Screening for Lynch Syndrome in Cases with Colorectal Carcinoma from Mashhad.

INTRODUCTION: Lynch Syndrome (LS) is a genetically inherited autosomal disorder that increases the risk of many types of cancer, especially colorectal cancer (CRC). Identifying these subjects improves morbidity and mortality. We aimed to assess the prevalence of LS with both clinical criteria and universal strategy in Mashhad, Iran. METHODS: In this retrospective study, we screened 322 patients with CRC between 2013 and 2016 in Mashhad, Iran. CRCs were screened based on Amsterdam II criteria, revised Bethesda guideline, and universal strategy. Information regarding the clinical criteria was obtained by interviewing the patients or, their families. Tumors were screened by pathologists with IHC staining of four Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2). Tumors with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs. RESULTS: Of 322 CRCs, 33 cases were found to be deficient-MMR; 22 of these had concurrent loss of MLH1 and PMS2, followed by concurrent loss of MSH2 and MSH6 in 8 CRCs. Twenty-two cases with a loss of MLH1 underwent testing for the BRAF mutation, 4 of which were recognized as a positive BRAF mutation. Finally, 29 CRCs were found as being positive screen for LS. Poor sensitivity (21.74%) was found for the Amsterdam II criteria and a poor positive predictive value (15.39%) for the revised Bethesda. CONCLUSION: Application of clinical criteria may not be effective enough to identify LS and at least 2-antibody panel (PMS2, MSH6) should be conducted for newly diagnosed CRCs.

Substitution in vertebral resections.

The authors discuss the reconstructive methods used after curettage and/or vertebral resection possibly associated with removal of surrounding muscular, visceral and nervous structures.

High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study.

With the intention of starting an international protocol between Italy and Scandinavia on neoadjuvant treatment of extremity osteosarcoma using the four active drugs at maximum doses (doxorubicin 75 mg/m2 pre-operatively, and 90 mg/m2 post-operatively, cisplatin 120 mg/m2, methotrexate 12 g/m2, and ifosfamide 15 g/m2), a single center (the Rizzoli institute) performed a pilot study to closely monitor toxicity, safety, and tumor necrosis. Only 7 patients (10%) had a reduced number of the scheduled cycles. A total of 1,050 of the expected 1,076 cycles (98%) were administered. Delays and dose reduction were minimal, leading to a mean received dose intensity of 89%. Limb salvage surgery was performed in 59 cases (87%), with 6 amputations and 3 rotation plasties. Chemotherapy-induced necrosis higher than 95% was observed in 38 patients (56%). Eleven patients had total necrosis (16%). At a median follow-up of 60 months (range 50-65 months), 53 patients (73%) were continuously disease-free. Six of the relapsed patients were rescued with further treatments leading to an overall survival of 87%. Hematological toxicity was remarkable despite the use of G-CSF and hospitalization due to febrile neutropenia occurred in 25 patients (37%). Platelet transfusions were required in 77 of the 194 episodes of grade 4 thrombocytopenia, but no case of major bleeding was observed. Red blood cell transfusions were necessary in all patients (in 15 cases perioperatively only). Non-hematological toxicity comprised grade 1-2 nephrotoxicity in 3 cases, CNS toxicity in 2 cases, and dilata- tive cardiopathy leading to heart transplantation in 1 case. In conclusion, the pilot study was feasible in the vast majority of cases with toxicity not superior to that of the previous protocols where chemotherapy was given in lower doses. The rate of limb salvage procedures, event-free survival and overall survival seemed to be higher than in previous protocols. On the basis of this study, in March 1997 the Italian and Scandinavian Sarcoma Groups started a new protocol for osteosarcoma of the extremities.

A portable instrument for measuring macular pigment with central fixation.

PURPOSE: To evaluate the reliability and validity of a portable instrument for measuring macular pigment optical density. METHODS: The instrument is small, uses light emitting diodes as light sources and the principles of heterochromatic flicker photometry of comparing foveal and extra-foveal minimum flicker matches. It uses central fixation for the extra-foveal matches, which subjects found easier than eccentric fixation. Subjects with healthy eyes used the instrument to measure their pigment density in a number of eye clinics. RESULTS: The mean pigment density in 124 eyes in 124 individuals was 0.41 +/- 0.16 (mean +/- SD), there was no significant change with age but the density was less in females, those with light irides, smokers, subjects on diets low in precursor carotenoids and in those exposed to several hours of daylight every day or who used sun beds. CONCLUSIONS: The portable instrument gave valid and reliable data that confirmed published values for macular pigment. It was convenient to use in the clinic and has potential as a screening tool.

Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol.

From January 1993 to March 1995, 162 patients with osteosarcoma of extremities were treated according to the IOR/OS-4 protocol. 133 patients had localised disease, while 29 had metastases at diagnosis. These last patients were simultaneously operated upon for their primary and metastatic lesions. Chemotherapy consisted preoperatively of two cycles of high dose methotrexate (HDMTX) and one cycle each of cisplatin (CDP)-doxorubicin (ADM), CDP/ifosfamide (IFO) and IFO/ADM. After surgery, patients were treated with the aforementioned drugs used as single agents. The mean follow-up of all patients was 6.5 years (5.5-8 years). Surgery was a limb salvage in 94% of cases, and the 5-year event-free survival (EFS) and overall survival (OS) rates were 56 and 71% for patients with localised disease, and 17 and 24% for patients with metastases at diagnosis. These results did not differ from those achieved in our previous study (IOR/OS-3) in which IFO was used only postoperatively in poor responders.

Current treatment of high grade osteosarcoma of the extremity: review.

The authors review their lengthy experience in treating high grade osteosarcoma of the extremity. During the past 20 years many advances have been made in treating high grade osteosarcoma of the extremity. Twenty years ago, in spite of amputation, most patients with this tumor died, whereas today most are cured and amputation is avoided. These advances are mainly due to the development of effective adjuvant and neoadjuvant chemotherapy regimens. This review reports on the progress and controversies in the treatment of osteosarcoma.

Relationship between dose-intensity of treatment and outcome for patients with osteosarcoma of the extremity treated with neoadjuvant chemotherapy.

One hundred and forty-four patients with osteosarcoma of the extremity treated with neoadjuvant chemotherapy at the authors' institution between 1986 and 1989 were retrospectively analyzed to evaluate the relationship between the dose-intensity of chemotherapy actually received (RDI) and the prognosis. Preoperative chemotherapy consisted of high-dose methotrexate i.v., cisplatin i.a., and doxorubicin i.v. After surgery "good responder" patients (90% or more tumor necrosis) had a 31-weeks of chemotherapy with the same drugs, while "poor responder" patients (less than 90% tumor necrosis) received a 40 weeks treatment with ifosfamide and etoposide added to the three drugs used preoperatively. Due to delays and dose-reductions, only 17 patients (12%) received the treatment exactly as scheduled by the protocol, 66 (46%) received a dose-intensity between 90 and 99%, and 61 (42%) a dose-intensity between 63 and 89%. At a follow-up ranging between 10 and 13 years, 97 patients (67%) remained continuously free of disease, 45 relapsed, and two died of doxorubicin-induced cardiopathy. The continuous disease-free survival (CDFS) was not related to patients' gender and age, tumor histology, site and size, serum value of alkaline phosphatase, type of surgery and histologic response to chemotherapy. According to the RDI, CDFS resulted significantly higher for those 81 patients who received 90% or more of the scheduled dose-intensity than for those 61 who had less than 90% of the scheduled dose-intensity (76.5% v.s. 57.3%; p<0.02). These results seem to suggest that in neoadjuvant treatment of osteosarcoma the dose-intensity of chemotherapy is crucial for outcome, therefore every effort should be made to avoid reductions of doses and/or delays in performing the cycles of chemotherapy.

Initiation of strand incision at G:T and O(6)-methylguanine:T base mismatches in DNA by human cell extracts.

Extracts of the human glioma cell line A1235 (lacking O(6)-methylguanine-DNA methyltransferase) are known to restore a G:T mismatch to a normal G:C pair in a G:T-containing model (45 bp) DNA substrate. Herein we demonstrate that substitution of G:T with O(6)-methylguanine:T (m6G:T) results in extract-induced intra-strand incision in the DNA at an efficiency comparable to that of complete repair of the G:T-containing substrate, although the m6G:T mispair serves as a poor substrate for later repair steps (e.g. gap filling, as judged by defective DNA repair synthesis). The A1235 extract, when supplemented with ATP and the four normal dNTPs, incises 5' to the mismatched T, as inferred by the generation of a single-stranded 20mer fragment. Unlike its parental (A1235) counterpart, an extract of the alkylation-tolerant derivative cell line A1235-MR4 produces no 20mer fragment, even when thymine-DNA glycosylase (TDG) is added to the reaction mixture. In contrast, the A1235 extract, when augmented with TDG, catalyzes enhanced incision at m6G:T in the 45 bp DNA, yielding 5-10-fold greater 20mer than that of either extract or TDG alone. Interestingly, the absence of m6G:T incision activity in the A1235-MR4 extract is similar to that seen for extracts of several known mismatch repair-deficient cell lines of colon tumor origin. Together these results suggest that derivative A1235-MR4 cells are defective in m6G:T incision activity and that the efficiency of this activity in the parental (A1235) cells may depend on the presence of several ill-defined mismatch repair recognition proteins along with TDG and ATP.

[General anaesthesia for orthopaedic pediatric surgery]. / Esperienze di anestesia generale in ambito ortopedico pediatrico.

When there are no precise indications or contraindications, the choice between general anaesthesia and locoregional anaesthesia is not clear-cut, especially in paediatrics where there are not enough prospective studies about the safety and main complications with the two techniques. This study aims at providing some clarification concerning this problem by outlining the practice of anaesthetics in the Children's Orthopaedic Ward of Rizzoli Orthopaedic Institute which, for logistical reasons and based on past experience, was carried out by the exclusive use of general anaesthesia. The organizational aspects of pre- and post-operative management of the patients are described. In addition, the data of 836 general anaesthetics carried out in the year 2000 were recorded prospectively on a daily basis. The data included the characteristics of the patient, type of surgery, anaesthesiological methods, and intra- and postoperative complications (first 24 hours). No major complications occurred. There was a small incidence of minor complications (13,3%), which all resolved without sequelae. In the group of younger children, where the lowest number of adverse events were recorded (9,7%), halothane was prevalently used, analgesic opiates were excluded, and breathing was maintained spontaneously. The authors deem the results satisfactory with regards to safety and morbidity, and recommend that anaesthetists use the anaesthesiological methods with which they are more experienced and that are most compatible with the logistical and organisational conditions in which they must work.

Adjuvant and neoadjuvant chemotherapy in osteosarcoma.

Associated chemotherapy (adjuvant or neoadjuvant) means the association of systemic pharmacological therapy to local therapy in the treatment of tumors that, although appearing to still be localized at the time of diagnosis, have a high probability of having already given systemic micrometastases. The purpose of this kind of treatment is that of controlling the micrometastases present, even if they can't be documented, in many tumors. These neoplasms, although still apparently localized, do not achieve healing with the simple removal of the primary tumor, precisely because of the presence of these micrometastases. The current treatment of osteosarcoma (OS) commonly makes use of these therapies. There are different types of OS and they are not indicated in all associated therapies, nor do they provide the same results. We may begin by distinguishing between "high-grade" forms, which have a considerable tendency to early metastasis (about 96% of cases) and "low-grade" forms, generally characterized by local malignancy alone (about 4% of cases). Based on the site on which they occur, OS may be "primary," that is, occurring on apparently normal bone (about 95% of cases) and "secondary," that instead occur on bone that is in some way already changed (as a result of radiation, infarction, Paget's disease, etc.). Based on the site and on the staging, OS can be subdivided into forms of the limbs (75% of cases) and "forms of the axile skeleton" (25% of cases) and in forms that are "still localized" at the time of diagnosis (80% of cases) and in forms "with metastases that are documented at the onset (20% of cases). The present review only concerns primary high-grade OS of the limbs that were not metastatic on diagnosis, representing about 60% of all OS, and it is based on the experience of the Rizzoli Orthopaedic Institute where, between 1983 and 1996, a total of 731 patients were treated by neoadjuvant chemotherapy using five different protocols that were subsequently activated (Table I).

Decreased host-cell reactivation of UV-irradiated adenovirus in human colon tumor cell lines that have normal post-UV survival.

An ongoing study in our laboratories is to examine the relationship of DNA repair defects to human cancer. Our underlying hypothesis has been that human tumors may arise that lack interesting DNA repair pathways if these pathways are important in preventing cancer. In this study, we found that the UV-irradiated adenoviruses showed hypersensitivity when assayed on monolayers of certain human colon tumor cell lines, including three that are reported to have defects in long patch DNA mismatch repair genes and one with no reported defect in mismatch repair. The survival curves showed two components. The first sensitive component was characteristic of 77-95% of the infections depending upon the cell line and the experiment and had an average slope indicating 4.8-fold hypersensitivity to UV. The average of the second-component slopes indicated that the remainder of the infections was accompanied by near-normal repair. Although the value of the first component indicated that the colon tumor lines supported the growth of UV-damaged adenoviruses poorly, the cell lines themselves showed the same post-UV colony-forming ability as did normal human fibroblasts, and their ability to support the growth of N-methyl-N'-nitro-N-nitrosoguanidine-damaged adenoviruses was normal, i.e. it parallelled their ability to repair O6-methylguanine in vitro. We previously observed two-component survival curves when assaying UV-irradiated adenovirus on monolayers of all of seven strains of fibroblasts from Cockayne's syndrome patients. By contrast, single-component curves have been obtained using 21 strains of normal human fibroblasts and seven other tumor lines. We interpret the two-component survival curves in terms of the defective transcription-coupled repair of UV-induced DNA damage that is characteristic both of Cockayne's and certain colon tumor cell lines. In addition, four mismatch repair-deficient colon tumor lines were resistant to killing by elevated levels of dG.

Major vertebral surgery: intra- and postoperative anaesthesia-related problems.

A personal experience concerning vertebral excision and resection in a single stage for neoplasm is discussed. The surgery requires anaesthesia of long duration, hemodynamic stability, compensation of significant blood loss, monitoring of heat loss, maintenance without injury of prolonged prone position. Experience, with 24 cases lasting an average of 14.5 hours proves that inhalation or intravenous anaesthesia with a strong analgesic component is satisfactory. Normal heat saving systems reduce intraoperative hypothermia. Transfusion is always abundant, autologous contribution is moderate. Hemodilution is well-tolerated up to Hb 7%; below this amount there may be problems of a hemodynamic and coagulative nature. The quantity and quality of filling is guided by monitoring of pre-loading pressures and availability of oxygen. There were no critical complications; all of the patients left the hospital in good condition.

Long-term results of spine surgery in Duchenne muscular dystrophy.

We report the long-term orthopaedic and functional results of segmental spinal instrumentation and fusion in 30 Duchenne patients. Twenty-nine had a mean 59% correction of scoliosis with post-operative immobilization in a brace of only three months on average and with a very limited loss of correction over time. One died after cardiac arrest. The mean vital capacity preoperatively was 57 +/- 17% with a decrease to 34 +/- 13% at 3.9 +/- 2 yr after surgery. The sitting position, aesthetic improvement and the quality of life after spinal fusion have been positively evaluated by the large majority of the patients and their parents. Head control was lost in the 14 patients who developed a more severe extension contracture of the neck measured as a significantly longer chin-sternum distance. More than 90% would have the operation or would give their consent again for their son having the operation.

[Complications of pediatric anesthesia. Survey carried out by the Study Group SIAARTI for anesthesia and intensive therapy in children]. / Le complicanze in anestesia pediatrica. A cura e per l'iniziativa del Gruppo di Studio SIAARTI per l'anestesia e la terapia intensiva in età infantile.

This study was designed to asses in a prospective survey the intra and post-operative adverse outcome of paediatric patients in Italy. The data was carried out in representative samples of anaesthetics performed in different Italian Institutions, which were chosen by the National Study Group for Paediatric Anaesthesia, and included: paediatric, general, specialistic hospitals and departments. A total of 9289 anaesthetics were collected and studied. The mean age of the patients was 62.5 months. In the 320 cases (3.4%) 299 minor (3.2%) and 21 major (0.2%) complications occurred during or within 24 hours of surgery and anaesthesia. Seven of the major complications resulted in the exitus of the patients (0.07%). Fifty percent of the accidents regarded respiratory and twenty percent cardiovascular systems. The major incidence (risk factors) of the minor complications was present in patients less than 6 months, ASA group 2-3-4, emergency surgery, patients with associated pathology, long duration of anaesthesia and high risk operations. The incidence of the major complications appears closely related to: patients age and clinical assessment, weight, ASA group, kind of the operation, indications and durations of the surgery, while in the exitus group the major risk factor is the preoperative pathology, surgical procedures, and then: age, weight, ASA and finally surgery.

The sitting position in posterior access to the cervical spine for the treatment of neoplasm.

The authors evaluate the posterior approach to the cervical spine with the patient in a sitting position for the surgical treatment of neoplasms of the vertebral arch. Advantages and risks, particularly those related to anesthesia, are examined. Two cases in which the sitting position was advantageous are reported.

Surgical technique: dorsal vertebral hemiresection for bone tumors.

The authors describe the technique of sagittal vertebral hemiresection used for the treatment of tumors of the thoracic spine involving one or more hemivertebrae. This type of treatment is not frequently indicated because of the rare asymmetrical distribution of vertebral tumors.

Low back pain in tumors: diagnosis and treatment.

On the basis of the authors' experience in the treatment of 257 skeletal neoplasms of the lumbar spine, the features of back pain, which in 96% of the cases constitutes the first symptom of these diseases, are discussed. The overall clinical aspects firstly depend on the stage of the primary tumor: latent, active, aggressive for benign tumors; intra- and extra-compartmental for malignant tumors. Symptoms may include elements which suggest specific lesions, such as osteoid osteoma, eosinophilic granuloma, aneurysmal bone cyst, or high-grade malignant tumors such as Ewing's sarcoma, while lumbar metastasis from carcinoma do not seem to have distinctive features. Site and localization of the tumor are also important variables. The treatment of neoplastic back pain depends on diagnosis, and cannot be adequate if it is not planned on the basis of a complete preoperative study, taking into account not only surgery, but also adjuvant therapy.

[Hypotension controlled with ATP in orthopedic surgery: incidence of atrio-ventricular conduction disorders]. / Ipotensione controllata con ATP in chirurgia ortopedica: incidenza di turbe della conduzione atrio-ventricolare.

Adenosine triphosphate (ATP) has been effectively used for induced hypotension in man. Atrio-Ventricular (A-V) conduction disturbances have been observed after adenosine bolus injection and during continuous ATP i.v. infusion. The present perspective investigation was designed to determine the incidence of A-V conduction disturbances during ATP-induced hypotension. Thirty-five normotensive healthy patients (ASA I-II) with no preoperative therapy were subjected to the same anesthetic technique for orthopedic surgery. Premedication consisted of diazepam and atropine. Anesthesia was induced with thiopental and fentanyl followed by atracurium for intubation. The maintenance anesthesia consisted of isoflurane (1.5% inspired)-N2O (60%) in oxygen and incremental doses of fentanyl; the lungs were mechanically ventilated. Dipyridamole (0.15 mg kg-1) was given 15 min prior to ATP-infusion. ATP was administered by an infusion pump at a dosage of 0.025-0.05 mg kg-1 min-1. The ECG was recorded with a Mingograph 34 tape-recorder using 3 pregelled electrodes positioned to give an effective V6 lead pattern. MAP was reduced by 25% and HR increased by 6%. The mean duration of ATP-induced hypotension was 75 min +/- 50 and the mean dose of ATP infused was 200 mg +/- 161. Six patients (17%) showed A-V conduction disturbances. There was a I A-V Block (AVB) in 2 cases, a II AVB in 2 cases and a III AVB in 2 cases. In every case the arrhythmia disappeared spontaneously or after ATP-infusion suspension.(ABSTRACT TRUNCATED AT 250 WORDS)

[Evaluation of the effectiveness of NSAIDs in the prevention of postoperative pain. Comparison between pre- and postoperative administration of sodium naproxen in orthopedic surgery]. / Valutazione dell'efficacia dei FANS nella prevenzione del dolore postoperatorio. Confronto tra somministrazione pre e postoperatoria di Naprossene sodico in chirurgia ortopedica.

The aim of the study was to assess the efficacy of the preoperative sodium Naproxen administration to reduce analgesic requirements in the postoperative period. 75 patients (ASA I-II), 50 male and 25 female, aged between 25 and 70 years and weighed between 50 and 90 kg, undergoing lumbar laminectomy were subjected to the same anesthetic technique. Patients were allocated randomly to one of three groups. Group I received intravenous sodium naproxen (550 mg) immediately after induction of anesthesia. Group II received intravenous sodium Naproxen (550 mg) at the end of surgery. Group III received intravenous normal saline immediately after induction of anesthesia. Postoperative every patient was given by request intramuscular Buprenorphine (0.3 mg) for pain relief (at 6 h intervals). Buprenorphine requirements in the group I were significantly lower than in either of the other groups (p < 0.01 and p < 0.0001 respectively), while significant differences were not observed between group II and III. Moreover the 54% of patients in the group I did not require analgesic drugs in the postoperative period in opposition to the 20% of pts. in the group II and the 12% of pts. in the group III (p < 0.05 and p < 0.01 respectively). We conclude that NSAIDs when given before tissue damage may prevent nociceptor sensitisation and probably reduce hyperexcitability of the spinal cord. Preoperative administration of NSAIDs provides better protection against peripheral nerve sensitisation than postoperative administration.