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Interpretations of Chemotherapeutic Protocols on SCLC J Int Transl Med, 2014, 2(3):354-358; doi: 10.11910/2227-6394.2014.02.03.01 Open Access
Interpretations of Chemotherapeutic Protocols on Small Cell Lung CancerFENG Ji-fengDepartment of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, Jiangsu, 210000, China Key words: Small Cell Lung Cancer; Diagnosis; Manifestations; Pathology; Staging; Prognostic factors; Chemotherapeutic protocols Overview
Small cell lung cancer (SCLC) accounts for approximately present, only if patients are with the symptoms suggesting
14% of neuroendocrine tumors (about 20% of lung cancer)[1-2].
advanced disease can SCLC be diagnosed[6]. According to It is reported that in United States only, about 31,000 patients Lung Screening Trial (NLST), annual and low-dose screening were confirmed with SCLC that are caused mainly by cigarette with spiral CT scans could decrease the mortality induced by smoking[2]. The incidence of SCLC in women is increasing and lung cancer in patients with asymptomatic high-risk, which male/female ratio is 1:1, though the general incidence has been could also be confirmed in NCCN Guidelines for Lung Cancer decreasing. The management of SCLC is described in the NCCN Screening. But it is also believed that the CT scan is more Guideline for Small Cell Lung Cancer. effective in detecting non-small cell lung cancer (NSCLC) than detecting SCLC, which is predicated to be associated SCLC is marked by early development of metastases, higher with the aggressiveness of SCLC, leading to the progression
growth fraction and fast doubling time, though it is very of symptomatic diseases between annual scans, subsequently
sensitive to radiotherapy or chemotherapy initially, most SCLC limiting the potential influences on cancer-specific mortality[6].
patients die eventually due to recurrent disease[4]. Some studies
indicated that compared with surgeries, radiotherapies and other Manifestations
protocols, chemotherapy alone could prolong the survival time Patients with SCLC are always presented with symptoms
and relieve symptoms of most patients with extensive-stage of large mediastinal lymphadenopathy and hilar mass that
SCLC, but long-term survival time was rarely reported[5].
could cause dyspnea and cough and with those of metastatic diseases widely spread in human body like neurological compromise, debility, weight loss and bone pain. However, a The disease at early stage should be detected by a screening test solitary peripheral nodule without central adenopathy is not if it still can be cured. However, there is no effective screening unusually seen in SCLC patients, under which condition fine-test available to accurately detect SCLC at an early stage at needle aspiration alone could not completely distinguish small Submit your manuscript jitm2012@jitm.hk www.jitm.hk
J Int Transl Med, 2014, 2(3):354-358 cell carcinoma from large-cell or low- and intermediate-grade nodules, is defined as stage Ⅰ~Ⅲ that can be efectively treated neuroendocrine carcinoma [7-8].
by definitive radiotherapies, while the extensive-stage SCLC as stage Ⅳ or T3 ~ 4. SCLC cells could produce polypeptide hormones consisting of adrenocorticotropic hormone and antidiuretic hormone Though the VA Lung Study Group also classifys SCLC into (ADH) that can cause Cushing syndrome and hyponatremia limited-stage and extensive-stage, the TNM is more useful for of malignancy such as syndrome of improper ADH secretion the selection of patients with T1-2, N0 disease in clinic, which (SIADH), respectively. The latter occurs more commonly should be used first for it is more precise in assessing the specific than the former in SCLC patients, whose treatment includes therapy and prognosis of SCLC in the future. demeclocycline, fluid restriction or vasopressin receptor inhibitor such as tolvaptan and conivaptin[9-10]. Complete staging data consist of physical and history examination, CT scans of adrenal glands, liver and chest, and brain imaging by CT scan and MRI. However, if the patients As a malignant epithelial tumor, SCLC consists of small cells is in extensive-stage, further staging is necessary except brain with finely granular nuclear chromatin, ill-defined cell borders, imaging[11]. If in limited stage, PET-CT scan could be used to inconspicuous or absent nucleoli and scant cytoplasm[7, 11], which detect the distant metastses[12]. PET scan is more accurate in is oval, spindle or round in shape, with high rate of mitotic staging patients with SCLC due to the highly metastatic property count. The SCLC can be sufficiently indentified by hematoxylin of SCLC[15-17], and PET-CT is more superior than PET alone. and eosin (HE) due to its distinctive and classic histology. Most Staging focuses not only on sites by laboratory tests or from of the small cell carcinoma, about 95%, originates from the lung, symptomatic disease. If PECT-CT is not effective, bone marrow but they can also arise from other parts besides pulmonary sites, with CT or MRI can be applied.
like genitourinary tract, gastrointestinal tract and nasopharynx,
etc., which have similar biological and clinical behaviors, Prognostic factors
triggering a rate of extensive metastasis. Almost all patients with The most critical adverse prognostic factors include weight
SCLC have immunological responses to epithelial membrane loss, extensive-stage disease, markers related with excessive
antigen, thyroid transcription factor-1 and keratin, in which most bulk of disease and poor PS (3-4). As to patients with limited-
of them have positive responses to neuroendocrine differentiation stage disease, normal lactate dehydrogenase (LDH), female
markers consisting of neuron-specific enolase, synaptophysin, gender, stage Ⅰ disease and younger < 70 years are connected
neuron cell adhesion module and chromogranin A[7].
with favorable prognosis, whereas to those with extensive-stage disease, good PS, normal LDH and creatinine level, a single metastatic site and younger age are most favorable prognostic A combined approach is adopted by NCCN Panel to stage factors[18]. SCLC for the 2014 update, in which both the previous Veterans Administration scheme and ACJJ TNM system are used[11- Indications of chemotherapy for
12]. Generally, ipsilateral supraclavcular and contralateral SCLC[6]
mediastinal lymphadenopathy are classified as limited diseases
☆ Patients who are diagnosed with SCLC pathologically and and about 2/3 patients have symptoms of overt hematogenous metastases involving controlateral lung, brain, liver, bones, ☆ Karnofsky performance status (KPS) scores > 50 ~ 60 adrenal gland and/or bone marrow. ☆ Expected survival time ≥ 1 month; In 2010, the International Association for the Study of Lung ☆ Ages ≤ 70 years. Cnacer revised the TNM staging system for lung cancer, and the system is applicable to both SCLC and NSCLC, showing that the Chemotherapy regiments for SCLC
various stage designations are of great prognostic significance in both cancers[13-14]. However, the limited-stage SCLC, includes Preferred single agentsT3 ~ 4 because of the over-large tumor volume or multiple lung The preferred single agents for SCLC include paclitaxel, Submit your manuscript jitm2012@jitm.hk www.jitm.hk
J Int Transl Med, 2014, 2(3):354-358 docetaxel, topotecan, irinotecan, temozolomide, gemcitabine, ☆ Temozolomide 75 mg/m2/day ×21 days ifosfamide (IFO), cyclophosphamide (CTX), vincristine (VCR), carboplatin (CBP), adriamycin (ADM), cis-platinum (DDP), vinorelbine (VLB) and etoposide (VP-16), etc. ☆ Relapse > 2 ~ 3 mo up to 6 mo: ☆ Topotecan PO or IV (category 1) Preferred combination agents Chemotherapeutic combination agents for SCLC consist of CAO (ADM + CTX + VCR), VP (DDP + VP-16),CE (CBP + VP- 16), COME (CTX + VCR + MTX + VP-16), DAE (DDP + ADM + VP-16), VIP (IFO + VP-16 + DDP), cisplatin/ etoposide, carboplatin/etoposide and cisplatin/irinotecan, etc. ☆ Oral etoposide ☆ Temozolomide 75 mg/m2/day×21 days Principles of chemotherapies for SCLC[19] ☆ Cyclophosphamide/doxorubicin/vincristine (CAV) Chemotherapy as primary or adjuvant therapy
☆ Relapse > 6 mo: Original regimen ☆ Limited stage (maximum of 4 ~ 6 cycles): ☆ Cisplatin 80 mg/m2 day 1 and etoposide 100 mg/m2 days 1, Interpretations of chemotherapeutic protocols for SCLC
Chemotherapy is the essential appropriate treatment for all ☆ Cisplatin 60 mg/m2 day 1 and etoposide 120 mg/m2 days 1, patients with SCLC, while the adjuvant one is usually applied to patients underwent surgical resections. As to patients with ☆ CBP AUC 5 ~ 6 day 1 and etoposide 120 mg/m2 days 1, 2, limited-stage disease and good PS, chemotherapy concomitant with concurrent thoracic radiotherapy is recommended[17]. ☆ During chemotherapy + RT, cisplatin/etoposide is However, chemotherapy alone could achieve favorable effect recommended (category 1).
on patients with extensive-stage diseases, though radiotherapy ☆ The use of myeloid growth factors is not recommended can also be used to alleviate patients' symptoms. In patients during concurrent chemotherapy plus radiotherapy (category with extensive-stage disease accompanied with brain metastasis, 1 for GMCFS).
whether the patients have neurological symptoms or not decides ☆ Extensive stage (maximum of 4 ~ 6 cycles): whether the chemotherapy is performed before or after whole- ☆ Cisplatin 80 mg/m2 day 1 and etoposide 80 mg/m2 days 1, 2, brain radiotherapy[6]. ☆ Cisplatin 75 mg/m2 day 1 and etoposide 100 mg/m2 days 1, Both single and combination chemotherapy agents are proved to be effective in SCLC[20]. EP is the most commonly used ☆ Cisplatin 25 mg/m2 days 1, 2, 3 and etoposide 100 mg/m2 combination agents that can replace anthracycline/alkylator- based regimens because of its advantages in safety and efficacy ☆ CBP AUC 5 ~ 6 day 1 and etoposide 100 mg/m2 days 1, 2, in limited-stage disease[21]. At present, EP combined with concurrent thoracic radiotherapy is the most recommended ☆ Cisplatin 60 mg/m2 day 1 and irinotecan 60 mg/m2 days 1, 8, therapy for patients with limited-stage disease[20]. However, during the combination, EP is easily to cause pulmonary and ☆ Cisplatin 30 mg/m2 and irinotecan 65 mg/m2 days 1, 8 hematologic toxicity and esophagitis, but myeloid growth ☆ CBP AUC 5 day 1 and irinotecan 50 mg/m2 days 1, 8, 15 factors are not advisable in the concurrent chemoradiation[21]. In clinical practice, CBP, which is often used instead of cisplatin to Subsequent chemotherapy
decrease the rates of nephropathy, neuropathy and emesis, can ☆ Relapse < 2 ~ 3 mo, PS 0 ~ 2 also cause higher rate of myelosuppression. In a meta-analysis of 4 randomized trials, 663 SCLC patients were enrolled, which concluded that the response rate (RR), overall survival (OS) and ☆ Topotecan PO or IV progression-free survival (PFS) of patients receiving cisplation- based versus CBP-based regimens were 67% vs. 66%, 9.6 vs. Submit your manuscript jitm2012@jitm.hk www.jitm.hk
J Int Transl Med, 2014, 2(3):354-358 9.4 months and 5.5 vs. 5.3 months, suggesting no significant 5 Demedts IK, Vermaelen KY, van Meerbeeck JP. Treatment differences between the two chemotherapeutic regimens[22]. of extensive-stage small cell lung carcinoma: current status and future prospects. Eur Respir J, 2010, 35(1): 202-15. The combination agents also have been evaluated in SCLC 6 Cuffe S, Moua T, Summerfield R, et al. Characteristics patients in extensive stage, whose results give greater challenge and outcomes of small cell lung cancer patients diagnosed to EP in clinical efficacy, especially irinotecan concomitant with during two lung cancer computed tomographic screening platinum-based agents. A Japanese phase Ⅲ trial found that the programs in heavy smokers. J Thorac Oncol, 2011, 6(4): medium survival time and 2-year survival of patients treated with irinotecan combined with cisplatin were 12.8 months 7 Travis WD. Advances in neuroendocrine lung tumors. Ann and 19.5%, evidently higher than the 9.4 months and 5.2% in Oncol, 2010, 21(Suppl 7): vii65-71.
patients treated with EP[23]. However, another two phase Ⅲ trials 8 Renshaw AA, Haja J, Lozano RL, et al. Distinguishing in United States showed no significant difference in RR and carcinoid tumor from small cell lung carcinoma of the OS between irinotecan combined with cisplatin and EP[24]. And lung: correlating cytologic features and performance in many other combination agents such as irinotecan plus CBP and, the College of American Pathologists Non-Gynecologic CBP plus oral etoposide, irinotecan plus platinum and etoposide Cytology Program. Arch Pathol Lab Med, 2005, 129(5): plus platinum were discovered to be effective in the treatment SCLC. However, it was also reported that paclitaxel combined 9 Castillo JJ, Vincent M, Justice E. Diagnosis and with either CBP or cisplation plus etoposide achieved promising management of hyponatremis in cancer patients. Oncologist, results in a study, which could not improve patients' survival 2012, 17(6): 756-65. time due to the unacceptable adverse responses[25]. Therefore, the 10 Verbalis JG, Zeltser D, Smith N, et al. Assessment of the NCCN Panel finally regard platinum combined with etoposide efficacy and safety of intravenous conivaptan in patients as the standard combination agents for SCLC patients. with euvolaemic hyponatraemia: subgroup analysis of a randomized, control study. Clin Endocrinol (Oxf), 2008, In conclusion, many attempts have been made all over the world to promote the long-term survival time of SCLC patients in both 11 Jett JR, Schild SE, Kesler KA, et al. Treatment of small cell limited and extensive stages by the complicated use of more lung cancer: Diagnosis and management of lung cancer, 3rd single or combination agents, or the utilization of dose-depended ed: American College of Chest Physicians evidence-based chemotherapy, non-cross-resistant chemotherapeutic regimens clinical practice guidelines. Chest, 2013, 143: e400S-19S. and maintenance therapies, however, which have failed to yield 12 Kalelerian GP, Gadgeel SM. Modern staging of small cell more significant advantages than the standard ones. lung cancer. J Natl Canc Netw, 2013, 11(1): 99-104. 13 Lgnatius Ou SH, Zell JA. The applicability of the proposed References
IASLC staging revisions to small cell lung cancer (SCLC) 1 Oberg K, Hellman P, Kwekkeboom D, et al. Neuroendocrine with comparison to the current UICC 6th TNM Edition. J bronchial and thymic tumours: ESMO Clinical Practice Thorac Oncol, 2009, 4(3): 300-10. Guidelines for diagnosis, treatment and follow-up. Ann 14 Goldstraw P, Crowley J, Chansky K, et al. The IASLC Oncol, 2010, 21(Suppl 5): v220-2. Lung Cancer Staging Project: proposals for the TNM stage 2 Govindan R, Page N, Morgenszterm D, et al. Changing groupings in the forthcoming (seventh) edition of the TNM epidemiology of small-cell lung cancer in the United Classification of malignant tumours. J Thorac Oncol, 2007, States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol, 15 Podoloff da, Ball DW, Ben-josef E, et al. NCCN task force: 2006, 24(28): 4539-44. clinical utility of PET in a variety of tumor types. J Narl 3 Siegel R, Naishadham D, Jemal S, et al. Cancer statistics, Compr Canc Netw, 2009, 7(Suppl 2): S1-26. 2013. CA Cancer J Clin, 2013, 63(1): 11-30. 16 Bradley JD, Dehdasgti F, Mintun MA, et al. Positron 4 Hann CL, Rudin CM. Management of small-cell lung emission tomography in limited-stage small-cell lung cancer: incremental changes but hope for the future. cancer: a prospective study. J Clin Oncol, 2004, 22(16): Oncology (Williston Park), 2008, 22(13): 1486-92. Submit your manuscript jitm2012@jitm.hk www.jitm.hk
J Int Transl Med, 2014, 2(3):354-358 17 Azad A, Chionh F, Scott AM, et al. High impact of 22 Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or 18F-FDG-PET on management and prognostic stratification cisplatin-based chemotherapy in first-line treatment of of newly diagnosed small cell lung cancer. Mol Imaging small-cell lung cancer: the COCIS meta-analysis of Biol, 2010, 12(4): 443-51. individual patient data. J Clin Oncol, 2012, 30(14): 1692-8. 18 Foster NR, Mandrekar SJ, Schild SE et al. Prognostic 23 Noda K, Nishiwaki Y, Kawahala M, et al. Irinotecan factors differ by tumor stage for small cell lung cancer: a plus cisplatin compared with etoposide plus cisplatin for pooled analysis of North Central Cancer Treatment Group extensive small-cell lung cancer. N Endl J Med, 2002, trails. Cancer, 2009, 115(12): 2721-31. 19 National Comprehensive Cancer Network. NCCN Clinical 24 Lara PN, Jr., Natale R, Crowley J, et al. Phase Ⅲ trial of Practice Guidelines in Oncology for Small Cell Lung irinotecan/cisplatin compared with etoposide/cisplatin Cancer (Version 1.2015) [EB/OL]. Fort Washington: NCCN, in extensive-stage small-cell lung cancer: clinical and 2015. Available at pharmacogenomic results from SEOG S0124. J Clin Oncl, 2009, 27(15): 2530-5. 20 Spira A, Ettinger DS. Multidisciplinary management of 25 Niell HB, Herndon JE 2ed, Miller AA, et al. Randomized lung cancer. N Engl J Med, 2004, 350(4): 379-92. phase Ⅲ intergroup trial of etoposide and cisplatin with 21 Sundstrom S, Bremnes RM, Kaasa S, et al. Cisplatin or without paclitaxel and granulocyte colony-stimulating and etoposide regimen is superior to cyclophosphamide, factor in patients with extensive-stage small-cell lung epirubicin, and vincristine regimen in small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin cancer: results from a randomized phase III trial with 5 Oncol, 2005, 23(16): 3752-9. years' follow-up. J Clin Oncol, 2002, 20(24): 4665-72. Submit your manuscript jitm2012@jitm.hk www.jitm.hk

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European Heart Journal (2013) 34, 1708–1715 Expert position paper on the use of proton pumpinhibitors in patients with cardiovascular diseaseand antithrombotic therapy Stefan Agewall1*, M. Cattaneo2, J.P. Collet3, F. Andreotti4, G.Y.H. Lip5,F.W.A. Verheugt6, K. Huber7, E.L. Grove8, J. Morais9, S. Husted10, S. Wassmann11,G. Rosano12, D. Atar1, A. Pathak13, K. Kjeldsen14, and R.F. Storey15, on behalf of ESCWorking Group on Cardiovascular Pharmacology and Drug Therapy and ESC

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Tohoku J. Exp. Med., 2006, 209,B e 2 a0l Effects of Fluvastatin in Rats Fluvastatin Alters Psychomotor Performance and Daily Activity but not the Spatial Memory in Rats SUKRUCAN H. BAYTAN, MEHMET ALKANAT, MEHMET OZEREN,1 MURAT EKINCI2 and AHMET AKGUNDepartment of Physiology, 1Department of Obstetrics and Gynecology, Karadeniz Technical University, Medical School, Trabzon, Turkey, and