levoleucovorin and Necrosis

Recently, bevacizumab has become a key drug for treatment of metastatic colorectal cancer. Molecularly targeted agents such as bevacizumab can cause life-threatening adverse effects, though they are generally considered less toxic than cytotoxic drugs. Here, we review the case of a 76-year-old male rectal cancer patient with liver metastasis who suffered extensive bowel necrosis after administration of 5-fluorouracil-based chemotherapy with bevacizumab, and required a subtotal colectomy and end-ileostomy. Microscopic findings revealed extensive mucosal necrosis in the resected colon specimen and necrosis at the muscularis propria of the descending colon. Pathological findings suggested that the mucosal damage induced by chemotherapy may be exacerbated by treatment with bevacizumab, resulting in extensive necrosis.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colectomy; Colon; Fatal Outcome; Fluorouracil; Humans; Ileostomy; Leucovorin; Liver Neoplasms; Male; Necrosis; Organoplatinum Compounds; Rectal Neoplasms

The prognosis for patients with advanced (stage III and IV) hepatocellular carcinoma (HCC) remains poor. Liver resection and liver transplantation have limited effects on overall survival. Our study was carried out to assess a novel therapeutic approach, which includes transarterial locoregional chemotherapy and in vivo locoregional dual immunostimulation, in patients with unresectable HCC. A group of 20 patients with stage III and IV hepatocellular carcinoma had 10 courses (once per day) of transarterial targeted locoregional immunotherapy with interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), emulsified in a Lipiodol-Urografin mixture. The target organs were the spleen and the liver tumor itself. One course of intrahepatic locoregional targeting transarterial chemotherapy was given 10 days after completion of immunotherapy (mitomycin C, carboplatin, Farmorubicin, Leucovorin, 5-fluorouracil, and IFN-gamma). This was followed after 2 months by another course of transarterial targeted locoregional immunotherapy-chemotherapy. All patients survived the operation and had a mean survival time of 18 months (4-22 months). There was a decrease in the tumor size of 14 of the 20 patients. Serum alpha-fetoprotein (AFP) levels declined in 14 patients, reaching normal levels in 12 patients. These preliminary results indicate that combined locoregional immunotherapy-chemotherapy is a promising therapeutic approach in patients suffering from advanced nonresectable HCC and merits further evaluation.

Topics: Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Interferon-gamma; Interleukin-2; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Mitomycin; Necrosis; Pilot Projects; Spleen; Survival Rate; Tomography, Emission-Computed

Methotrexate-induced epidermal necrosis (MEN) is an uncommon but potentially fatal complication. We present two pediatric oncology patients, a 5-year-old girl and a 3-year-old boy, who developed MEN from high-dose methotrexate therapy for pre-B-cell acute lymphocytic leukemia. Following administration of systemic methotrexate, the patients developed erythematous lesions with subsequent skin erosions. Pre-medication with systemic corticosteroids and administration of folinic acid rescue following the methotrexate infusion allowed both patients to resume their chemotherapy regimen with methotrexate.

Topics: Child; Child, Preschool; Female; Humans; Leucovorin; Male; Methotrexate; Necrosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Skin Diseases

Systemic chemotherapy-mediated cell toxicity is a major risk factor for cardiovascular disease and atherosclerosis. Life-threatening acute events of the FOLFIRI (irinotecan, folinic acid and 5-fluorouracil) regimen are mainly due to DNA damage induced by antimetabolite and topoisomerase inhibition effects. However, the role of human aortic smooth muscle cells (HaVSMCs) in this process and the mechanisms of oxidative stress, DNA and protein damage and apoptosis have not been investigated. Therefore, the effects of curcumin and quercetin on HaVSMC survival in the generation of molecular and cellular toxicity by FOLFIRI treatment and the involvement of vital cellular signalling pathways were investigated. We analysed both FOLFIRI toxicity and the therapeutic potential of quercetin and curcumin in terms of HaVSMC damage using molecular probe and florescence staining, Random Amplified Polymorphic DNA (RAPD), qRT-PCR and Western blot assays. Our study presents two preliminary findings: (a) in HaVSMCs, FOLFIRI treatment significantly induces oxidative damage to both DNA and protein, leading to a dramatic increase in caspase-dependent apoptotic death through P53-mediated Caspase3-dependent mitochondrial apoptosis, and results in TNF-α/Caspase8-mediated necrotic death, and (b) flavonoids not only regulate the expression of genes encoding antioxidant enzymes and increase DNA damage but also limit programmed and necrotic cell death processes in HaVSMCs. Our results clearly indicate the potential for curcumin and, particularly, quercetin as preventative chemotherapeutic interventions for cardiovascular toxicity induced by the FOLFIRI regime in HaVSMCs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aorta; Apoptosis; Apoptosis Regulatory Proteins; Camptothecin; Cells, Cultured; Curcumin; DNA Damage; Fluorouracil; Humans; Leucovorin; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Necrosis; Oxidative Stress; Quercetin; Signal Transduction

Topics: Aged; Anti-Bacterial Agents; Exanthema; Febrile Neutropenia; Female; Folic Acid; Humans; Leucovorin; Methotrexate; Necrosis; Pancytopenia; Rheumatic Fever; Skin; Stomatitis

Methotrexate-induced epidermal necrosis (MEN) is a rare but life-threatening cutaneous reaction that mimics Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).. To investigate the clinicopathology, risk factors, and prognostic factors of MEN.. We enrolled 24 patients with MEN and 150 controls and analyzed the demographics, pathology, and plasma concentrations of methotrexate (MTX).. Patients with MEN showed extensive skin necrosis (mean, 33.2% total body surface area) but no target lesions. The histopathology displayed keratinocyte dystrophy. Early signs of MEN included painful skin erosions, oral ulcers, and leukopenia/thrombocytopenia. Although 79.2% patients received leucovorin treatment, there was 16.7% mortality. Risk factors for MEN included older age (>60 years), chronic kidney disease, and high initial dosage of MTX without folic acid supplementation. Renal insufficiency delayed MTX clearance. Severe renal disease and leukopenia predicted poor prognosis in MEN, but none of the SCORe of Toxic Epidermal Necrosis criteria were associated with mortality of MEN.. The study was limited by the small sample size.. MEN exhibited distinct clinicopathologic features from SJS/TEN. Recognition of the early signs and prognostic factors is important, because the rapid institution of leucovorin may be helpful. To reduce the risk of MEN, physicians should avoid prescribing MTX to high-risk patients and titrate the dosage slowly upward with folic acid supplementation.

Topics: Adult; Age Factors; Aged; Body Surface Area; Case-Control Studies; Drug Eruptions; Epidermis; Female; Folic Acid Antagonists; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Necrosis; Prognosis; Renal Insufficiency, Chronic; Survival Rate; Vitamin B Complex

We evaluated the impacts of a series of novel histopathological factors on clinical-surgical outcomes and survival of patients who underwent surgery for colorectal cancer liver metastasis, with and without neoadjuvant chemotherapy.. A prospective database including 150 consecutive patients who underwent 183 hepatic resections for metastatic colorectal cancer was evaluated. Among them, 74 (49.3%) received neoadjuvant chemotherapy before surgery. The histopathological factors studied were: a) microsatellitosis, b) type and pattern of tumour growth, c) nuclear grade and the number of mitoses/mm(2), d) perilesional pseudocapsule, e) intratumoural fibrosis, f) lesion cellularity, g) hypoxic-angiogenic perilesional growth pattern, and h) the tumour normal interface.. Three or more metastatic lesions, R1 resection margins, and <50% tumour necrosis were prognostic factors for a worse OS, but only the former was confirmed to be an independent prognostic factor in the multivariate analysis. Furthermore, tumour fibrosis <40% and cellularity >10% were predictive of a worse neoadjuvant therapy response, but these findings were not confirmed in the multivariate analysis. Finally, tumour necrosis <50%, cellularity >10%, and TNI >0.5 mm were prognostic factors for a worse DFS and AS in the univariate but not in the multivariate analysis.. Several factors seem to influence the outcomes of surgery for colorectal cancer liver metastasis, especially the number of the lesions, the margins of resection, the percentage of necrosis and fibrosis, as well as the cellularity and the TNI.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Carcinoma; Cetuximab; Colorectal Neoplasms; Databases, Factual; Deoxycytidine; Fibrosis; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Metastasectomy; Mitotic Index; Multivariate Analysis; Necrosis; Neoadjuvant Therapy; Neoplasm Grading; Organoplatinum Compounds; Oxaloacetates; Panitumumab; Prognosis; Retrospective Studies; Tumor Burden

To assess intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for monitoring early efficacy of chemotherapy in a human gastric cancer mouse model.. IVIM-DWI was performed with 12 b-values (0-800 s/mm(2)) in 25 human gastric cancer-bearing nude mice at baseline (day 0), and then they were randomly divided into control and 1-, 3-, 5- and 7-d treatment groups (n = 5 per group). The control group underwent longitudinal MRI scans at days 1, 3, 5 and 7, and the treatment groups underwent subsequent MRI scans after a specified 5-fluorouracil/calcium folinate treatment. Together with tumor volumes (TV), the apparent diffusion coefficient (ADC) and IVIM parameters [true water molecular diffusion coefficient (D), perfusion fraction (f) and pseudo-related diffusion coefficient (D(*))] were measured. The differences in those parameters from baseline to each measurement (ΔTV%, ΔADC%, ΔD%, Δf% and ΔD(*)%) were calculated. After image acquisition, tumor necrosis, microvessel density (MVD) and cellular apoptosis were evaluated by hematoxylin-eosin (HE), CD31 and terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining respectively, to confirm the imaging findings. Mann-Whitney test and Spearman's correlation coefficient analysis were performed.. The observed relative volume increase (ΔTV%) in the treatment group were significantly smaller than those in the control group at day 5 (ΔTVtreatment% = 19.63% ± 3.01% and ΔTVcontrol% = 83.60% ± 14.87%, P = 0.008) and day 7 (ΔTVtreatment% = 29.07% ± 10.01% and ΔTVcontrol% = 177.06% ± 63.00%, P = 0.008). The difference in ΔTV% between the treatment and the control groups was not significant at days 1 and 3 after a short duration of treatment. Increases in ADC in the treatment group (ΔADC%treatment, median, 30.10% ± 18.32%, 36.11% ± 21.82%, 45.22% ± 24.36%) were significantly higher compared with the control group (ΔADC%control, median, 4.98% ± 3.39%, 6.26% ± 3.08%, 9.24% ± 6.33%) at days 3, 5 and 7 (P = 0.008, P = 0.016, P = 0.008, respectively). Increases in D in the treatment group (ΔD%treatment, median 17.12% ± 8.20%, 24.16% ± 16.87%, 38.54% ± 19.36%) were higher than those in the control group (ΔD%control, median -0.13% ± 4.23%, 5.89% ± 4.56%, 5.54% ± 4.44%) at days 1, 3, and 5 (P = 0.032, P = 0.008, P = 0.016, respectively). Relative changes in f were significantly lower in the treatment group compared with the control group at days 1, 3, 5 and 7 follow-up (median, -34.13% ± 16.61% vs 1.68% ± 3.40%, P = 0.016; -50.64% ± 6.82% vs 3.01% ± 6.50%, P = 0.008; -49.93% ± 6.05% vs 0.97% ± 4.38%, P = 0.008, and -46.22% ± 7.75% vs 8.14% ± 6.75%, P = 0.008, respectively). D* in the treatment group decreased significantly compared to those in the control group at all time points (median, -32.10% ± 12.22% vs 1.85% ± 5.54%, P = 0.008; -44.14% ± 14.83% vs 2.29% ± 10.38%, P = 0.008; -59.06% ± 19.10% vs 3.86% ± 5.10%, P = 0.008 and -47.20% ± 20.48% vs 7.13% ± 9.88%, P = 0.016, respectively). Furthermore, histopathologic findings showed positive correlations with ADC and D and tumor necrosis (r s = 0.720, P < 0.001; r s = 0.522, P = 0.007, respectively). The cellular apoptosis of the tumor also showed positive correlations with ADC and D (r s = 0.626, P = 0.001; r s = 0.542, P = 0.005, respectively). Perfusion-related parameters (f and D(*)) were positively correlated to MVD (r s = 0.618, P = 0.001; r s = 0.538, P = 0.006, respectively), and negatively correlated to cellular apoptosis of the tumor (r s = -0.550, P = 0.004; r s = -0.692, P < 0.001, respectively).. IVIM-DWI is potentially useful for predicting the early efficacy of chemotherapy in a human gastric cancer mouse model.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Fluorouracil; Humans; Image Processing, Computer-Assisted; In Situ Nick-End Labeling; Leucovorin; Mice; Mice, Nude; Microvessels; Necrosis; Neoplasm Transplantation; Stomach Neoplasms; Transplantation, Heterologous; Xenograft Model Antitumor Assays

The Port-a-cath (PAC) is a catheter totally implanted under the skin. It is commonly used in oncology for permanent venous access. It provides a more simple way to infuse chemotherapies, antibiotics or parenteral nutrition, while offering improved comfort to patients. The usual complications of these devices (infections and catheter obstructions) are well documented. More exceptional events are catheter fractures with systemic migration, and endopleural perfusions due to a wrong positioning of the catheter. Since 1998, 10 cases of mediastinal infusion of cytotoxics have been reported. Surgical management was necessary in only two cases. We are reporting the case of a 57-year-old female suffering from a multimetastatic sigmoid adenocarcinoma. A mediastinal infusion of Folfiri and bevacizumab with a tracheal necrosis complicated the PAC use and required a latissimus dorsi myoplasty to fill up the tracheo-bronchial defect.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bronchoscopy; Camptothecin; Catheters, Indwelling; Equipment Design; Equipment Failure; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Necrosis; Sigmoid Neoplasms; Surgical Flaps; Thoracotomy; Tomography, X-Ray Computed; Trachea; Tracheal Diseases

In addition to the well-known signs of methotrexate toxicity, rare cutaneous side effects have been described. These cutaneous signs may provide a diagnostic clue into the diagnosis of toxicity as well as facilitate early and aggressive therapy. We describe the case of a 37-year-old male, with a diagnosis of psoriasis, who developed characteristic signs and symptoms of acute methotrexate toxicity after receiving an unknown amount of intravenous methotrexate. The patient experienced a distinct change in the morphology of his existing psoriatic plaques, which became ulcerated and necrotic in the week following the methotrexate injection. Shortly after the development of cutaneous erosions, the patient developed pancytopenia, which ultimately led to his death. Ulceration and necrosis of cutaneous psoriasis plaques may serve as a herald for the impending development of life-threatening pancytopenia in patients with acute methotrexate toxicity.

Topics: Acute Kidney Injury; Adult; Azithromycin; Biopsy; Fatal Outcome; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Leucovorin; Male; Methotrexate; Mucositis; Necrosis; Pancytopenia; Plasma; Psoriasis; Recombinant Proteins; Self Medication; Skin Ulcer; Trimethoprim, Sulfamethoxazole Drug Combination

Recent advances in chemotherapy for colorectal cancer prolonged survival. Tumor necrosis may develop as a side effect of chemotherapeutic agents. Recently, radiofrequency ablation sometimes indicated to patients with colorectal liver metastasis, when hepatectomy cannot be performed due to impaired hepatic functional reserve or general condition. We experienced hepatectomy for colorectal liver metastasis containing necrotic foci which was induced by anti-cancer drugs and radiofrequency ablation. Massive liver necrosis and abscess developed in a patient with initially unresectable large liver metastasis 6 months after induction of mFOLFOX6 and bevacizumab. Chemotherapy was discontinued due to systemic inflammatory responses. Extended right hepatectomy resulted in both resection of the tumor and significant improvement of septic condition. Chemotherapy was re-started after the operation. Bevacizumab targeted to tumor-related vascular endotherial cells might be responsible for the massive tumor necrosis. Another patient with chronic renal dysfunction underwent radiofrequency ablation for colorectal liver metastasis 2 cm in diameter in the segment 7. Three months after ablation, the tumor grew very rapidly to 6 cm in diameter. After extended posterior sectorectomy of the liver, blood CEA levels were normalized. Resected specimen showed a massive tumor growth around the necrotic foci of radiofrequency ablation. Hepatectomy played significant roles in these patients with necrotic foci of the liver. Decision and timing of hepatectomy are very important to save the patient.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Catheter Ablation; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Necrosis; Organoplatinum Compounds

Cryosurgery must be performed in a manner that produces a predictable response in an appropriate volume of tissue. In present-day clinical practice, that goal is not always achieved. Concerns with cryosurgical techniques in cancer therapy focus in part on the incidence of recurrent disease in the treated site, which is commonly approximately 20-40% in metastatic liver tumors, and prostate cancers. Whether the cause of this failure is disease-based or technique related, cryosurgery for cancer commonly needs the support of adjunctive therapy in the form of anti-cancer drugs or radiotherapy to increase the rate of cell death in the peripheral zone of the therapeutic lesion where cell survival is in balance for several days post-treatment. Recent evidence has identified a third mechanism of cell death associated with cryosurgery. This mechanism, apoptosis or gene regulated cell death, is additive with both the direct ice-related cell damage that occurs during the operative freeze-thaw intervals and coagulative necrosis that occurs over days post-treatment. In this manuscript we discuss, through a combination of literature review and new data, the combined roles of these distinct modes of cell death in a prostate and colorectal cancer. Data are presented suggesting that sub-freezing temperatures, when sequentially applied with low dose chemotherapy, may provide improved cancer cell death in the freeze zone periphery. Since the mechanism of action of most common chemotherapeutic agents is to initiate apoptosis in cancer cells, the observation that sub-freezing exposures yields a similar effect provides a possible route toward molecular-based procedural optimization to improve therapeutic outcome.

Topics: Antineoplastic Agents; Apoptosis; Caspase Inhibitors; Caspases; Cell Death; Cell Line, Tumor; Cell Survival; Chemotherapy, Adjuvant; Cisplatin; Colorectal Neoplasms; Cryosurgery; Cryotherapy; Cysteine Proteinase Inhibitors; Fluorouracil; Humans; Leucovorin; Male; Necrosis; Prostatic Neoplasms; Time Factors

Radiological and clinical evidence of acute necrosis in a meningioma following one cycle of chemotherapy with 5-fluorouracil, folinic acid, and levamisole was observed in a patient being treated for invasive rectal carcinoma. The possible mechanisms and implications of this occurrence are discussed.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Embolization, Therapeutic; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Necrosis; Neoplasms, Multiple Primary; Radiotherapy Dosage; Rectal Neoplasms

Three cases of bile duct necrosis owing to hepatic arterial infusion chemotherapy (HAI) were reported. Regarding HAI, transcatheter hepatic arterial embolization (TAE) was applied in two cases (hepatocellular carcinoma: 1; metastasis: 1) and 5-fluorouracil (continuous) combined with leucovorin (one shot) therapy (LV + 5-FU) was given to one metastatic case. In the data of blood biochemistry, serum alkaline phosphatase, gamma-glutamyl transpeptidase, and leucine aminopeptidase values characteristically elevated without the elevation of total bilirubin value. Hepatic tumors degenerated with necrosis in all cases and no viable cells were histologically recognized. Although the destruction of bile ducts was locally detected adjacent to these tumors in TAE cases and was more widespread in the LV + 5-FU case, these lesions were very similar in each case. Therefore, we concluded that both ischemia and drug toxicity induced bile duct necrosis and the necrosis around the bile duct was the secondary change due to the leaked bile juice.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Embolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Necrosis

We report two patients with large-cell non-Hodgkin's lymphomas who were treated with intensive chemotherapy (MACOP-B), and in whom large isolated intraparenchymal masses (splenic in one case, renal in the other) were found with computed tomography after clinical remission. It was found at surgery that both masses were constituted by acellular necrotic material, without tumoral infiltration and limited by fibrous tissue. The finding of these residual masses in patients in remission raises problems of approach, as they may be nontumoral and not require new therapy. At present, until new radiological or biochemical markers are available, a judicious clinical attitude should be taken, with radiological control of the evolution of the masses and reserving surgery only for those cases with progression, diagnostic doubts, or patient's decision to know his real status.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Doxorubicin; Fibrosis; Humans; Kidney; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Necrosis; Prednisone; Spleen; Vincristine

Twenty patients with osteogenic sarcoma of the distal portion of the femur and the proximal portion of the tibia received chemotherapy (vincristine sulfate, methotrexate with leucovorin calcium rescue, [citrovorum factor; folinade calcium], and doxorubicin hydrochloride [Adriamycin]), followed by radical en bloc resection and prosthetic bone replacement. Histologic examination of surgical specimens obtained after chemotherapy showed variable degrees of tumor destruction and, in some cases, massive tumor necrosis, attesting to the profound effects of vigorous chemotherapy. This new therapeutic regimen, when feasible, may prove to be the treatment of choice in osteogenic sarcoma.

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Child; Drug Therapy, Combination; Female; Femoral Neoplasms; Humans; Leucovorin; Male; Methotrexate; Necrosis; Osteocytes; Osteosarcoma; Tibia; Vincristine

Topics: Aphasia; Brain Neoplasms; Carotid Arteries; Cerebral Angiography; Drug Therapy; Glioma; Humans; Infusions, Intra-Arterial; Leucovorin; Methotrexate; Necrosis; Paralysis; Parietal Lobe; Surgical Procedures, Operative; Temporal Lobe