Isolated limb perfusion with melphalan as treatment for regionally advanced melanoma of the limbs: results of 60 patients treated in Finland during 2007-2018.

Isolated limb perfusion (ILP) is widely accepted as treatment for recurrent melanoma limited to the limbs. The use of ILP has decreased in recent years with the introduction of potentially effective new systemic therapies. We evaluated retrospectively if ILP still may be a treatment option in locally advanced melanoma. In Finland, ILP is centralized to the Comprehensive Cancer Center of Helsinki University Hospital. We included all ILP patients treated at our hospital between 2007 and 2018. Clinical factors and treatment outcomes were retrospectively evaluated. Altogether 60 patients received ILP. Toxicity was mostly transient. The overall response rate was 77% with 35% complete responses and 42% partial responses. The median progression-free survival (PFS) was 6.1 months (range 0.6-116.5 months) and the median melanoma-specific survival (MSS) was 29.9 months (range 3.5-138.7 months). Patients with CR had superior median PFS (19.7 months, range 2.5-116.5 vs. 4.5 months, range 0.6-39.7 months, P = 0.00003) and median MSS (median MSS not reached vs. 25.9 months, range 3.5-98.7 months, P = 0.0005) compared to other responders. Younger patients (<69 years) had longer median MSS (47.2 months, range 3.5-138.7 vs. 25.9 months, range 8.4-125.4 months, P = 0.015) compared to patients over 69 years. Treatment outcomes of Finnish ILP patients were comparable to earlier studies and some long-term survivors were observed in the group of complete responders. Median PFS and OS were longer for patients achieving a CR. Treatment was well-tolerated also among older patients.

Selective Ophthalmic Artery Chemotherapy with Melphalan in the Management of Unilateral Retinoblastoma: A Prospective Study.

PURPOSE: To determine prospectively the efficacy and to assess potential side effects of melphalan selective ophthalmic artery chemotherapy (SOAC) as first-line treatment for unilateral retinoblastoma. DESIGN: Phase 2 nonrandomized, prospective study. PARTICIPANTS: Patients with unilateral retinoblastoma group B, C, or D of the International Classification for Intraocular Retinoblastoma (IRC). Group D eyes with massive vitreous seeding were not eligible. METHODS: Melphalan SOAC associated with diode laser thermotherapy, cryotherapy, or both at 4-week intervals (3-6 cycles). For persistent vitreous seeding, intravitreal melphalan chemotherapy also was used. MAIN OUTCOME MEASURES: The primary outcome was globe preservation rate. Secondary outcomes were tumor relapse rate, occurrence of ocular or systemic adverse events, and measurement of the dose area product (DAP). RESULTS: Between 2012 and 2017, 39 patients (39 eyes) with unilateral retinoblastoma were included prospectively. Three included patients did not receive SOAC (2 catheterization failures and 1 case of viral syndrome) and were considered failures. At diagnosis, IRC groups for the 36 treated patients were: B, n = 4 (11%); C, n = 13 (36%); and D, n = 19 (53%); median age was 21.5 months (range, 3.2-61.6 months). Median number of SOAC cycles was 3.9 (range, 1-6 cycles), and median melphalan dose was 4.9 mg/procedure. The median DAP was 1.24 Gy.cm2/procedure. Median follow-up was 63 months (range, 34-93 months). SOAC was associated with local treatments for 31 patients (86%): diode laser thermotherapy for all of them and cryotherapy or intravitreal chemotherapy for 10 (32%) and 9 patients (25%), respectively. SOAC treatment was interrupted in 5 patients because of severe ophthalmic (ptosis, n = 2; retinal ischemia, n = 2) or systemic (hypotension, n = 1) adverse events. At the cutoff date analysis, all patients were alive without metastasis. The 18-month eye preservation rate was 80% (range, 68.6%-94.6%). After a follow-up of at least 30 months, the ocular preservation rate was 69% (n = 24 preservations). CONCLUSIONS: This first prospective trial demonstrated that SOAC with melphalan alone as first-line treatment for retinoblastoma is efficient and well tolerated with no metastatic events, although ocular ischemic complications were observed.

Study on the Changes of Chemical Constituents in Different Compatibilities of Ginseng-Prepared Rehmannia Root and Their Effects on Bone Marrow Inhibition after Chemotherapy.

Ginseng (G) and Prepared Rehmannia Root (PRR) are commonly used in traditional Chinese medicine for blood supplementation. This study aimed to study G and PRR with different compatibility ratios changes in chemical composition and inhibition of cyclophosphamide-induced myelosuppression. HPLC was used to determine the chemical constituents of 13 ginsenosides, 5-hydroxymethylfurfural (5-HMF) and verbascoside in different proportions of G-PRR. Balb/c mice were injected intraperitoneally with cyclophosphamide (CTX) to induce bone marrow suppression. The effects of different proportions of G-PRR on peripheral blood, bone marrow nucleated cells, thymus and spleen index of myelosuppressed mice were analyzed. The results showed that the compatibility of G and PRR can promote the dissolution of ginsenosides, and the content of conventional ginsenosides decreased, and the content of rare ginsenosides increased. Different proportions of G-PRR increased the number of peripheral blood and bone marrow nucleated cells in cyclophosphamide-induced bone marrow suppression mice (p < 0.01), increased thymus index (p < 0.01), decreased spleen index (p < 0.01). Different proportions of G-PRR can improve the myelosuppression induced by cyclophosphamide in mice, and the combined effect of G-PRR is better than the single decoction of G and PRR. Among them, G-PRR 2 : 3 and G-PRR 1 : 2 were better than the other groups. These results indicate that different proportion of G-PRR can improve bone marrow suppression, and the combined decoction of G-PRR is better than the separate Decoction in improving bone marrow suppression. This improvement may be related to the changes of the substance basis and active ingredients of G-PRR.

Combination of cyclophosphamide and shengbai decoction has synergistic effect against melanoma.

Shengbai decoction (SBD), a famous Chinese herbal prescription, has been used for treatment of leukopenia for decades in China. In this study, its synergistic antitumor effect in combination with cyclophosphamide (CTX) on melanoma-bearing mice was investigated. A total of forty C57BL/6 male mice successfully modeled (6-8 weeks old, 18-22 g) were randomly divided into 4 groups (n = 10): 1) the model group, 2) the CTX group, 3) the low dose of SBD (10.66 g/kg/d, raw medicine) and CTX group, and 4) the high dose of SBD (31.98 g/kg/d, raw medicine) and CTX group. Melanoma mice models were established by injection of 0.1 mL of melanoma cell suspension under the midline of the back of each C57BL/6 mouse. Treatment started five days after modeling. The results showed that SBD significantly alleviated histopathological damage, and reduced tumor growth and the concentrations of IL-6, IFN-γ and TNF-α in serum. Furthermore, the combined therapy increased the positive expression of NF-κB and promoted apoptosis compared with CTX alone. These results indicated that SBD could improve the antitumor effect of CTX on melanoma in vivo. And this combination treatment may be an ideal therapy against melanoma.

Core­shell type thermo­nanoparticles loaded with temozolomide combined with photothermal therapy in melanoma cells.

A novel core­shell type thermo­nanoparticle (CSTNP) co­loaded with temozolomide (TMZ) and the fluorescein new indocyanine green dye IR820 (termed IT­CSTNPs) was designed and combined with a near­infrared (NIR) laser to realize its photothermal conversion. The IT­CSTNPs were prepared using a two­step synthesis method and comprised a thermosensitive shell and a biodegradable core. IR820 and TMZ were entrapped in the shell and the core, respectively. Dynamic light scattering results demonstrated that the average hydrodynamic size of the IT­CSTNPs was 196.4±3.1 nm with a ζ potential of ­24.9±1.3 mV. The encapsulation efficiencies of TMZ and IR820 were 6.1 and 16.6%, respectively. Temperature increase curves under NIR laser irradiation indicated that the IT­CSTNPs exhibited the desired photothermal conversion efficiency. The in vitro drug release curves revealed a suitable release capability of IT­CSTNP under physiological conditions, whereas NIR laser irradiation accelerated the drug release. Inverted fluorescence microscopy and flow cytometry results revealed that the uptake of IT­CSTNPs by A375 melanoma cells occurred in a concentration­dependent manner. Confocal laser scanning microscopy results indicated that IT­CSTNPs entered tumour cells via endocytosis and were located in intercellular lysosomes. In summary, the present study explored the photothermal conversion capability, cellular uptake, and intracellular localization of IT­CSTNPs.

[Pharmaceutical consultations in oncology: Implementation, one-year review and outlooks]. / Consultations pharmaceutiques en oncologie : mise en place, bilan à un an et perspectives.

OBJECTIVES: The oral route is becoming increasingly important in the panel of anti-cancer therapeutics, but it generates difficulties (adherence, management of adverse effects...). In order to secure medication management, the pharmaceutic team chose to set up pharmaceutical consultations. Its objectives are multiple: understanding of treatment for better adherence, pharmaceutical analysis, enhancement of the city-hospital link. This work presents the setting up of the pharmaceutical consultations and makes an assessment after one year. METHODS: The initial step was a meeting with institutional health professionals who work with patients to define the place, the objectives, and the patients targeted by the pharmaceutical consultation. The targeted patients are all patients receiving temozolomide and some patients initiating oral chemotherapy, considered at risk, on medical solicitation. Documents were created to standardize practices in the team from the collection of information and pharmaceutical analysis until the conduct of the consultation and the consultation report (integrated into the computerized patient's medical file). Activity indicators were defined and collected. RESULTS: Over one year, 65 pharmaceutical consultations were conducted, of which 23 % resulted in pharmaceutical interventions. The average duration of consultation was 34minutes. The whole team (four pharmacists and two residents) was involved in this activity. CONCLUSIONS: Pharmaceutical consultations help secure medical care of patients, providing tools, dedicated and personalized time, pharmaceutical analysis, etc. Ultimately, the goal is to accompany the patient throughout his treatment by having follow-up pharmaceutical consultations, in collaboration with community pharmacists thanks to the city-hospital link that we have established.

Target therapy versus dacarbazine in first-line treatment of advanced non-surgical and metastatic melanoma: budget impact analysis from the perspective of the Brazilian National Health System, 2018-2020. / Terapia-alvo versus dacarbazina no tratamento de primeira linha do melanoma avançado não cirúrgico e metastático: análise de impacto orçamentário na perspectiva do Sistema Único de Saúde, 2018-2020.

OBJECTIVE: to estimate the incremental budget impact of target therapy for first-line treatment of advanced non-surgical and metastatic melanoma compared to dacarbazine treatment. METHODS: budget impact analysis, from the Brazilian National Health System (SUS) perspective; based on demographic data and incidence estimates, the population over a three-year time horizon (2018-2020) was delimited and the direct medical costs were estimated; the reference scenario was treatment with dacarbazine, and the alternative scenarios were target therapy with vemurafenib, dabrafenib, vemurafenib + cobimetinib and dabrafenib + trametinib; uncertainty assessment was conducted through scenario analysis. RESULTS: the incremental budget impact ranged from R$ 451,867,881.00 to R$ 768,860,968.00, representing 0.70 to 1.53% of total SUS annual outpatient drugs expenditure; in best and worst scenario, results ranged from R$ 289,160,835.00 to R$ 1,107,081,926.00. CONCLUSION: the use of target therapy compared to dacarbazine implies an excessive impact on the budget, this bring unfovorable to its possible incorporation.

Micronized, Heat-Treated Lactobacillus plantarum LM1004 Alleviates Cyclophosphamide-Induced Immune Suppression.

The present study investigated the immunomodulatory activity and associated mechanisms of heat-treated Lactobacillus plantarum LM1004 (HT-LM1004) in a cyclophosphamide (CTX)-induced mouse model of immunosuppression. HT-LM1004 induced phagocytic activity and nitric oxide production in RAW264.7 macrophages and stimulated the release of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, and IL-12p70. In mice with CTX-induced immunosuppression, oral HT-LM1004 administration restored thymus and spleen indices, including spleen weight. Consistent with the in vitro results, HT-LM1004 increased TNF-α, IFN-γ, IL-2, and IL-12p70 levels in mice after 14 days of treatment and enhanced the natural killer (NK) cell activity of splenocytes from mice with CTX-induced immunosuppression against YAC-1 lymphoma cells. The method of HT-LM1004 generation influenced this activity: L. plantarum LM1004 grown in a membrane bioreactor, which reduced the size of the cells to <1.0 µm through physical stress (micronization), promoted NK cell cytotoxicity to a greater extent than LM1004 subjected to heat treatment alone. These findings indicate that HT-LM1004 without or with micronization can reverse CTX-induced immunosuppression without adverse side effects by potentiating NK cell function.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei in a liver-transplanted patient: a case report.

BACKGROUND: Diagnostic work-ups in transplanted immunosuppressed patients are a challenge as non-specific findings may be interpreted as transplant-related complications. If the disease in question is rare and slowly developing like pseudomyxoma peritonei (PMP), it is even more difficult. Cytoreductive surgery (CRS) and subsequent hyperthermic intraperitoneal chemotherapy (HIPEC) is the recommended treatment for PMP even with extensive peritoneal spread. CRS-HIPEC for PMP after liver transplantation (LTX) has not been described before. CASE PRESENTATION: A 48-year-old female patient with end-stage primary sclerosing cholangitis (PSC) underwent orthotopic LTX and subsequent pancreaticoduodenectomy after the finding of cholangiocarcinoma in situ in the native common bile duct. Ten years after the transplantation, she developed symptoms and signs suspected to represent graft-related complications. An extensive work-up revealed PMP. Upon reassessment, a cystic mass near the coecum could be seen on computed tomography scan 1 year after transplantation. The multidisiplinary team was hesitant to accept the patient for CRS-HIPEC because of extensive PMP and possible risk to the graft. However, she was eventually accepted and underwent the procedure. The Peritoneal Cancer Index (PCI) was 28 of 39, and surgical debulking was performed followed by HIPEC. The transplant control 2 months after surgery showed no harm to the graft. CONCLUSIONS: Previous LTX should not exclude the possibility for CRS-HIPEC in PMP, even with extensive burden of disease.

Triptolide enhances chemotherapeutic efficacy of antitumor drugs in non-small-cell lung cancer cells by inhibiting Nrf2-ARE activity.

Non-small cell lung cancer (NSCLC) has a high mortality rate worldwide. Various treatments strategies have been used against NSCLC including individualized chemotherapies, but innate or acquired cancer cell drug resistance remains a major obstacle. Recent studies revealed that the Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway is intimately involved in cancer progression and chemoresistance. Thus, antagonizing Nrf2 would seem to be a viable strategy in cancer therapy. In the present study a traditional Chinese medicine, triptolide, was identified that markedly inhibited expression and transcriptional activity of Nrf2 in various cancer cells, including NSCLC and liver cancer cells. Consequently, triptolide made cancer cells more chemosensitivity toward antitumor drugs both in vitro and in a xenograft tumor model system using lung carcinoma cells. These results suggest that triptolide blocks chemoresistance in cancer cells by targeting the Nrf2 pathway. Triptolide should be further investigated in clinical cancer trials.

Sorafenib improves alkylating therapy by blocking induced inflammation, invasion and angiogenesis in breast cancer cells.

Molecular targeted compounds are emerging as a strategy to improve classical chemotherapy. Herein, we describe that using low dose of the multikinase inhibitor sorafenib improves cyclophosphamide antitumor activity by inhibiting angiogenesis, metastasis and promoting tumor healing in MDA-MB231 xenografts and the 4T1-12B syngeneic breast cancer metastasis model. Mechanistic studies in MDA-MB231 cells revealed that alkylation upregulates inflammatory genes/proteins such as COX-2, IL8, CXCL2 and MMP1 in a MEK1/2-ERK1/2-dependent manner. These proteins enrich the secretome of cancer cells, stimulating cell invasion and angiogenesis via autocrine and paracrine mechanisms. Sorafenib inhibits MEK1/2-ERK1/2 pathway thereby decreasing inflammatory genes and mitigating cell invasion and angiogenesis at basal and alkylation-induced conditions whereas NRF2 and ER stress pathways involved in alkylation survival are not affected. In non-invasive/non-angiogenic breast cancer cells (SKBR3 and MCF7), alkylation did not elicit inflammatory responses with the only sorafenib effect being ERK1/2-independent ROS-dependent cytotoxicity when using higher drug concentrations. In summary, our data show that alkylating agents may elicit inflammatory responses that seems to contribute to malignant progression in specific breast cancer cells. Identifying and targeting drivers of this phenotype may offer opportunities to optimize combined drug regimens between classical chemotherapeutics and targeted agents.

[Short-term efficacy of intravitreal injection of melphalan for refractory vitreous seeding from retinoblastoma].

Objective: To evaluate the efficacy and safety of intravitreal chemotherapy for refractory vitreous seeding from retinoblastoma. Methods: Retrospective series of case studies. Nine patients (13 eyes) with the diagnosis of refractory vitreous seeding were enrolled in Department of Ophthalmology of Eye& ENT Hospital of Fudan University from March 2014 to October 2015.There were 6 males and 3 females. Children aged 8 to 40 months, median age of 18 months. In the 13 eyes, 3 eyes were E period, 9 eyes were D period, and 1 eyes were C period. The fundus was examined by indirect ophthalmoscope and recorded by RetcamIII. Systemic chemotherapy was performed using the VEC protocol, that is vincristine, etoposide, and carboplatin. Local treatment also involves cryotherapy and/or thermotherapy. All patients were treated with intravitreal injection of melphalan. They underwent intravitreal melphalan, once every 4 weeks, with an average of 3 times of injections. The treatment dose of melphalan is 20 to 40 µg per dose. Observe the vitreous seed control and complications of therapy. Results: Vitreous seeds control was attained in all cases. There was no case of orbital extension or remote metastasis. Complications included retinal pigment epithelial and choroidal atrophy in 7 eyes, pupillary synechia and iris atrophy in 2 eyes,retinal vasculitis and vascular occlusion in 2 eyes, optic atrophy in 2 eyes, vitreous hemorrhage in 1 eye, and temporary hypotony in 3 eyes. Conclusions: Intravitreal melphalan is an effective treatment for refractory vitreous seeding from retinoblastoma. High dose may lead to local adverse reactions. (Chin J Ophthalmol, 2017, 53: 570-574).

Peritoneal metastases from adrenal cortical carcinoma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

PURPOSE: Adrenal cortical carcinoma is a rare cancer that often presents in an advanced stage. Not only systemic metastases but also local recurrence and peritoneal metastases prevent long-term survival in these patients. METHODS: A profoundly symptomatic patient with extensive peritoneal metastases and local recurrence was treated using cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with melphalan as the chemotherapy agent. RESULTS: Relative sparing of the small bowel within the abdomen and pelvis allowed a visible complete resection of all cancer. The HIPEC with melphalan was used to control microscopic residual disease. Similar surgical technology used in this patient could be used to prevent local recurrence and peritoneal metastases in patients at the time of resection of the primary adrenal cortical carcinoma. CONCLUSIONS: Rare diseases may have peritoneal metastases as a component of disease progression and profit from treatment with CRS plus HIPEC. The clinical features suggesting a favorable outcome from this combined treatment are relative sparing of small bowel and its mesentery, absence of disease outside the abdomen, low-grade disease, or limited extent of high-grade disease.

Soy-Based Multiple Amino Acid Oral Supplementation Increases the Anti-Sarcoma Effect of Cyclophosphamide.

The use of a mixture of amino acids caused a selective apoptosis induction against a variety of tumor cell lines, reduced the adverse effects of anti-cancer drugs and increased the sensitivity of tumor cells to chemotherapeutic agents. We evaluated the effects and underlying mechanisms of soy-derived multiple amino acids' oral supplementation on the therapeutic efficacy of low-dose cyclophosphamide (CTX) and on tumor growth, apoptosis, and autophagy in severe combined immunodeficiency (SCID) mice that were injected with sarcoma-180 (S-180) cells. 3-methyladenine or siRNA knockdown of Atg5 was used to evaluate its effect on sarcoma growth. A comparison of mice with implanted sarcoma cells, CTX, and oral saline and mice with implanted sarcoma cells, CTX, and an oral soy-derived multiple amino acid supplement indicated that the soy-derived multiple amino acid supplement significantly decreased overall sarcoma growth, increased the Bax/Bcl-2 ratio, caspase 3 expression, and apoptosis, and depressed LC3 II-mediated autophagy. Treatment with 3-methyladenine or Atg5 siRNA elicited similar responses as CTX plus soy-derived multiple amino acid in downregulating autophagy and upregulating apoptosis. A low dose of CTX combined with an oral soy-derived multiple amino acid supplement had a potent anti-tumor effect mediated through downregulation of autophagy and upregulation of apoptosis.

Additive antiangiogenesis effect of ginsenoside Rg3 with low-dose metronomic temozolomide on rat glioma cells both in vivo and in vitro.

BACKGROUND: Glioblastoma is the most common and deadly primary brain tumor in adults. Low-dose,metronomic (LDM) temozolomide (TMZ) displays improved efficacy in the treatment of glioblastoma by targeting angiogenesis, but has a limited effect on recurrence. The antiangiogenesis drug ginsenoside Rg3 (RG3) is the main active ingredient of ginseng, a popular herbal medicine. METHODS: Using an in vitro and a rat model of an orthotopic glioma allograft, this study was to determine whether RG3 enhanced the antiangiogenesis activity of LDM TMZ in the treatment of glioblastoma. RESULTS: Our results showed that combined use of TMZ with RG3 displayed additive inhibition on proliferation of both human umbilical vein endothelial cells (HUVEC) and rat C6 glioma cells in vitro. They additively arrested cell cycle, increased apoptosis, and decreased VEGF-A and BCL-2 expression in HUVEC. Antiangiogenesis effect was also evaluated in the rat model of orthotopic glioma allograft, based upon markers including relative cerebral blood volume (rCBV) by magnetic resonance imaging (MRI), VEGF levels and microvessel density (MVD)/CD34 staining. LDM TMZ alone was potent in suppressing angiogenesis and tumor growth, whereas RG3 alone only had modest antiangiogenesis effects. Combined treatment significantly and additively suppressed angiogenesis, without additive inhibitory effects on allografted tumor growth. CONCLUSIONS: These data provide evidence showing the efficacy of LDM TMZ on glioma treatment. The combined additive antiangiogenesis effect suggests that RG3 has the potential to further increase the efficacy of LDM TMZ in the treatment of glioblastoma.

Low dose cyclophosphamide: Mechanisms of T cell modulation.

Cyclophosphamide is considered one of the most successful chemotherapy drugs and is listed on the World Health Organisations List of Essential Medicines. Since its initial synthesis in 1958, it has been widely used to treat a range of cancers but its use has been declining due to the advent of platinum based and other chemotherapy agents. However, cyclophosphamide is still used either as a single agent or as adjuvant therapy to treat lymphomas, and breast and ovarian cancers at much lower doses. The efficacy of low dose cyclophosphamide is primarily due to its ability to promote anti-tumour immunity, by selectively depleting regulatory T cells and enhancing effector T cell function. Compared to effecter T cells, regulatory T cells have metabolic adaptations that make them more susceptible to cyclophosphamide-mediated cytotoxicity. In this review, we highlight the potential for improving the efficacy of low dose cyclophosphamide by combining insights on the mechanisms of cyclophosphamide-mediated cytotoxicity, and how these cytotoxic effects of cyclophosphamide influence T cell function, thereby contributing to anti-tumour immunity.

Both heat and new chemotherapeutic drug dioxadet in hyperthermic intraperitoneal chemoperfusion improved survival in rat ovarian cancer model.

BACKGROUND AND OBJECTIVES: Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the time of Cytoreductive Surgery (CRS) is an actively researched treatment in patients with advanced ovarian cancer. Relative contribution of heat and chemotherapeutic agents during HIPEC as well as efficacy of a new agent dioxadet for regional chemotherapy in a rat model of ovarian cancer was studied. METHODS: Sixty rats were divided into three groups: no treatment control group (n = 19), hyperthermia without chemotherapy (HIPEP) (n = 14), HIPEC + cisplatin (n = 14), HIPEC + dioxadet (n = 13). The intra-abdominal tumor was not resected. End points were: median survival (primary), cause of death (secondary). RESULTS: The median survival of the animals in the control group, HIPEP group, HIPEC + cisplatin, HIPEC + dioxadet were 9 (CI; 8-23), 22.5 (CI; 12-43), 25.5 (CI; 13-62), 49 (Cl; 28-70) days, respectively. The P-values control versus HIPEP, HIPEC + cisplatin versus HIPEC + dioxadet were 0.006, 0.002, and 0.001, respectively. CONCLUSION: During HIPEC both the heat and the cytotoxic drug had antitumor effects in a rat ovarian cancer model. Dioxadet showed potential as a drug for regional chemotherapy. J. Surg. Oncol. 2016;113:438-442. © 2015 Wiley Periodicals, Inc.

Protective effect of combined pumpkin seed and ginger extracts on sperm characteristics, biochemical parameters and epididymal histology in adult male rats treated with cyclophosphamide.

Reproductive toxicity is one of the side effects of cyclophosphamide (CP) in cancer treatment. Pumpkin seeds and Zingiber officinale are natural sources of antioxidants. We investigated the possible protective effect of combined pumpkin seed and Zingiber officinale extracts on sperm characteristics, epididymal histology and biochemical parameters of CP-treated rats. Male adult Wistar rats were divided randomly into six groups. Group 1, as a control, received an isotonic saline solution injection intraperitoneally (IP). Group 2 were injected IP with a single dose of CP (100 mg/kg) once. Groups 3 and 4 received CP plus 300 and 600 mg/kg combined pumpkin seed and Zingiber officinale extract (50:50). Groups 5 and 6 received only 300 and 600 mg/kg combined pumpkin seed and Zingiber officinale extract. Six weeks after treatment, sperm characteristics, histopathological changes and biochemical parameters were assessed. In CP-treated rats, motile spermatozoa were decreased, and abnormal or dead spermatozoa increased significantly (P < 0.001) but administration of the mixed extract improved sperm parameters. Epididymal epithelium and fibromascular thickness were also improved in extract-treated rats compared to control or CP groups. Biochemical analysis showed that the administration of combined extracts could increase the total antioxidant capacity (TAC) level significantly in groups 3, 4, 5 and 6. Interestingly, the mixed extract could decrease most of the side effects of CP such as vacuolization and separation of epididymal tissue. Our findings indicated that the combined extracts might be used as a protective agent against CP-induced reproductive toxicity.

TNF-alpha and melphalan-based isolated limb perfusion: no evidence supporting the early destruction of tumour vasculature.

BACKGROUND: Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a highly effective treatment for locally advanced tumours of the extremities. Previous research suggests an almost immediate disintegration of the blood supply of the tumour. The aim of the present study was to verify this hypothesis using non-invasive measurements of microvascular perfusion and tissue oxygenation. METHODS: A total of 11 patients were included in the study. TM-ILP was performed under mildly hyperthermic conditions (39 °C) in the extremities via proximal vascular access. Capillary-venous microvascular blood flow, haemoglobin level (Hb) and oxygen saturation (SO2) were determined using laser Doppler and white-light spectroscopy, respectively, before TM-ILP and at 30 min, 4 h, 1 day, 4 days, 1 week, 2 weeks and 6 weeks after TM-ILP from tumour and healthy muscle tissues. RESULTS: Blood flow and Hb were mostly higher, whereas SO2 was lower, in tumour tissue compared with muscle tissue. In both tumour and muscle tissues, blood flow significantly increased immediately after TM-ILP and remained elevated for at least 2 weeks, followed by a return to the initial values 6 weeks after the procedure. CONCLUSION: No signs were found of early destruction of the tumour vasculature. The observations suggest that an inflammatory reaction is one of the key elements of TM-ILP.