An atypical presentation of diffuse midline pontine glioma in a middle age patient: Case report.

INTRODUCTION: Diffuse midline glioma is a newly WHO defined entity (grade IV) (Louis et al., 2016) which includes diffuse intrinsic pontine glioma (DIPG) reported in pediatric population and, occasionally, in young adults. Here, we present a detailed description of an atypical case of diffuse midline glioma in a 53 years old woman. CASE REPORT: A caucasian woman aged 53 from Ukraine, was referred to another neurological department complaining of 3 months history of progressive postural instability and gait impairment with frequent falling. Magnetic resonance demonstrated two brainstem lesions, hyperintense in FLAIR with "patchy" peripheral enhancement, leptomeningeal and cranial nerves enhancement. CSF was normal. Due to positive antinuclear antibodies test (ANA 1:360), intravenous steroid treatment was administered and reported to initially improve the patient condition. However, the following weeks the lady worsened. Imaging features were unchanged. Because quantiferon test resulted positive, MRI-Spectroscopy showed an inflammatory pattern and MRI perfusion study and brain FDG-PET, were normal, tubercolar granulomatous hypothesis was initially favored. Antitubercular therapy with isoniazid, pyrazinamide, ethambutol and rifampicin was started without any clinical improvement. Hence, the biopsy was proposed. The procedure revealed a diffuse midline pontine glioma. Considering the advanced stage of the disease, radiotherapy was not indicated. Patient died after eight months from the onset of neurological disturbances. CONCLUSION: Our case shows that diffuse midline glioma is a CNS tumor not limited to young population but occurring also in middle aged patients with an insidious pattern. We therefore recommend to perform biopsy at very early stages in patients with atypical brainstem lesions.

[Adult-Onset Still's Disease, an improbable differential diagnosis: a case report]. / Malattia di Still dell'adulto, un'improbabile diagnosi differenziale: caso clinico

Juvenile idiopathic arthritides (JIA) comprehend a heterogeneous group of inflammatory diseases of the joints, with an unknown aetiology, arising within 16 years of age, and lasting more than six weeks. The systemic form, known as Still's disease, represents from 4 to 17% of all the JIA. AOSD (Adult Onset Still's Disease) is a variant of JIA affecting adults, with identical clinical manifestations. Here we describe the case of a 36 year old woman, with a symptomatology characterized by fever, skin rash, arthralgies and lymphadenopathy. The arise of the fever in this case has uncommonly preceded by several weeks the arise of the other signs; this has determined a considerable delay in the diagnosis: Still's disease diagnosis is made hard as it shares its signs and symptoms with several infectious, immunological as well as tumoral diseases. In this case, the blossoming of the laboratory parameters at the sixth day of hospitalization with leucocytosis and neutrophilia represented the solving clue. Still's disease, though a rare nosographic entity, must be kept into consideration in unclear cases occurring in an internal medicine department.

SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells.

Melanoma is one of the most aggressive types of human cancer, characterized by enhanced heterogeneity and resistance to conventional therapy at advanced stages. We and others have previously shown that HEDGEHOG-GLI (HH-GLI) signaling is required for melanoma growth and for survival and expansion of melanoma-initiating cells (MICs). Recent reports indicate that HH-GLI signaling regulates a set of genes typically expressed in embryonic stem cells, including SOX2 (sex-determining region Y (SRY)-Box2). Here we address the function of SOX2 in human melanomas and MICs and its interaction with HH-GLI signaling. We find that SOX2 is highly expressed in melanoma stem cells. Knockdown of SOX2 sharply decreases self-renewal in melanoma spheres and in putative melanoma stem cells with high aldehyde dehydrogenase activity (ALDH(high)). Conversely, ectopic expression of SOX2 in melanoma cells enhances their self-renewal in vitro. SOX2 silencing also inhibits cell growth and induces apoptosis in melanoma cells. In addition, depletion of SOX2 progressively abrogates tumor growth and leads to a significant decrease in tumor-initiating capability of ALDH(high) MICs upon xenotransplantation, suggesting that SOX2 is required for tumor initiation and for continuous tumor growth. We show that SOX2 is regulated by HH signaling and that the transcription factors GLI1 and GLI2, the downstream effectors of HH-GLI signaling, bind to the proximal promoter region of SOX2 in primary melanoma cells. In functional studies, we find that SOX2 function is required for HH-induced melanoma cell growth and MIC self-renewal in vitro. Thus SOX2 is a critical factor for self-renewal and tumorigenicity of MICs and an important mediator of HH-GLI signaling in melanoma. These findings could provide the basis for novel therapeutic strategies based on the inhibition of SOX2 for the treatment of a subset of human melanomas.

Antiangiogenic therapy inhibits the recruitment of vascular accessory cells to the perivascular niche in glioma angiogenesis.

OBJECTIVE: Antiangiogenic therapies could be limited by various escape mechanisms including bone marrow-derived myeloid cell-induced vasculogenesis. The recruitment of vascular accessory cells (VACs) to the tumor neovasculature is as a multistep process. However, the recruitment process of these cells during antiangiogenic treatment remains unknown. The aim of our study was to characterize the recruitment of VACs during antiangiogenic therapy using sunitinib. METHODS: C6 glioma cells were implanted into dorsal skinfold chambers. Animals received antiangiogenic therapy intraperitoneally for 5 days prior to VAC application intra-arterially. Intravital microscopy was performed during VAC injection and 1 and 48 h after injection. Analyses included total (TVD) and functional vessel densities (FVD), the perfusion index (PI), microvascular permeability, blood flow rate (Q), microvascular diameter (D), red blood cell velocity (RBCV), wall shear rate (γ), wall shear stress (τ), first and firm adhesions of VACs, and accumulation in the perivascular niche. RESULTS: Antiangiogenic therapy resulted in a significant reduction in TVD (365 ± 47 cm/cm(2) vs. 183 ± 37 cm/cm(2)) and FVD (227 ± 65 cm/cm(2) vs. 147 ± 25 cm/cm(2)) and an increase in PI, Q, D, and RBCV. γ and τ remained unaltered. Initial adhesion and firm adhesion were unaffected by antiangiogenic therapy; however, the accumulation in the perivascular niche was significantly diminished in treated tumors (53.7 ± 8% vs. 24.0 ± 17%). CONCLUSIONS: Antiangiogenic treatment inhibits the accumulation of VACs in the perivascular niche and therefore interferes with consecutive neovascularization.

WIP1 phosphatase modulates the Hedgehog signaling by enhancing GLI1 function.

The Hedgehog-GLI (HH-GLI) signaling plays a critical role in controlling growth and tissue patterning during embryogenesis and is implicated in a variety of human malignancies, including those of the skin. Phosphorylation events have been shown to regulate the activity of the GLI transcription factors, the final effectors of the HH-GLI signaling pathway. Here, we show that WIP1 (or PPM1D), an oncogenic phosphatase amplified/overexpressed in several types of human cancer, is a positive modulator of the HH signaling. Mechanistically, WIP1 enhances the function of GLI1 by increasing its transcriptional activity, nuclear localization and protein stability, but not of GLI2 nor GLI3. We also find that WIP1 and GLI1 are in a complex. Modulation of the transcriptional activity of GLI1 by WIP1 depends on the latter's phosphatase activity and, remarkably, does not require p53, a known WIP1 target. Functionally, we find that WIP1 is required for melanoma and breast cancer cell proliferation and self-renewal in vitro and melanoma xenograft growth induced by activation of the HH signaling. Pharmacological blockade of the HH pathway with the SMOOTHENED antagonist cyclopamine acts synergistically with inhibition of WIP1 in reducing growth of melanoma and breast cancer cells in vitro. Overall, our data uncover a role for WIP1 in modulating the activity of GLI1 and in sustaining cancer cell growth and cancer stem cell self-renewal induced by activation of the HH pathway. These findings open a novel therapeutic approach for human melanomas and, possibly, other cancer types expressing WIP1 and with activated HH pathway.

[Atypical onset cryoglobulinemia: case report]. / Crioglobulinemia ad esordio atipico: caso clinico.

Cryoglobulinemia is a disease mediated by antibodies with the property to precipitate at temperatures below 37°C. It can be distinguished into a primitive form (also referred to as 'essential mixed cryoglobulinemia'), and a secondary form. In the essential mixed variant a key role is played by HCV infection. The pathogenesis of mixed cryoglobulinemia is mediated by immune complexes that are the most important cause of the vasculitic phenomena, typical of the disease. However, the severity of the clinical manifestations is not always related to the serum levels of cryoglobulins and immune complexes. In our case report, a 46-year old man came to our observation with asymmetric diffuse and invalidating arthralgies, with both substitutive and additive behaviour, located at pelvic girdle, inferior limbs and elbows, associated to skin lesion vascultis-like. The remote pathological anamnesis was characterized by a previous surgically treated non-Hodgkin lymphoma, and HCV infection. Despite several attempts were done, it was not possible to reveal cryoglobulins, nor reumatoid factor in the serum. Cryoglobulins resulted positive only after the third day of hospitalization, along with a new fever attack and a worsening of the vasculitic manifestations. In conclusion, this case demonstrated that cryoglobulinemia can occur with a totally atypical sequence of clinical manifestations which can be present before and in absence of the typical laboratory proofs.

Heterogeneous expression of cyclooxygenase-2 and inducible nitric oxide synthase within colorectal tumors: correlation with tumor angiogenesis.

BACKGROUND: Recent studies have shown that the cyclooxygenase (COX) and the inducible nitric oxide synthase (iNOS) pathways are involved in the development of tumor angiogenesis in human cancers. AIMS: To investigate whether a different pattern of COX-2 and iNOS expression/activity exists within different areas of colorectal tumors and to analyze the relationship between these two enzymes and tumor angiogenesis. METHODS: Microvessel density (MVD) and COX-2, iNOS, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein expression were evaluated at both the invasive front (IF) and the tumor center (TC) in 46 human colorectal cancer specimens. We also investigated the concentration of PGE2 and NO at the same sites. RESULTS: COX-2 and iNOS protein expression and activity were significantly higher within the IF than the TC of the tumor specimens. Similarly, MVD and VEGF/VEGFR-2 expression significantly increased from the TC to the IF. Only COX-2 expression was significantly correlated with MVD and VEGF/VEGFR-2 expression at both the TC and the IF. CONCLUSION: Our study shows a heterogeneous expression of COX-2 and iNOS in colorectal cancer. The up-regulation of COX-2 at the IF parallels an increase in vessel density and VEGF/VEGFR-2 expression, thus supporting the hypothesis that the tumor periphery is the most aggressive portion of a colorectal tumor.

Biventricular pacing concomitant to on-pump heart surgery: a case series.

AIM: The aim of this paper was to report the authors' experience on biventricular epicardial pacing (BEP) as first-choice procedure concomitant to on-pump heart surgery for other definite indications. METHODS: BEP was performed in 13 consecutive patients with stage IV heart failure (HF) undergoing on-pump cardiac surgery for other definite indications. All patients were treated with optimized pharmacologic therapy, and showed complete left bundle branch block and reduced (<30%) left ventricular ejection fraction. RESULTS: In all patients, effective BEP was achieved. All patients were discharged alive; functional, ECG and echocardiographic parameters showed significant improvement, better observed at 4-month interval. However, a high mortality rate was noticed during follow up (about 70% at 6 months) with a significant number of sudden cardiac deaths. The absence of functional improvement in the mid-term period (4-month control) related to a poor prognosis. CONCLUSIONS: Epicardial lead placement during cardiac surgery of severe HF patients is safe and effective. A clear evaluation of the effect of BEP alone is precluded because of the interference of the concomitant indications for cardiac surgery and the absence of randomization. The high rate of sudden death noticed in this study raises the important question of whether implantation of a defibrillator would be warranted in such population.

Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation.

The effective treatment of pain is typically limited by a decrease in the pain-relieving action of morphine that follows its chronic administration (tolerance). Therefore, restoring opioid efficacy is of great clinical importance. In a murine model of opioid antinociceptive tolerance, repeated administration of morphine significantly stimulated the enzymatic activities of spinal cord serine palmitoyltransferase, ceramide synthase, and acid sphingomyelinase (enzymes involved in the de novo and sphingomyelinase pathways of ceramide biosynthesis, respectively) and led to peroxynitrite-derive nitroxidative stress and neuroimmune activation [activation of spinal glial cells and increase formation of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6]. Inhibition of ceramide biosynthesis with various pharmacological inhibitors significantly attenuated the increase in spinal ceramide production, nitroxidative stress, and neuroimmune activation. These events culminated in a significant inhibition of the development of morphine antinociceptive tolerance at doses devoid of behavioral side effects. Our findings implicate ceramide as a key upstream signaling molecule in the development of morphine antinociceptive tolerance and provide the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain.

Weekly paclitaxel for advanced aggressive classic Kaposi sarcoma: experience in 17 cases.

BACKGROUND: Paclitaxel has proved to be highly effective in the treatment of severe AIDS-related Kaposi sarcoma (KS), for which it is now considered as a second-line monotherapy. Taxanes were recently shown to be active also in classic, endemic and post-transplantation KS. OBJECTIVES: To evaluate the clinical efficacy and tolerability of standardized paclitaxel treatment (100 mg weekly, intravenously) in a homogeneous group of 17 patients with advanced aggressive and refractory classic KS (cKS). METHODS: Seventeen patients with aggressive refractory cKS (stage IIIBc-IVBcv) were treated with intravenous paclitaxel 100 mg weekly. The response to the therapy was evaluated after 12 weeks. A maintenance treatment every 2 weeks was introduced for most of the patients and a final evaluation was made. RESULTS: A partial/complete response was achieved in 14 of 17 patients. Two patients had allergic reactions, for which treatment was discontinued. One patient had progression of disease despite initial improvement. Patients received a mean of 16.8 courses. The treatment was generally well tolerated. Mean time to recurrence was 4.5 months from the end of the therapy and 7.35 months from the 12th course. In four of 10 patients who relapsed at follow-up, the recurrence was mild and responsive to local treatment, while the other six relapsing patients repeated paclitaxel with good response in five of them. CONCLUSIONS: This study shows that low-dose paclitaxel proved to be effective and well tolerated in patients with aggressive refractory cKS, controlling the aggressiveness of the disease. The treatment can be repeated with good response.

Combination of vinblastine and bleomycin as first line therapy in advanced classic Kaposi's sarcoma.

BACKGROUND: Classic KS (CKS) mainly affects elderly people, has an irregular course, and is relatively benign for years. However, sometimes the disease may progress rapidly and spread to internal organs, thus necessitating systemic chemotherapy. We therefore decided to carry out a prospective trial using vinblastine and bleomycin, which are active, easy to administer and control, and low cost. METHODS: We treated 29 patients affected by CKS with vinblastine i.v., up to 10 mg in combination with bleomycin i.m., 15 IU every 3 weeks. We administered a median of seven cycles of therapy. RESULTS: All the 29 enrolled patients were evaluated: 21% reached a complete response and 76% had an intermediate response. Toxicity was limited. The maximal response was attained in a median of 5 months, with a mean duration of 4 months. CONCLUSION: The combination of vinblastine and bleomycin achieved a high rate of objective responses in a subgroup of elderly and symptomatic patients, without considerable toxicity. We recommend the combination as first line chemotherapy for advanced CKS.

Clinical and endoscopic presentation of primary gastric lymphoma: a multicentre study.

BACKGROUND: Although the stomach is the most frequent site of intestinal lymphomas, few data are available on both clinical endoscopic presentation of gastric lymphoma and possible differences between low-grade and high-grade lymphomas. METHODS: Clinical, histological and endoscopic records of consecutive patients with primary low-grade or high-grade lymphoma diagnosed were retrieved. Symptoms were categorized as 'alarm' or 'not alarm'. The endoscopic findings were classified as 'normal' or 'abnormal'. RESULTS: Overall, 144 patients with primary gastric lymphoma were detected, including 74 low-grade and 70 high-grade lymphoma. Alarm symptoms, particularly persistent vomiting and weight loss, were more frequently present in patients with high-grade lymphoma than in those with low-grade lymphoma (54% vs. 28%; P = 0.002). Low-grade lymphomas presented as 'normal' appearing mucosa (20% vs. 0%; P = 0.0004) or petechial haemorrhage in the fundus (9% vs. 0%; P = 0.02) more frequently than high-grade lymphomas, being also more often confined to the antrum (47% vs. 27%, P = 0.03) and associated with Helicobacter pylori infection (88% vs. 52%, P < 0.0001). On the contrary, high-grade lymphomas presented more commonly as ulcerative type (70% vs. 52%; P = 0.03), being also more frequently diagnosed in stage >I when compared with low-grade lymphomas (70% vs. 21%, P < 0.0001). CONCLUSIONS: The overall prevalence of alarm symptoms is quite low and may be absent in more than 70% of patients with low-grade lymphoma.

Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens.

BACKGROUND: Recent data demonstrate that endothelin-1 (ET-1) concentration increases in plasma of men with advanced, hormone-refractory prostate adenocarcinoma. In addition, ET-1 is involved in osteblastic remodelling and new bone formation, suggesting a role for this vasoactive peptide in the metastatic progression of prostate cancer to the bone. METHODS: We investigated the regulation of ET-1 expression in androgen-sensitive and insensitive prostate cancer cell lines by androgens and several factors involved in progression of prostate cancer (EGF) and bone remodelling (TGFbeta-1, IL1-alpha and IGF-1). RESULTS: Northern analysis and radio immunoassay demonstrated that all the ET-1 pathways are tuned off in the androgen-sensitive LNCaP cell line when compared to the androgen-insensitive PC-3 and DU145. In PC-3 cells transfected with a full-length androgen receptor expression vector (PC-3-AR), treatment with androgens reduced gene expression and secretion of ET-1 without affecting the gene expression of ET-3. Collectively, these data support a role for androgens in the regulation of ET-1 production by prostate adenocarcinoma cells. In PC-3 and DU145 cells, ET-1 gene expression and secretion were up-regulated by TGFbeta-1, EGF and IL1-alpha, whereas IGF-1 was ineffective. Conversely, none of the treatments affected ECE-1 or ET-3 gene expression. CONCLUSIONS: In conclusion, ET-1 production by prostate adenocarcinoma cells is down-regulated by androgens and up-regulated by factors involved in tumour progression indicating a role for this peptide in the biology of prostate cancer. In view of the role exerted by ET-1 in the process of bone metastasis, our data suggest the use of ET-1 receptor antagonists in the treatment of advanced prostate cancer.

Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma.

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based immunosuppressive regimen to allow engraftment of HLA-sibling donors' mobilized stem cells and induction of a graft-versus-lymphoma effect for patients with advanced resistant Hodgkin's disease and non-Hodgkin's lymphoma. PATIENTS AND METHODS: Fifteen patients with Hodgkin's disease (n = 10) and non-Hodgkin's lymphoma (n = 5) were studied. All patients received cyclophosphamide and granulocyte colony-stimulating factor to mobilize autologous hematopoietic stem cells (HSCs). Subsequently, they received high-dose therapy with carmustine, etoposide, cytarabine, and melphalan and reinfusion of HSCs. At a median of 61 days after engraftment, patients were given fludarabine 30 mg/m(2) with cyclophosphamide 300 mg/m(2) daily for 3 days. Donor-mobilized HSC collections were prepared for fresh infusion and were not T-cell depleted. Methotrexate and cyclosporine were used to prevent graft rejection and as graft-versus-host disease (GVHD) prophylaxis. RESULTS: Combined treatment was well tolerated. After mini-allografting, hematologic recovery was prompt. Thirteen patients had 100% donor cell engraftment. Eleven patients achieved complete remission (CR) after the combined procedure. Nine patients, who were in partial remission after autografting, achieved CR after mini-allografting. Seven patients developed >/= grade 2 acute GVHD (aGVHD) and two developed extensive chronic GVHD (cGVHD). Three patients who received the highest number of donor lymphocyte infusions (DLIs) developed grade 3 GVHD (two patients) and extensive cGVHD (one patient). Ten patients are currently alive, and five are in continuous CR. Seven patients received DLI, with five CRs. Five patients died: one of progressive disease, two of progressive disease combined with aGVHD or cGVHD, one of extensive cGVHD, and one of infection. CONCLUSION: Fludarabine/cyclophosphamide was well tolerated and allowed consistent engraftment in lymphoma allografted patients. Response rates were high in this group of refractory and heavily pretreated patients. This dual procedure seems to be most promising in patients with end-stage malignant lymphomas.

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a multicentric phase II study.

We have recently reported high clinical activity against advanced colorectal cancer of a regimen-alternating bolus FUra, modulated by methotrexate (MTX), and continuous infusion FUra, modulated by 6-s-leucovorin (6-s-LV). Considering the low toxicity of the bolus part of this regimen and our recent in vitro finding of a strong synergism between bolus FUra and natural-beta-IFN (n-beta-IFN), this cytokine was incorporated in the bolus part of our treatment programme. Fifty-six patients with untreated, advanced, measurable colorectal cancer were treated with two biweekly cycles of FUra bolus (600 mg m(-2)), modulated by MTX (24 h earlier, 200 mg m(-2)), and n-beta-IFN (3 x 10(6) IU i.m. every 12 h, starting at the time of FUra administration for four doses), alternating with a 3-week continuous infusion of FUra (200 mg m(-2) daily), modulated by 6-s-LV (20 mg m(-2) weekly bolus). After a 1-week rest, the whole cycle (8 weeks) was repeated if indicated. A total of 5 complete and 17 partial responses were obtained (response rate, 41%; 95% confidence limits, 28-55%) in 54 assessable patients. After a median follow-up time of 36 months, five patients are still alive. Overall, the median time to treatment failure was 6.4 months. The median duration of survival was 15.0 months. There was one treatment-related death after a course of MTX --> bolus FUra/n-beta-IFN and grade III-IV toxicity occurred in 18% of the patients. As the addition of n-beta-IFN results in high toxicity, whereas the efficacy seems to be similar to that of the same regimen without the cytokine, our groups are currently randomizing the original regimen, without IFN, against standard modulated bolus FUra.

Sequential methotrexate and 5-fluorouracil as second-line chemotherapy for advanced colorectal cancer patients pretreated with 5-fluorouracil and leucovorin: a GISCAD study.

The biochemical modulation of 5-fluorouracil (5-FU) by means of methotrexate (MTX) and 6-S leucovorin (LV) seems mainly directed at two different intracellular targets, supporting the hypothesis of possible non-cross resistance between these two methods of 5-FU potentiation. Thirty-one patients, all previously treated with 5-FU and LV for advanced colorectal cancer (ACC), were treated with MTX = 200 mg/m2 iv day 1 and 5-FU 600 mg/m2 day 2 with 6-S LV 10 mg/m2 po q 6 h X 6 starting 24 h after MTX, repeated every 2 weeks. Of 30 evaluable patients, 2 Partial Remissions (PR) were achieved (Response Rate = 6.6%; 95% Confidence Interval 0%-14%). Eight patients had disease stabilization (SD). The overall median survival was 5 months (range 1-11). No WHO grade III-IV toxicities were reported. Despite the good tolerability, this combination of MTX, 5-FU and LV rescue has minimal activity in ACC after the failure of 5FU+LV-based chemotherapy.

Stages I and II non-Hodgkin's lymphoma of the gastrointestinal tract. Retrospective analysis of 79 patients and review of the literature.

We reviewed the medical records of 79 patients with primary gastrointestinal lymphoma (GI-NHL), defined according to the criteria of Dawson et al. (without involvement of liver, spleen, peripheral or mediastinal lymph nodes, or bone marrow), observed and treated in our institution between 1973-90. The most common disease site was the stomach (70 patients), followed by the small bowel (five patients) and the large bowel (four patients). The stage was IE in 36 cases and IIE in 43. Radical surgery or surgical debulking was the main therapeutic approach (67 patients); 12 patients received only chemotherapy, eight of whom had tumors considered unresectable at laparotomy. After surgery, most of the patients received chemotherapy; radiotherapy (RT) was given to only four patients. Surgically calculated overall survival (OS) rates at 5 years for the patients treated with surgery plus chemotherapy were 64% (radical surgery) and 46% (surgical debulking with microscopic lymphoma residue). For the 12 patients treated with chemotherapy alone, OS at 5 years was 0%. Our findings, in accordance with most published data, suggest that surgery, together with stage and tumor size, remains an important prognostic factor of survival in primary GI-NHL, especially when it is radical. In patients with negative prognostic factors (bulky disease, high-grade histologic type, microscopic residue, and stage II), postoperative chemotherapy and RT decrease the risk of distant failure and local recurrence.

A cisplatinum-cyclophosphamide regimen in advanced ovarian cancer: reporting 5-year results.

The following paper reports the evaluation of 53 consecutive patients with advanced ovarian epithelial carcinoma (FIGO stage III-IV), treated between October 1984 and December 1987 with immediate or delayed cytoreduction surgery and chemotherapy. Combination chemotherapy consisted of cisplatinum 45 mg/m2 i.v. for 2 consecutive days and cyclophosphamide 900 mg/m2 i.v. on the second day, administered every 28 days for a maximum of 8 courses. Objective responses were observed in 35 of 50 evaluable patients (70%), 17 (34%) of whom were pathological complete remissions (pCR). For patients with minimal residual disease before chemotherapy a higher pCR rate was achieved (10/20 vs. 7/30; p = N.S.). Median survival time of all patients was 29 months; subjects with minimal residual disease and good performance status before treatment had higher survival (48 vs. 22 months-p < 0.05 and 29 vs. 9 months-p < 0.05, respectively). Median time to progression was 25 months. After a median follow-up of 60 months, 15 (28%) patients were alive, 14 of whom disease-free. Toxicity was moderate with a particularly low incidence of nephrotoxicity and no case of serious long-lasting neuropathy. These findings suggest that the described combination has an efficacy comparable to other CDDP-containing combinations, using 2, 3 or more drugs, with a low incidence of acute serious toxicities and of disabling delayed sequelae.

A phase II study of combination chemotherapy in advanced ovarian carcinoma with cisplatin and cyclophosphamide plus reduced glutathione as potential protective agent against cisplatin toxicity.

AIMS AND BACKGROUND: The clinical use of cisplatin (CDDP), one of the most active agents in advanced ovarian cancer, is limited by nephrotoxicity and cumulative neurotoxicity. In preclinical studies, reduced glutathione (GSH) demonstrated a protective action against CDDP nephrotoxicity. We treated 20 patients with advanced ovarian carcinoma, with polychemotherapy containing CDDP + GSH, to assess the protective action of GSH against CDDP nephrotoxicity. METHODS: Between January 1988 and December 1989, 20 patients, with advanced ovarian carcinoma (St. III-IV-FIGO), not pretreated received CDDP: 45 mg/m2 i.v., on day 1-2, + cyclophosphamide (CPA): 900 mg/m2 i.v. on day 2 + GSH 2500 mg i.v. in normal saline 100 ml (in 15 min), before CDDP, every 21-28 days. RESULTS: A pathologic complete response rate (PCR) of 55% (11/20) was observed (7/14 patients with bulky disease). Median survival was 26.5 months and 5 patients were still alive and disease free at 35 months. Toxicity was limited, without any case of nephrotoxicity. CONCLUSIONS: On the basis of our previous experience with the same regimen without GSH, this study suggests that also in the clinical setting, GSH has no negative interference on CDDP activity and that GSH might improve the therapeutic index of CDDP. However, our data need to be confirmed by large randomized clinical studies.