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By I. Konrad. Caldwell College. 2018.
Combination IP chemotherapy generic tamsulosin 0.2 mg online prostate cancer rates, the appropriate drugs, correct treatments are associated with higher response rates, dose and the appropriate scheduling of treatment. Combina- chemotherapy is currently discouraged in low- resource settings22. The combination of paclitaxel with carboplatin is considered to be the standard first-line therapy Table 2 Chemotherapy in advanced ovarian cancer (Table 2, Appendices 2 and 3). Single-agent carbo- platin may be a reasonable alternative for first-line 3-weekly paclitaxel/carboplatin 3-weekly carboplatin in patients with ovarian cancer because of its rela- Paclitaxel 175 mg/m² Carboplatin AUC 6 tive safety, tolerability, ease of administration and Carboplatin AUC 6 repeat day 22 fewer side-effects20. The myelotoxicity of the repeat day 22 carboplatin monotherapy is of concern, and treat- ment delays may affect treatment efficacy. AUC, area under the curve 349 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS Interval cytoreductive surgery in advanced Box 4 Landmark studies in neoadjuvant epithelial ovarian cancer chemotherapy Interval debulking (IDS) is a repeat surgical attempt In the EORTC/NCIC-CTG trial the primary after induction chemotherapy in a patient who debulking surgery followed by chemotherapy could not be optimally debulked at primary sur- with or without interval debulking was com- gery. The main aim is to achieve complete cyto- pared with neoadjuvant chemotherapy and de- reduction of residual tumor. In patients who did layed primary surgery in stage IIIC and stage IV not have a maximal effort for cytoreduction by an ovarian cancer9. The progression-free and experienced surgeon at initial surgery, IDS is bene- overall survival rate was not significantly differ- ficial (Box 3). The advantages of neoadjuvant chemotherapy Box 3 Landmark studies on interval debulking include an increased rate of optimal surgery, re- surgery duced blood loss, lower morbidity, shortened The EORTC 55865 trial performed a random- hospital stay, improved quality of life, and acting ized study in FIGO stage IIB–IV patients in as a mechanism to select out patients with plati- which patients with residual disease after primary num resistance. In the multivariate analyses, debulking surgery were randomized to either complete resection of all macroscopic lesions ≥6 cycles of chemotherapy without additional was the strongest independent prognostic factor surgery or 3 cycles of chemotherapy followed by for overall survival. The results of the trial are interval debulking surgery and additional ≥3 not applicable to patients with lower stage cycles of chemotherapy. Recently many institutions continues to show with over 10 years of follow- have switched to using neoadjuvant chemo- up, that there is a significant survival advantage therapy in selected patients with advanced to the patients who underwent IDS23. The GOG ovarian cancer (without primary attempt of de- 158 study showed no benefit of interval debulk- bulking), followed by an IDS (usually after three ing surgery. However, there were some signifi- courses of chemotherapy). In the GOG study The lack of specialized care facilities and experi- all patients were operated on by gynecological enced gynecology oncologists in low-resourced oncologists but in the EORTC there was a mix- countries makes neoadjuvant chemotherapy an ture of general gynecologists and gynecological appealing option. In addition in the GOG 158 a maxi- adjuvant therapy is that it would allow the patient’s mal surgical effort at primary surgery was re- general condition to improve and would reduce the quired for inclusion, which was not needed for bulk of the tumor, thereby rendering the surgery inclusion in the EORTC study. Many oncolo- easier with fewer surgical complications. The deci- gists have interpreted these results as showing sion to offer neoadjuvant chemotherapy should be that when an initial surgery has been performed made when the diagnosis of primary ovarian cancer by a gynecological oncologist then IDS probably is most certain. This diagnosis is preferably based on has a minimal role to play, in all other cases IDS a histologically obtained sample of the tumor or is of benefit. An alternative way (although less pre- cise) is the presence of the following three features: 1. A cytological diagnosis of adenocarcinoma, Neoadjuvant chemotherapy in epithelial achieved through fluid aspiration of the ascites ovarian cancer or pleural fluid. Neoadjuvant chemotherapy refers to initial use of 2. A typical clinical picture with a mass arising chemotherapy in patients with advanced-stage epi- from the pelvis associated with macroscopic tu- thelial ovarian cancer in order to reduce the tumor mor >2cm in abdomen or extraperitoneal tu- volume prior to surgical intervention (Box 4). Ratio of CA-125/CEA >25; in cases of a MANAGEMENT OF GRANULOSA CELL lower ratio, additional examinations (digestive CANCER tract endoscopy and mammography) should be Granulosa cell cancer of the ovaries occurs at all performed to exclude intestinal and breast ages. Many granulosa cell tumors produce estrogens cancer. The corner- Response to chemotherapy should be assessed after stone of granulosa cell tumor therapy is surgery. Inoperable granulosa cell tumors may a drop (ideally logarithmic) in the tumor marker be treated with (B)EP (bleomycin, etoposide and level and improvement in the patient’s general con- cisplatin) chemotherapy (see Appendix 4).
The higher the levels of CMV viremia purchase tamsulosin 0.4 mg fast delivery prostate cancer blog, the higher the risk of CMV disease. Patients with positive CMV PCR have a 3-5-fold elevated mortality risk (Casado 1999, Nokta 2002). Positive CMV PCR is also independently associated with a poor prognosis for the patient (Deayton 2004, Jabs 2005, Wohl 2005). As with Toxoplasma gondii, there have been efforts to determine the antigen-specific immune response more precisely (Jacobsen 2004), although such testing is not yet routine. Treatment CMV treatment should always be initiated promptly and strictly monitored by fun- doscopy at least once a week in the beginning. Initially, an intensive induction therapy is administered for two to three weeks, until there is scar formation of the lesions. HIV clinicians and ophthalmologists should work closely together, particularly during the induction therapy, and when possible, communicate several times a week. Induction therapy is followed by maintenance therapy at a reduced dose. ART in particular has dramatically improved the prognosis of patients. That said, all diagnosed patients should start ART without delay. This can restore CMV-specific immune responses (Komandouri 1998), so that CMV viremia may disappear even without specific therapy after a few weeks (Deayton 1999, O’Sullivan 1999). However, if retinitis is present, CMV-specific treatment should also be started, as immune recon- stitution may take several months. Treating asymptomatic CMV patients with CMV agents remains controversial. There is some evidence that preemptive therapy lowers the incidence of CMV end-organ disease in some patients with CMV viremia (Mizushima 2013). However, monitoring of potential treatment-related side effects is required. Treating a positive CMV IgM serology (without any further diagnosis) is not only expensive, but also usually an unnecessary risk. Systemic treatment Valganciclovir, a prodrug of ganciclovir with good oral absorption, is the first choice in CMV treatment. In a randomized study (Martin 2002) on 160 patients with retini- tis valganciclovir tablets were just as effective as ganciclovir infusions. However, the toxicity profile of both agents was comparable. This means that the blood count has to be as frequently monitored as for infusions and that the indication has to be equally carefully set. However, there are some experts in the field who prefer intra- venous CMV treatment to oral treatment in advanced cases. Other options for systemic treatment have become less important, and are only used in cases of recurrence. If there is intolerability or more rarely (Martin 2007) resist- ance to valganciclovir (Drew 1999), then foscarnet remains an option. Further problems with this drug include nephrotoxicity, and very painful penile ulcers. Very intensive hydration of the patient is therefore nec- essary in all circumstances. The benefit of the long half-life (once weekly dosing possible) is out- weighed by the considerable renal toxicity of this drug (Plosker 1999). We observed creatinine elevations in every second patient treated, despite the fact that a strict infusion plan was closely followed (see Drugs section). Maribavir failed to show a benefit in Phase III studies (Snydman 2011). Letermovir is a new agent with a novel mech- anism of action targeting the CMV terminase. In a Phase II trial, letermovir was effec- tive in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants, with an acceptable safety profile (Chemaly 2014). The drug has been granted fast track status by FDA and orphan drug status by EMA. Additional treatment with G-CSF (filgrastim) improved survival in one analysis of three large studies enrolling patients with CMV retinitis in the years 1990–1997.
Blood (ASH cyclophosphamide improves response and progression-free Annual Meeting Abstracts) 0.2mg tamsulosin amex mens health 5 day workout. Fludarabine plus chemoimmunotherapy regimens in patients with chronic lym- cyclophosphamide versus fludarabine alone in first-line therapy phocytic leukemia: results of sequential cancer and leukemia of younger patients with chronic lymphocytic leukemia. The addition of rituximab to analogues for the treatment of chronic lymphocytic leukae- fludarabine may prolong progression-free survival and overall mia: a systematic review and meta-analysis. Cancer Treat survival in patients with previously untreated chronic lympho- Rev. Fludarabine in comparison of CALGB 9712 and CALGB 9011. Combination chemoimmu- lymphocytic leukemia: a systematic review and meta-analysis. Chlorambucil–still not toxicity in previously untreated B chronic lymphocytic leuke- bad: a reappraisal. Rituximab plus combination with rituximab for previously untreated patients chlorambucil in patients with CD20-positive B-cell chronic with chronic lymphocytic leukemia: a multicenter phase II lymphocytic leukemia (CLL): final response analysis of an 166 American Society of Hematology open-label phase II study [abstract]. Blood (ASH Annual chronic lymphocytic leukemia recurrence. Lenalidomide as initial (GA101) plus chlorambucil (Clb) or tituximab (R) plus Clb therapy of elderly patients with chronic lymphocytic leuke- versus Clb alone in pateints with chronic lymphocytic mia. Phase II study of bidities): Final Stage 1 results of the CLL11 (BO21004) lenalidomide and rituximab as salvage therapy for patients phase III trial. Single-agent treatment with rituximab in symptomatic, untreated patients rituximab as first-line and maintenance treatment for patients with B-cell chronic lymphocytic leukemia: results from Can- with chronic lymphocytic leukemia or small lymphocytic cer and Leukemia Group B 9712 (CALGB 9712). The combination of rituximab as initial therapy for chronic lymphocytic leukemia rituximab and GM-CSF as frontline treatment for elderly or small lymphocytic lymphoma: population-based experi- patients with chronic lymphocytic leukemia. Rituximab in therapy with low-dose fludarabine and cyclophosphamide and combination with high-dose methylprednisolone for the treat- high dose rituximab in previously untreated patients with ment of chronic lymphocytic leukemia. Low-dose fludara- biological and psychosocial function. The European cytic leukemia/small lymphocytic lymphoma (CLL/SLL): Organization for Research and Treatment of Cancer. QLQ- preliminary results of project Q-Lite by Czech CLL Study C30: a quality-of-life instrument for use in international Group [abstract]. Signaling the end of chronic lymphocytic leukemia: 103. Assessment of older people: self- new frontline treatment strategies. Hematology Am Soc Hema- maintaining and instrumental activities of daily living. A research and ibrutinib in relapsed chronic lymphocytic leukemia. N Engl service oriented multilevel assessment instrument. The Functional Assess- selective inhibitor of phosphatidylinositol 3-Kinase P110d, ment of Cancer. Therapy scale: development and validation of demonstrates clinical activity and pharmacodynamic effects in the general measure. Prognostic impor- randomized study of bendamustine compared with chloram- tance of comorbidity in a hospital-based cancer registry. The Patient Reported Outcomes Measurement Information 92. Alemtuzumab System (PROMIS): a walk through the first four years, 2009. Recommendations alemtuzumab plus rituximab in patients with relapsed and for incorporating patient-reported outcomes into clinical com- refractory lymphoid malignancies.
Identifica- mediated by down-regulation of hepcidin and up-regulation of ferropor- tion of erythroferrone as an erythroid regulator of iron metabolism buy tamsulosin 0.4 mg with visa prostate 45 psa. BMP4 and Madh5 regulate the phenotype in a mouse model of beta-thalassemia. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe( / ) mice and erythropoiesis in polycythemia vera and beta-thalassemia. Vemula S, Ramdas B, Hanneman P, Martin J, Beggs HE, Kapur R. Essential role for focal adhesion kinase in regulating stress hematopoi- 33. Curr Opin tissue-iron accumulation in disorders of iron overload with anemia. The role of ineffective erythropoiesis in non-transfusion- 35. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC. Decreased differentiation of Hepcidin antimicrobial peptide transgenic mice exhibit features of the erythroid cells exacerbates ineffective erythropoiesis in beta-thalasse- anemia of inflammation. An activin receptor IIA ligand tool to limit iron overload and improve anemia in beta-thalassemic trap corrects ineffective erythropoiesis in beta-thalassemia. Modified activin receptor IIB designed small peptides that mimic hepcidin activity in mice and may be ligand trap mitigates ineffective erythropoiesis and disease complica- useful for the treatment of iron overload. Schmidt P, Racie T, Butler JS, Fitzgerald K, Fleming MD. Minihepcidins prevent iron RNAi-therapeutic targeting tmprss6, in conjunction with oral chelator overload in a hepcidin-deficient mouse model of severe hemochromato- therapy, ameliorates anemia and additively diminishes secondary iron sis. Tmprss6 is a genetic Blood (ASH Annual Meeting Abstracts). Ineffective erythropoiesis beta-thalassemia major: a longitudinal study. Freeman2 1Department of Medical & Molecular Genetics, King’s College London School of Medicine, London, United Kingdom; and 2Department of Clinical Immunology, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a “one size fits all” approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient. Although cytogenet- Learning Objectives ics continues to provide the framework for risk stratification used to ● Consideration of technical aspects of flow cytometry and guide the management of AML, there has been inconsistency in the molecular-based approaches to minimal residual disease classification systems employed by different trial groups, with (MRD) detection in acute myeloid leukemia (AML). After advances in sequencing technology that led to the discovery of ● Appreciation of the assays that are now ready for clinical a number of novel recurrent mutational targets in AML, there has implementation and those which are currently investigational. It is reprinted with permission from Blood 2014, Volume 124. The prognostic impact of MFC-MRD is strong enough to Although pretreatment characterization of AML based on cytoge- have emerged despite study differences in the MFC assays and the netic analysis and molecular profiling can evidently distinguish limitations of now-outdated restricted antibody panels. Its clinical broad subgroups of patients with relatively favorable, unfavorable, value as a biomarker to inform therapy is therefore difficult to or intermediate prognosis, major drawbacks are that it lacks the ignore, particularly with its applicability to the majority of patients. Because replica- to reliably identify those most likely to benefit from early transplan- tion of this requires the organization of specialized core laborato- tation. Importantly, although cytogenetics and molecular profiling ries, the implementation of flow cytometric measurement of MRD can provide a snapshot of the genetic makeup of each case of has lagged behind that of real-time quantitative PCR.
Possibly order tamsulosin 0.4 mg line androgen hormone use in chickens, both enantiomers have different resistance profiles so that, theoretically, the development of resistance is impeded (Hurwitz 2005). It has shown good antiviral activity in combination with d4T and efavirenz after two weeks (Herzmann 2005). In a study in 42 patients harbouring the M184V mutation, viral load declined by 0. Pharmasset has been looking to out-license this compound, without success, since 2008. Stampidine is a nucleoside analog developed by the Parker Hughes Institute. It resembles d4T and is apparently 100 times more potent than AZT in vitro (Uckun 2002). It also has activity against HIV mutants with up to 5 TAMs (Uckun 2006). It has been discussed also as a potential microbicide (D’Cruz 2004). Out of sight, out of mind: the following NRTIs are no longer being pursued: • Adefovir dipivoxil from Gilead, low activity against HIV, nephrotoxicity • Dexelvucitabine (DFC or Reverset) from Incyte, pancreatitis • dOTC from Biochem Pharma, toxicity in monkeys • FddA (Lodenosine) from US Bioscience, severe liver/kidney damage • KP-1461 from Koronis, lack of efficacy • Lobucavir from BMS, carcinogenicity • MIV-210 from Medivir/Tibotec, currently being developed for HBV • MIV-310 (alovudine)) from Boehringer Ingelheim, disappointing Phase II study • SPD-756 (BCH-13520) and SPD-761 References Bam RA, Yant SR, Cihlar T. Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Bogner JR, Roecken M, Herrmann DB, Boerner D, Kaufmann B, Gurtler L, Plewig G, Goebel FD. Antiviral activity of apricitabine in treatment-experienced HIV-1-infected patients with M184V who are failing combination therapy. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretro- viral-naive, HIV-infected patients. A phase-II study of 14 days monotherapy with the nucleoside-analogue Fosalvudine Tidoxil in treatment-naïve HIV-1 infected adults. Racivir demonstrates safety and efficacy in patients harbouring HIV with the M184V mutation and > 3 TAM. Dioxolane thymine nucleoside is active against a variety of NRTI-resistant mutants. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phospho- noamidate prodrug, GS-9131. The different clinical pharmacology of elvucitabine (beta-L-Fd4C) enables the drug to be given in a safe and effective manner with innovative drug dosing. Multiple-dose pharmacokinetic behavior of elvucitabine, a nucleoside reverse transcriptase inhibitor, administered over 21 days with lopinavir-ritonavir in human immunodeficiency virus type 1-infected subjects. Stampidine is a potential nonspermicidal broad-spectrum anti-HIV microbicide. Elvucitabine phase II 48 week interim results show safety and effi- cacy profiles similar to lamivudine in treatment naive HIV-1 infected patients with a unique pharmacokinetic profile. Elvucitabine vs lamivudine with tenofovir and efavirenz in anti- retroviral-treatment-naïve HIV-1 infected patients: 96 week final results. ART 2017/2018: The horizon and beyond 123 Dunkle LM, Gathe JC, Pedevillano DE, et al. Elvucitabine: potent antiviral activity demonstrated in multidrug- resistant HIV infection. In vitro induction of HIV variants with reduced susceptibility to elvucitabine (ACH-126,443,beta-L-Fd4C). In vitro investigation of the resistance profile of apricitabine. Apricitabine: a nucleoside reverse transcriptase inhibitor for HIV infec- tion. Ann Pharmacother 2009, 43:1676-83 Girard PM, Pegram PS, Diquet B, et al. Phase II placebo-controlled trial of fozivudine tidoxil for HIV infection: pharmacokinetics, tolerability, and efficacy. In vitro antiretroviral activity and in vitro toxicity profile of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus infec- tion. Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R.
Record the bladder size and feel for stones absence of a metal catheter in this case an artery forceps now tamsulosin 0.2mg line prostate cancer vitamin d. The has been inserted through the urethra and held towards the sensation and sound when tapping a stone is distinctive. This may help in finding the right plane between the vagina and bladder and will reduce bleeding (there should be very little anyway) 250 Vesico-vaginal and Recto-vaginal Fistula (e) (g) (f) (h) Figure 13 (cont) (e) The forceps that are through the urethra are held towards the surgeon to steady the anterior vaginal wall and an Allis forceps lifts up the mucosa over the urethra. It may help to make a little vertical extension towards the urethra. Note ‘big bites’ of bladder are taken traversing the full thickness of the bladder wall but barely picking up the mucosa. Note: never hold any instruments in your hands while tying knots. It is difficult to judge tension and tie accurately if you do. This is quite sufficient provided you have taken ‘big bites’ and placed your sutures accurately. Now do a dye test to check your repair is watertight. Use 60 ml of dilute methylene blue (or Gentian violet) introduced through a Foley catheter 253 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS (q) (s) (t) (r) (u) Figure 13 (cont) (q) Press over the bladder or ask the patient to cough. In the unlikely event of a leak through the suture line put in another suture. The main purpose of a dye test in a simple case is to exclude a second unsuspected fistula, especially an intra-cervical one if the patient has had a cesarean section. The catheter has been sutured to the top of the labia 254 Vesico-vaginal and Recto-vaginal Fistula (a) (e) (b) (f) (c) (g) (h) (d) Figure 14 (a) A large soft mid-vaginal fistula. If possible this should pick up the periosteum of the pubic arch for extra security. Note that the fistula margins fall together because mobilization has been so good. Note the size of the bites 255 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS (a) Figure 15 A large stone has been removed though a suprapubic incision margin between the fistula and the cervix must be clearly seen. Those that extend into the cervical canal can be challenging to close. They should all (b) be approached with caution because the ureters are at risk (Figure 16). The experienced surgeon can find them quickly by eye with a probe, but the best way when starting is to ask the anesthetist to give furosemide 10 mg IV. In 5 min a brisk diuresis will make the orifices obvi- ous if they are near the fistula margin. This can be held by an assistant during the mobiliza- tion and while the first inverting corner suture is inserted as illustrated in the case described below. An easy, type 1 case (c) An example is shown in Figure 17. As a general rule if the fistula is very small (less than 0. However if one can see into the bladder they should always be identified. Use a Babcock’s for- ceps to evert the bladder (Figure 17b,c). Give furosemide 20mg IV (Lasix) if there is still difficulty. Ureteric catheters are notoriously difficult to obtain in Africa and one must rely on outside Figure 16 (a) Diagram illustrating danger area for donations. Beware: probes have been lost up a ureter situ by an assistant, thus protecting it from harm (Figure 18).
Continued vigilance in encouraging Close monitoring is important for those at risk 0.2mg tamsulosin mastercard prostate oncology of san antonio. Screening recommen- appropriate cancer screening and healthy behaviors for HCT dations for radiation-related second cancers include careful physical survivors is critical. Because outcome after treatment for breast cancer is closely linked Healthcare utilization by HCT survivors to stage at diagnosis, close surveillance to promote early diagnosis In a survey of 10 year HCT survivors, whereas 99% should confer survival advantage. The Children’s Oncology Group maintained some level of medical contact, only 25% returned to (COG) recommendations39 for those at risk (ie, radiation doses of 20 the transplantation center for management of ongoing health Gy or higher to the mantle, mediastinal, whole lung, and axillary issues in the 2 years before study participation. The observation radiation or at age 25 (whichever occurs later). Screening of those at that a large proportion of allogeneic HCT recipients do not return risk for early-onset colorectal cancer (ie, radiation doses of 30 Gy or to the transplantation center for long-term care (despite the high higher to the abdomen, pelvis, or spine) should include colonoscopy burden of morbidity) emphasizes the need for ensuring that every 5 years beginning at age 35 years or 10 years after radiation standardized recommendations for the follow-up of this vulner- (whichever occurs last). Further- identification of treatment-related complications, potentially allow- more, there is a need for the transplantation team to develop an ing for early intervention with a resultant reduction in morbidity and ongoing partnership with the primary care physicians as patients mortality and an attendant reduction in healthcare costs. Because are transitioned from the transplantation center to ensure that treatment exposures vary by primary diagnosis, HCT type, patient comprehensive care is delivered long-term to the survivors. These guidelines have been developed as a resource for clinicians who Long-term follow-up guidelines provide ongoing healthcare to HCT survivors. The COG guidelines Theoretically, if screening resulted in an earlier diagnosis of key are intended for use beginning 2 or more years after completion of complications, then management of these complications would therapy and provide a framework for monitoring of late effects in be more successful. The issue of whom to screen, how to screen, survivors. The recommendations for periodic screening evaluations and when to do it are all important but largely unanswered provided in these guidelines are appropriate for asymptomatic questions. For HCT survivors, screening recommendations must survivors who present for routine medical follow-up. Therefore, incorporate risks associated with pre-HCT therapy, transplanta- unlike the EBMT/CIBMTR/ASBMT guidelines, the COG guide- tion conditioning therapy, and other HCT-associated conditions lines utilize the cumulative therapeutic exposures to generate a such as chronic GVHD. The Center for International Blood and tailored list of potential late effects and the recommended Marrow Transplantation Research (CIBMTR), the European screening for early detection of those late effects. The intensity Group for Blood and Marrow Transplantation (EBMT), and the of screening is determined by whether the patient is at standard American Society for Bone Marrow Transplantation (ASBMT) risk or increased risk due to cumulative therapeutic exposures have developed recommendations for screening and early detec- and/or host/demographic characteristics. This provides a greater tion of complications after HCT. Most of these recommendations are derived from overscreening or underscreening. The guide- In summary, each patient should receive a summary of their lines are organized by organ system and time after HCT; details therapeutic exposures. These should include exposures experienced include potential late effects, known risk factors, and recommen- before and at the time of HCT, as well as their GVHD status. Figure 1 serves as an example of the For the pediatric survivor population, COG has developed compre- template for therapeutic exposure summary for the patients. Table 1 hensive long-term follow-up guidelines that provide risk-adapted suggests some of the screening recommendations drawn from the yet consensus-based recommendations. Follow-up guidelines for patients undergoing allogeneic HCT Exposure Complications Screening Any cancer experience Hematological malignancy Fatigue; limitations in healthcare and insurance access; mental History health disorders such as depression and anxiety; psychosocial disability due to pain Blood products Diagnosis 1972 in the U. Chronic hepatitis B Hep B surface antigen Diagnosis outside U. Chemotherapy Alkylating agents Alkylating agents (all) Gonadal dysfunction (ovarian) FSH, LH, estradiol (females) Gonadal dysfunction (testicular: Leydig cell dysfunction) FSH, LH, testicular (males) Busulfan Pulmonary fibrosis Chest x-ray CCNU PFTs Cyclophosphamide Bladder malignancy Urinanalysis Ifosfamide Renal toxicity Renal function/electrolytes; urinalysis Heavy metals Carboplatin (myeloablative doses) Ototoxicity Audiology evaluation Cisplatin Carboplatin Peripheral sensory neuropathy History and physical Cisplatin Renal toxicity Renal function/electrolytes; urinalysis Antimetabolites Cytarabine (high dose) Cognitive deficits Neuropsychologic testing Clinical leukoencephalopathy History and physical 6MP Venoocclusive disease Liver function tests 6TG Hepatic dysfunction MTX (high-dose IV) Reduced bone mineral density DEXA MTX PO Renal toxicity Renal function/electrolytes; urinalysis Anthracycline antibiotics Daunorubicin Cardiac toxicity Echocardiogram Doxorubicin Epirubicin Idarubicin EKG Mitoxantrone Antitumor antibiotics Bleomycin Pulmonary toxicity Chest x-ray; PFTs Corticosteroids Dexamethasone Reduced bone mineral density DEXA Prednisone Osteonecrosis History and physical Plant alkaloids Vincristine Peripheral sensory or motor neuropathy History and physical Vinblastine Vasospastic attacks (Raynaud’s phenomenon) Radiation Total body irradiation SMNs (except breast cancer or colorectal cancer) History and physical SMN (breast cancer, females) Breast MRI; mammogram Neurocognitive deficits Neuropsychological testing Dyslipidemia and insulin resistance Fasting glucose and lipid panel Cataracts Ophthalmological examination Hypothyroidism TSH, Free T4 Pulmonary toxicity Chest x-ray; PFTs Renal toxicity Renal function/electrolytes; urinalysis Gonadal dysfunction (ovarian) FSH, LH, estradiol (females) Gonadal dysfunction (testicular, germ cell failure) FSH, LH, testicular (males) Cranial radiation Brain tumor (benign or malignant) History and physical Neurocognitive deficits Neuropsychological testing Cataracts Ophthalmologic examination Salivary gland dysfunction Dental examination/cleaning every 6 months Xerostomia Thyroid cancer History and physical Hypothyroidism TSH, free T4 500 American Society of Hematology Table 1. Continued Exposure Complications Screening Neck radiation Salivary gland dysfunction Dental examination/cleaning every 6 months Xerostomia Thyroid cancer History and physical Hypothyroidism TSH, free T4 Esophageal stricture History and physical Carotid artery disease History and physical Subclavian artery disease History and physical Thoracic radiation Thyroid cancer History and physical Hypothyroidism TSH, free T4 SMN (breast cancer, females) Breast MRI; mammogram Pulmonary toxicity Chest x-ray; PFTs Coronary artery disease Fasting glucose and lipid panel Cardiac disease Echocardiogram; EKG Esophageal stricture History and physical Carotid artery disease History and physical Subclavian artery disease History and physical Abdominal radiation Renal toxicity Renal function/electrolytes; urinalysis Cirrhosis Liver function tests Hepatic fibrosis SMN (colorectal cancer) Colonoscopy Pelvic radiation Gonadal dysfunction (ovarian) FSH, LH, estradiol (females) Vaginal fibrosis/stenosis History (females) Gonadal dysfunction (testicular, germ cell failure) Semen analysis (males) Gonadal dysfunction (testicular, Leydig cell function) FSH, LH, testicular (males) Allogeneic HCT Chronic GVHD Xerophthalmia History and physical Salivary gland dysfunction Dental examination/cleaning every 6 months Xerostomia Bronchiolitis obliterans Chest x-ray; PFTs; high-resolution CT scan Pulmonary fibrosis Chest x-ray; PFTs Renal toxicity Renal function/electrolytes; urinalysis Osteonecrosis History and physical Vaginal fibrosis/stenosis History (females) SMNs (skin and oropharyngeal mucosa) History and physical FSHindicatesfollicle-stimulatinghormone;LH,luteinizinghormone;andPFT,pulmonaryfunctiontest. Risk-reduction strategies avoidance of tobacco and alcohol, use of sunscreen, and HPV Although strategies aimed at altering therapeutic exposures (chemo- vaccination, may help to reduce the risk of complications in HCT therapy and radiation) will most likely result in a reduction in the survivors. Furthermore, it is often not feasible to alter Acknowledgments therapeutic exposures while preserving clinical outcomes. There is This work was supported in part by grants from the National increasing concern related to the risk of cancer and cancer death Institutes of Health (Grant R01 CA078938 to S. This state of sarcopenic Correspondence obesity contributes to the development insulin resistance, hyperinsu- S. Bhatia, City of Hope National Medical Center, 1500 East Duarte linemia, and chronic inflammation, all factors that have been Road, Duarte, CA 91010-3000; Phone: (626)471-7321; Fax: implicated in the causal pathway of obesity-associated cancer risk (626)301-8983; e-mail: sbhatia@coh.
