radiotherapy in patients with head and neck carcinoma during external beam radiation.

AIM: Increased serum or urinary concentrations of neopterin are predictive of poor prognosis in patients with tumors across a spectrum of primary locations. Less information is available about the significance of changes of urinary neopterin concentrations during therapy. The aim of the present study was to examine the association between urinary neopterin and toxicity of radiotherapy. PATIENTS AND METHODS: We analyzed changes of urinary neopterin and toxicity of therapy in 12 patients with head and neck carcinoma during external-beam radiation. Urinary neopterin was determined daily by high-performance liquid chromatography. RESULTS: In addition to a trend for increased neopterin concentrations during radiation therapy, a significant association between changes of neopterin and toxicity and vice versa was observed with a rise of neopterin predicting a later manifestation of toxicity as well as manifestion of toxicity predicting a later rise of neopterin. CONCLUSION: Urinary neopterin is predictive of toxicity in patients with head and neck carcinoma. An association between toxicity and subsequent rise of urinary neopterin concentrations was also observed.