What is a kidney stone?

A kidney stone is a hard, crystalline mineral material formed within the kidney or urinary tract. Kidney stones are a common cause of blood in the urine and often severe pain in the abdomen, flank, or groin. Kidney stones are sometimes called renal calculi. One in every 20 people develops a kidney stone at some point in their life.

The condition of having kidney stones is termed nephrolithiasis. Having stones at any location in the urinary tract is referred to as urolithiasis.

What causes kidney stones?

Kidney stones form when there is a decrease in urine volume and/or an excess of stone-forming substances in the urine. The most common type of kidney stone contains calcium in combination with either oxalate or phosphate. Other chemical compounds that can form stones in the urinary tract include uric acid and the amino acid cystine.

Dehydration from reduced fluid intake or strenuous exercise without adequate fluid replacement increases the risk of kidney stones. Obstruction to the flow of urine can also lead to stone formation. Kidney stones can also result from infection in the urinary tract; these are known as struvite or infection stones.

Men are especially likely to develop kidney stones, and Caucasians are more often affected than blacks. The prevalence of kidney stones begins to rise when men reach their 40s, and it continues to climb into their 70s. People who have already had more than one kidney stone are prone to develop more stones. A family history of kidney stones is also a risk factor for developing kidney stones.

A number of different medical conditions can lead to an increased risk for developing kidney stones:

• Gout results in an increased amount of uric acid in the urine and can lead to the formation of uric acid stones.
• Hypercalciuria (high calcium in the urine), another inherited condition, causes stones in more than half of cases. In this condition, too much calcium is absorbed from food and excreted into the urine, where it may form calcium phosphate or calcium oxalate stones.
• Other conditions associated with an increased risk of kidney stones include hyperparathyroidism, kidney diseases such as renal tubular acidosis, and some inherited metabolic conditions including cystinuria and hyperoxaluria. Chronic diseases such as diabetes and high blood pressure (hypertension) are also associated with an increased risk of developing kidney stones.
• People with inflammatory bowel disease or who have had an intestinal bypass or ostomy surgery are also more likely to develop kidney stones.
• Some medications also raise the risk of kidney stones. These medications include some diuretics, calcium-containing antacids, and the protease inhibitor indinavir (Crixivan), a drug used to treat HIV infection.

• What are symptoms of kidney stones?

  While some kidney stones may not produce symptoms (known as “silent” stones), people who have kidney stones often report the sudden onset of excruciating, cramping pain in their low back and/or side, groin, or abdomen. Changes in body position do not relieve this pain. The pain typically waxes and wanes in severity, characteristic of colicky pain (the pain is sometimes referred to as renal colic). It may be so severe that it is often accompanied by nausea and vomiting. Kidney stones also characteristically cause blood in the urine. If infection is present in the urinary tract along with the stones, there may be fever and chills. Sometimes, symptoms such as difficulty urinating, urinary urgency, penile pain, or testicular pain may occur due to kidney stones.

  How are kidney stones diagnosed?

  The diagnosis of kidney stones is suspected by the typical pattern of symptoms when other possible causes of the abdominal or flank pain are excluded. Imaging tests are usually done to confirm the diagnosis. A helical CT scan without contrast material is the most common test to detect stones or obstruction within the urinary tract. Formerly, an intravenous pyelogram (IVP; an X-ray of the abdomen along with the administration of contrast dye into the bloodstream) was the test most commonly used to detect urinary tract stones, but this test has a greater risk of complications, takes longer, and involves higher radiation exposure than the non-contrasted helical CT scan. Helical CT scans have been shown to be a significantly more effective diagnostic tool than the IVP in the diagnosis of kidney or urinary tract stones.

  In pregnant women or those who should avoid radiation exposure, an ultrasound examination may be done to help establish the diagnosis.

• What is the treatment for kidney stones?

  Most kidney stones eventually pass through the urinary tract on their own within 48 hours, with ample fluid intake. Pain medications are used for symptom relief. When over-the-counter medications are not sufficient for pain control, narcotics may be prescribed. Intravenous pain medications can be given when nausea and vomiting are present.

  There are several factors which influence the ability to pass a stone. These include the size of the person, prior stone passage, prostate enlargement, pregnancy, and the size of the stone. A 4 mm stone has an 80% chance of passage while a 5 mm stone has a 20% chance. Stones larger than 9 mm-10 mm rarely pass without specific treatment.

  Some medications have been used to increase the passage rates of kidney stones. These include calcium channel blockers such as nifedipine (Adalat, Procardia, Afeditab, Nifediac) and alpha blockers such as tamsulosin (Flomax). These drugs may be prescribed to some people who have stones that do not rapidly pass through the urinary tract.

  For kidney stones that do not pass on their own, a procedure called lithotripsy is often used. In this procedure, shock waves are used to break up a large stone into smaller pieces that can then pass through the urinary system.

  Surgical techniques have also been developed to remove kidney stones when other treatment methods are not effective. This may be done through a small incision in the skin (percutaneous nephrolithotomy) or through an instrument known as an ureteroscope passed through the urethra and bladder up into the ureter.

• How can kidney stones be prevented?

  Rather than having to undergo treatment, it is best to avoid kidney stones in the first place when possible. It can be especially helpful to drink more water, since low fluid intake and dehydration are major risk factors for kidney stone formation.

  Depending on the cause of the kidney stones and an individual’s medical history, dietary changes or medications are sometimes recommended to decrease the likelihood of developing further kidney stones. If one has passed a stone, it can be particularly helpful to have it analyzed in a laboratory to determine the precise type of stone so specific prevention measures can be considered.

Sızanaq problemini bəslənmə nizamı, stres, siqaret, spirt kimi faktorlar tetikləyə bilər. Bu səbəblə bunlardan uzaq durun. Tətbiq edəcəyiniz düstura gəlincə: Bir çay qaşığı düyü nişastası, yarım çay qaşığı karbonat, bir çay qaşığı alma sirkəsini qarışdırın. Zeytunyağlı sabunla yuduğunuz yüzünüzə maskanı sürün və 20 dəqiqə gözlədin. Yuduqdan sonra bir şüşə mineral suya yarım limon sıxıb, dərinizi bununla silin. Bunları hər gün tətbiq edin.

sızanaq problemi xüsusilə yetkinlik çaığında bizi çox məcbur edir. hələ də dərimiz meyllidirsə vay halımıza. bunun üçün bəzi praktik təriflər var . təbii və praktik qara nöqtə aradan qaldırma yolları :

Qara Nöqtələr üçün, ümumiyyətlə tövsiyə edilən maska üçün ehtiyacınız olan; yalnız bir kasa qatıq və bir limonun suyu…

Limon suyu ilə qatığı qarışdırıb gözlərinizə dəyməyəcək şəkildə yüzünüzə sürün və 15 dəqiqə qədər gözləyin.

Limon suyu dərinizi dezinfeksiya edər, sızanaqlarınızı qurudar və qara nöqtələrin azalmasına köməkçi olarkən; qatıq isə dərinizi beseleyerek nəmləndirici vəzifəsi görər. Eyni zamanda dərinizin yağ miqdarını tarazlıqlar.

Həftədə bir dəfə tətbiq edə biləcəyiniz bu maskanın ardından üzünüzü ilıq su ilə yuya bilərsiniz.

Ayrıca istəsəniz, maskanızı çıxardıqdan sonra, dərinizi içərisinə papatya çiçəkləri atılmış, qaynamış su buxarına 5 dəqiqə qədər tuta bilərsiniz. Papatya dərinizi stirahət etdirər və canlılıq qazandırar..

Bir başqa təsirli olan üsul isə;

1 cay qaşığı qargidali unu və 1 cay qaşığı qatığı qarışdırıb, göz ətrafınız xaric dərinizə tətbiq edin.. 15 dəqiqə qədər sonra dərinizi yuyun..

İstəsəniz, ardından papatyalı su buxarına yüzünüzü 5 dəqiqə qədər tuta bilərsiniz.

Həftədə bir dəfə tətbiq edə biləcəyiniz bu maska, qara nöqtələrin azalmasına köməkçi olacaq.

Overview

Warfarin (Coumadin) is the most commonly used vitamin K antagonist. It has demonstrated effectiveness for the primary and secondary prevention of venous thromboembolism, for the prevention of systemic embolism in patients with prosthetic heart valves or atrial fibrillation, as an adjunct in the prophylaxis of systemic embolism after myocardial infarction, and for reducing the risk of recurrent myocardial infarction.

However, anticoagulant therapy with warfarin is characterized by a wide inter-individual variation in dose requirements and a narrow therapeutic index. Therefore, accurate dosing is critical for safely managing patients on this drug. Because nongenetic influences such as body size and age are poor predictors of an individual’s dose requirement, there has been considerable investigation into the genetic influences on warfarin dose requirements.

Warfarin is metabolized primarily via oxidation in the liver by CYP2C9, and exerts its anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single nucleotide polymorphisms (SNPs), two in the CYP2C9 gene and one in the VKORC1 gene, have been found to play key roles in determining the effect of warfarin therapy on coagulation.

The nomenclature for the CYP2C9 SNPs is unique: the normal, or wild-type, variant is referred to as *1 (”star 1″), the two polymorphic versions are *2 (”star 2″) and *3 (”star 3″), and each person can carry any two versions of the SNP. For example, a person with two normal copies would be *1/*1, a person with only one polymorphism could be *1/*2, and a person with both polymorphisms could be *2/*3. The prevalence of each variant varies by race; 10% and 6% of Caucasians carry the *2 and *3 variants, respectively, but both variants are rare (<2%) in those of African or Asian descent.¹

CYP2C9*1 metabolizes warfarin normally, CYP2C9*2 reduces warfarin metabolism by 30%, and CYP2C9*3 reduces warfarin metabolism by 90%. Because warfarin given to patients with *2 or *3 variants will be metabolized less efficiently, the drug will remain in circulation longer, so lower warfarin doses will be needed to achieve anticoagulation.

In the VKORC1 1639 (or 3673) SNP, the common G allele is replaced by the A allele. Because people with an A allele (or the “A haplotype”) produce less VKORC1 than do those with the G allele (or the “non-A haplotype”), lower warfarin doses are needed to inhibit VKORC1 and to produce an anticoagulant effect in carriers of the A allele. The prevalence of these variants also varies by race, with 37% of Caucasians and 14% of Africans carrying the A allele.²

Clinical Implications of the Genetic Mutation

These three SNPs play key roles in determining (1) the dose of warfarin required to produce a therapeutic INR (typically 2.0 to 3.0); (2) the risk of bleeding or of producing supratherapeutic INR (>4.0); and (3) the time required to achieve a stable therapeutic dose.

Carriers of CYP2C9*2 and CYP2C9*3 require, on average, a 19% and 33% reduction, respectively, per allele in warfarin dose vs those who carry the *1 allele. Carriers of the VKORC1 A allele require, on average, a 28% reduction per allele in their warfarin dose compared to those who carry none.^3,4

As expected, using standard dosing algorithms in patients with these variants leads to adverse clinical and laboratory outcomes because of their genetically mediated sensitivity to the drug. In particular, standard dosing algorithms lead, on average, to a 2- to 3-fold increased risk of serious or life threatening bleeding or an out-of-range INR (>4.0) in carriers of the *2 or *3 alleles of CYP2C9.³ Similarly, carriers of the VKORC1 A allele are also at a 2- to 3-fold higher risk of an INR >4.0 during initiation of warfarin therapy when standard dosing algorithms are used.⁴

Finally, as a result of the sensitivity of these patients to warfarin and the additional dose adjustments required, the time required to achieve a “stable” INR between 2.0 and 3.0 is significantly delayed in carriers of all three SNPs.^3,4 Overall, using a combination of genetic and clinical factors to predict the maintenance warfarin dose appears to be more accurate than using clinical factors alone.⁵

Because incorporating the various factors that influence warfarin dose is difficult to implement clinically, online warfarin dosing calculators, such as the one at http://www.WarfarinDosing.org run by Barnes-Jewish Hospital at Washington University Medical Center, are available to help with the appropriate dose adjustments.⁶

Recommendations
Based on the influence of these SNPs and the observations that carriers of certain alleles are at higher risk for adverse clinical and laboratory outcomes with standard warfarin dosing algorithms, the FDA updated the label for warfarin in 2007 by recommending lower initiation doses in carriers of the CYP2C9 and VKORC1 variants.

Two attempts have been made to improve laboratory outcomes by initiating warfarin therapy using a pharmacogenetics-guided approach. The first study only used the CYP2C9 SNPs and showed that the 95 patients who were randomized to pharmacogenetics-based therapy achieved a stable INR significantly sooner than did the 96 patients given standard warfarin therapy. The second study tailored the dose to all three SNPs, but failed to show any significant advantage of a pharmacogenetic-guided approach with respect to their primary endpoint of percent out-of-range INRs. Nevertheless, they did show that the pharmacogenetic approach more accurately approximated stable doses with smaller and fewer dosing changes and INRs.⁷

Because of the small size and conflicting results of these trials, the NHLBI is sponsoring a 1200-patient, laboratory-outcomes based, randomized clinical trial of pharmacogenetics-based warfarin therapy. Until results from this study are available in 2011, most guidelines do not recommend performing testing of these SNPs to guide warfarin therapy. However, they note that testing might be helpful in managing or diagnosing individuals with unusual dose requirements.

In patients where genetic information is not available but are at increased risk of bleeding with standard dosing algorithms, guidelines suggest starting with a reduced (< 5mg) initial dose and basing the frequency of monitoring on the INR response.⁹

Testing for the Genetic Mutation

A variety of methods can be used to detect CYP2C9 and VKORC1 SNPs; none has yet emerged as the dominant method. Peripheral blood or a buccal swab may be used as the source of DNA.

Overview

Clopidogrel (Plavix), a second-generation thienopyridine that inhibits platelet aggregation, is a mainstay, along with aspirin, in the management of patients with coronary artery disease, with acute coronary syndromes (ACS), and/or after percutaneous coronary interventions (PCI). Yet, a significant proportion of patients remains at risk for subsequent death, myocardial infarction (MI), stent thrombosis, and stroke because of insufficient clopidogrel-induced platelet inhibition.

Clopidogrel is an inactive prodrug that requires hepatic bioactivation via several cytochrome P450 enzymes, including CYP2C19. The active metabolite irreversibly inhibits the platelet ADP receptor, P2Y12. A number of different alleles of CYP2C19 have been identified; depending on the allele present, laboratory demonstrations of the enzymatic activity of CYP2C19 can be normal, reduced, or increased.^1,2,3,4

The *1 (”star 1″) allele is the normal copy that has full enzymatic activity. The *2 (”star 2″) and *3 (”star 3″) alleles are the most common variants and result in complete loss of enzymatic activity.¹ Consequently, carriers of the *2 and *3 alleles have reduced formation of clopidogrel’s active metabolite and demonstrate reduced clopidogrel-induced platelet inhibition.^2,3

The prevalence of the *2 and *3 alleles vary by ethnicity. In Caucasians, Blacks, and Asians, the proportion of patients who carry at least one copy of *2 is 25%, 30%, and 40-50% respectively, while the proportion for *3 is <1%, <1%, and 7%, respectively. Additional variants, *4 and *5, also result in no enzymatic activity, but these variants are rare in all ethnicities (< 1%) and their effect on laboratory outcomes has not been fully documented. Finally, the variant *17 is present in nearly 40% of Caucasians, Blacks, and Asians, and results in increased CYP2C19 activity, higher production of active metabolite, and improved clopidogrel-induced platelet inhibition.

Clinical Implications of the Genetic Mutation

Because of the profound influences of genetic variation in CYP2C19 activity on clopidogrel-induced inhibition of platelet aggregation, there has been considerable investigation in extending these observations to clinical outcomes.

In patients who received PCI after ACS (71% non-ST segment elevation ACS, 29% ST segment elevation MI) and were treated with clopidogrel, carriers of at least one *2 allele experienced a 1.5-fold increase in the risk of cardiovascular death, MI, and stroke in the subsequent year of follow up compared with noncarriers.^[3] In patients treated for ST-segment elevation MI (69% with primary PCI), carriers of any two alleles (*2, *3, *4, or *5) who were treated with clopidogrel had a 2-fold increase in the risk of the same composite outcome during follow up.⁵ The highest risk appears to be in young (age < 45) patients with ST-segment elevation MI, who demonstrated a 3-fold increased risk with at least one *2 allele.

In addition to an increased risk of this composite endpoint, these and additional studies demonstrated that, in patients treated with PCI, the incidence of stent thrombosis is increased 3- to 6-fold in carriers of at least one *2 allele.^3,6,7,8 These risks appear to be consistent across indications for PCI (elective vs ACS) and stent type (bare metal vs drug-eluting).

Recommendations
Due to the totality of evidence supporting the influence of genetic variation in CYP2C19 activity on clopidogrel’s pharmacokinetics, degree of platelet inhibition, and protection from subsequent cardiovascular events, the Food and Drug Administration updated clopidogrel’s package insert to reflect these genetic associations in June 2009. However, they do not provide any specific recommendations with respect to which patients to test and how to tailor therapy based on genetic testing results.

Because carriers of *2 alleles demonstrate no CYP2C19 enzymatic activity with normal dosing of clopidogrel, two potential alternative treatment strategies for carriers of *2 are to either use higher doses of clopidogrel or to use alternate P2Y12 inhibitors. Higher loading and maintenance doses (eg, 1200 mg loading and 150 mg maintenance) appear, in part, to overcome the genetic deficiency of the *2 allele, although maintenance doses of up to 300 mg/day might be required to achieve adequate platelet inhibition.^9,10

Ticlopidine (Ticlid), a first-generation thienopyridine, is also a prodrug, but it is unclear to what extent CYP2C19 enzymatic activity is required for its bioactivation. Prasugrel (Effient), a third-generation thienopyridine that was recently approved by the FDA, is also a prodrug, but is unique in that its bioactivation appears to be less dependent on CYP2C19 activity. In fact, carriers of the *2 allele produce equivalent concentrations of active metabolite and achieve similar degrees of platelet inhibition compared with noncarriers.^11,12,13 Accordingly, when carriers of the *2 allele are treated with prasugrel after PCI for ACS there appears to be no increased risk of cardiovascular death, MI, stroke, or stent thrombosis.¹¹

There are currently no guideline recommendations regarding the use of genetic testing to guide thienopyridine therapy. Additionally, the extent to which the number of variants carried influences the risk for cardiovascular events with clopidogrel remains unknown. It is unclear whether those who carry only one variant have the same risk as those who carry two variants. Further studies will hopefully clarify these issues.

Testing for the Genetic Mutation

A variety of genotyping platforms are available to test for CYP2C19 variants. Although all vendors report CYP2C19*2 status, to what extent less common variants (eg, *3, *4, *5) are reported is variable.

Overview

A substantial percentage of lung cancers express cell surface epidermal growth factor receptors (EGFRs). As activation of these cell surface receptors has been shown in experimental systems to result in the growth and progression of the malignancy, there have been considerable pre-clinical and clinical research efforts directed toward the development of effective inhibitors of the EGFR.

Initial studies with small molecules designed to inhibit the tyrosine kinase (TK) domain of the EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva), demonstrated biologic and clinical activity in only a relatively limited subset of lung cancers.¹ Further investigation demonstrated that the highest response rates were seen in patients with somatic mutations within the EGFR-TK domain, 90% of which involve a relatively small number of amino acids within a specific region (exons 19 and 21).²

Although the reasons for the association remain unclear, these mutations are more commonly observed in patients with the following clinical characteristics: (a) adenocarcinoma histology (particularly bronchioloalveolar subtype); (b) no prior history of smoking; (c) female sex; and (d) Asian ethnicity.

Clinical Implications of the Genetic Mutation

The majority of evidence supporting the clinical utility of the evaluation for the presence of mutations in EGFR has been provided from retrospective examinations of previously reported clinical experiences.

Results from a phase III trial evaluating the EGFR-TKI gefitinib demonstrated that only approximately 10% of patients responded well to the therapy, and no survival benefit was conferred.³ Follow-up analysis of tissue samples identified mutations in the TK domain of the EGFR in 8 of 9 responders whereas no mutations were seen in seven patients who did not respond to gefitinib therapy.² Neverthless, the lack of a significant clinical benefit led to changes in the approval status of gefitinib in the United States; it is now only available for patients who have already demonstrated response to the drug.

Phase III trials with erlotinib demonstrated small but significant improvements in overall survival (6.7 months vs. 4.7 months; P < 0.001) and in progression-free survival (2.2 months vs. 1.8 months; P < 0.001) compared with placebo.⁴ However, review of 325 tumor-biopsy samples demonstrated that although EGFR expression was associated with response on univariate analysis (P = 0.03), multivariate analysis demonstrated that neither status of EGFR expression, the number of EGFR copies, nor the presence of an EGFR mutation independently predicted survival benefit .⁵

Based on data from these and other trials, NCCN Clinical Practice Guidelines note that patients with EGFR exon 19 deletion or exon 21 L858R mutation have significantly better response to EGFR-TKIs. However, no formal recommendation is made for altering therapy based on mutation status.⁶ Additional studies are required before mutation analysis can be considered mandatory or strongly recommended prior to the administration of an EGFR-TKI to a patient with advanced or metastatic non-small cell lung cancer.^1,7

Nevertheless, prior to deciding whether to administer an EGFR-TKI to a patient with advanced or metastatic  non-small cell lung cancer, it is reasonable to consider having the tumor specimen examined for the presence of mutations within the EGFR-TK domain. But it is also appropriate to note that the decision to follow this course of action will include other considerations, such as: (a) the time available before the management decision must be made; (b) third-party payment for the test; (c) the relative toxicities of alternative therapeutic options in this specific patient; (d) the availability and quality of a clinical laboratory that will be performing the test.

Testing for the Genetic Mutation

Testing for mutations in exons 18 through 21 in the EGFR-TK domain is conducted via PCR analysis of tumor samples (formalin-fixed, paraffin-embedded, unstained slides, or fresh snap frozen biopsy) or via MALDI-TOF mass spectrometry of pretreatment serum samples.

The clinical significance of EGFR gene amplification by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) remains unclear.

Overview

5-Fluorouracil (5FU) is a fluorinated pyrimidine analogue commonly used in combination chemotherapy regimens for patients with breast, colorectal, lung, and other malignancies. Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates more than 80% of standard doses of 5FU and the oral 5FU prodrug capecitabine.

True deficiency of DPD affects approximately 5% of the overall population. In these patients, the lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity.¹ In addition, 3% to 5% of the population has a partial DPD deficiency due to sequence variations in DPYD gene, which potentially limits their ability to fully metabolize the drug, thereby resulting in toxicity.²

The IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion (known as DPYD*2A) is the most well known variant resulting in partial DPD deficiency and 5FU toxicity.¹ Other recognized variants associated with toxicity include 496A>G in exon 6; 2846A>T in exon 22;^3,4 and T1679G (DPYD*13) in exon 13,⁵ although multiple other mutations have been detected in individual families and via full gene sequences.

Clinical Implications of the Genetic Mutation

Patients with DPD deficiency who are treated with 5FU or capecitabine are at significantly increased risk of developing severe (grade III/IV) and potentially fatal neutropenia, mucositis, diarrhea.^2,3,4,6 As noted in their respective product labels, both 5FU and capecitabine are therefore contraindicated in patients with known DPD deficiency.

By contrast, the clinical effects of DPYD variants and partial DPD deficiency are unclear. Different series have demonstrated increased toxicity to varying degrees,^3,4 but mutations in DPYD have, for the most part, been unable to account for the magnitude of toxicity seen in the general population. Some groups have begun to evaluate the contribution of mutations in other candidate genes,⁴ but the effects of these and other genetic and nongenetic factors will remain unknown until there is clear elucidation of all of the pathways involved in 5FU/capecitabine metabolism.⁷

Based on what is known to date about the role of DPD in 5FU/capecitabine metabolism, patients with known DPD deficiency and/or a family history of known mutations should avoid therapy with 5FU/capecitabine. For the general population, because true DPD deficiency is rare and because the clinical implications of partial deficiency are still unclear, screening for mutations prior to initiating therapy is not warranted.^2,7 In addition, even if a partial deficiency is detected, there are no guidelines on how to tailor therapy to minimize toxicity, so the clinical utility of testing for DPYD variants remains unclear.

Until such time that guidelines are available, patients with known or suspected partial DPD deficiency who might be at greater risk for fluorouracil toxicity can be managed per the dose modification guidelines outlined in the capecitabine product label. In this rare situation, alternative non-5FU containing treatment regimens (if available) may also be considered.

Testing for the Genetic Mutation

Enzymatic activity in patients with suspected DPD deficiency can be determined via RNA extracted from peripheral blood mononuclear cells and measurement of DPD mRNA copy number. High-throughput genetic analysis using denaturing high performance liquid chromatography (DHPLC) can be used if the patient is severely neutropenic.⁸

Testing for DPD deficiency and the IVS14+1G>A DPYD variant (DPYD*2A) is available; testing for other variants is not currently available.

Overview

One actively investigated approach in the management of advanced and metastatic colorectal cancer (CRC) has been the delivery of agents whose primary purpose is to interfere with the biological activity of the epidermal growth factor receptor (EGFR).

However, it is well-recognized that only a subset of patients whose colorectal tumors have been demonstrated to overexpress the EGFR receptor on their cell surfaces will actually exhibit a favorable biological and clinical response to anti-EGFR antibody therapy. Both the costs and potential toxicities associated with this management paradigm add to the relevance of efforts to more critically define particular patient populations that would be most likely to respond to treatment with this class of agents, or, conversely, that would be highly unlikely to exhibit clinical benefit.
Randomized trials in patients with metastatic CRC that included anti-EGFR antibody therapy have specifically evaluated the impact of the mutational status of KRAS (wild-type [normal] versus mutated [abnormal]) on patient outcome. Notably, the presence of a KRAS mutation was found to be associated with the absence of biological and clinical activity for the anti-EGFR antibody treatment.^1,2 Approximately 30% to 50% of colorectal tumors are known to have a mutated (abnormal) KRAS.

Clinical Implications of the Genetic Mutation

Several phase 3 randomized trials have revealed the favorable impact on survival associated with the administration of one of two currently available anti-EGFR antibodies (cetuximab [Erbitux], panitumumab [Vectibix]) in patients with KRAS wild type.^1,2,3

Analysis of tumor samples obtained from 394 patients with metastatic CRC who were randomly assigned in a phase III trial to receive cetuximab plus best supportive care or best supportive care alone demonstrated improved overall survival (median, 9.5 vs. 4.8 months; P < 0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; P < 0.001) in those in the cetuximab arm who had KRAS wild type.  By contrast, patients with mutated KRAS showed no significant benefit from cetuximab vs. best supportive care alone.¹ Similarly, a significantly greater response rate (61% v 37%; P = 0.011) and a significantly lower risk of disease progression (hazard ratio = 0.57; P = 0.0163) was seen in patients with KRAS wild type being treated with cetuximab and FOLFOX (fluorouracil + leucovorin + oxaliplatin) vs. patients withmutated KRAS receiving the same treatment.³

Using tissue from 427 patients with metastatic CRC enrolled in a phase III trial comparing panitumumab plus best supportive care or best supportive care alone demonstrated significantly greater progression-free survival (median, 12.3 weeks vs. 7.3 weeks; P < 0.0001) in patients with KRAS wild type treated with panitumumab, while no difference was seen in patients with mutated KRAS treated with the same regimen (median, 7.4 weeks vs. 7.3 weeks). Although there was no significant overall survival difference between the groups, multivariate analysis showed that KRAS wild type status independently predicted overall survival in both the panitumumab (hazard ratio, 0.64; P = 0004) and best supportive care (HR, 0.68; P = 0.007) arms.²

A careful read of the data from these and other trials clearly demonstrates that patients with mutated KRAS are unlikely to benefit from anti-EGFR antibody therapy. However, it is not clear that patients with KRAS wild type will definitely respond, only that they have a reasonable opportunity to derive clinical benefit from the therapy. For example, in the panitumumab trial, there were no responders in the mutated KRAS group randomized to the therapy and only a 17% partial response rate was noted in the KRAS wild type group.²

Based on these observations, it is strongly recommended that patients with metastatic CRC who are being considered for treatment with anti-EGFR antibody therapy should be tested for the presence of a KRAS mutation prior to the administration of therapy. This will ensure that the therapy is not administered to patients who are unlikely to obtain benefit.

Accordingly, NCCN Clinical Practice Guidelines as well as a Provisional Clinical Opinion from the American Society of Clinical Oncology recommend initiating use of anti-EGFR therapy in patients with KRAS wild type only.^4,5

Testing for the Genetic Mutation

KRAS status is determined via PCR analysis of formalin-fixed, paraffin-embedded block, unstained slides, or fresh snap frozen biopsy tissue for the presence of a mutation in codons 12, 13, or 61 of the KRAS gene on chromosome 12.

Overview

Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is one of the few cancers that is known to caused by a single, specific genetic mutation in more than 90% of cases.

The transformation to CML is caused by a reciprocal translocation of the BCR gene on chromosome 22 (at 22q11) and the ABL gene on chromosome 9 (at 9q34), resulting in a fused BCR-ABL gene dubbed the “Philadelphia chromosome.” The protein that results from the fused genes promotes transition to the malignant state, increasing proliferation and decreasing apoptosis of the malignant cells (see Images 1 and 2).^1,2

The disease is characterized by an overabundance of hematopoietic stem cells and progresses through three phases. In the chronic phase of disease, mature cells proliferate; in the accelerated phase, additional cytogenetic abnormalities occur; in the blast phase, immature cells rapidly proliferate.² Approximately 85% of patients are diagnosed in chronic phase, and progress to accelerated and blast phases after three to five years.

Clinical Implications of the Genetic Mutation

The tyrosine kinase inhibitors (TKIs) imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) inhibit activity of the BCR-ABL fusion protein, resulting in both hematologic response, ie, normal cell counts in the peripheral blood and normal bone marrow morphology, as well as cytogenetic response, ie, disappearance or reduction of the Philadelphia (Ph) chromosome.^3,4,5,6,7,8

Imatinib
Imatinib was the first of the three TKIs to be evaluated in patients with CML. The drug was first evaluated in the second line, following interferon, in 532 patients, 454 of whom had confirmed chronic phase CML. At 18 months, 60% of patients had a major cytogenetic response (MCyR) and 41% had a complete cytogenetic response (CCyR), with no Ph-positive cells in metaphase seen in the bone marrow. Nearly all patients (95%) had a complete hematologic response (CHR).⁹ At 60 months, 67% had achieved MCyR and 57% had achieved CCyR.¹⁰ In the final analysis, at 72 months, the overall survival (OS) rate was 76% and the progression-free survival (PFS) rate was 61%.¹⁰

Following on these data, investigators moved imatinib to the first line. In a trial known as IRIS, 1106 patients with treatment-naïve, Ph-positive CML were randomized to imatinib or to interferon alfa + cytarabine. In patients enrolled in the imatinib arm, the CHR rate was 96% at 12 months and reached 98% at 60 months; the MCyR rate was 85% at 12 months and 92% at 60 months; and the CCyR rate was 69% at 12 months and 87% at 60 months. In the final analysis, the 60-month OS rate in the imatinib arm was 89%.³

Based on results from this trial, imatinib was approved as first-line therapy for patients with Ph-positive chronic phase CML.

Dasatinib
Dasatinib was the second BCR-ABL TKI to be evaluated in patients with CML, and separate trials were conducted for patients in the three different phases of disease. In the chronic phase, the target population was imatinib failures, or patients who were resistant to or intolerant of imatinib. A total of 387 patients with chronic phase CML, 40% of whom had confirmed BCR-ABL mutations, were treated with dasatinib following imatinib therapy. Prior to imatinib failure, 37% had achieved MCyR and 19% had achieved CCyR. After 24 months of dasatinib therapy, 62% had achieved MCyR and 53% had achieved CCyR; 91% of patients achieved CHR. In the final analysis, the 24-month PFS rate was 80% and the OS rate was 94%.⁴

Smaller trials of dasatinib were conducted in patients with accelerated and blast phase CML who were resistant to or intolerant of imatinib. One hundred seven patients with accelerated phase CML were treated with dasatinib and followed for 8 months. At study end, 33% had achieved MCyR, 39% of patients achieved CHR, and the PFS rate was 76%.⁵ Similar results were seen in 116 patients in myeloid or lymphoid blast crisis: at 6 months, 31% and 50% of patients in myeloid and lymphoid blast crisis, respectively, had achieved MCyR, 86% of whom achieved CCyR in both groups.⁶

Dasatinib is approved for use in patients with Ph-positive chronic phase, accelerated phase, or blast phase CML who are resistant to or intolerant of imatinib.
Nilotinib
Finally, nilotinib, the third BCR-ABL TKI, was tested in patients resistant to or intolerant of imatinib with chronic phase and accelerated phase CML. Of the 321 patients in chronic phase treated with nilotinib, 58% had achieved MCyR and 42% had achieved CCyR at 18 months. The PFS rate in the final analysis was 67% and the OS rate was 91%.⁸ In a far smaller trial of 18 patients in accelerated phase, 32% had achieved MCyR and 19% had achieved CCyR at 6 months; at 12 months, the PFS rate was 56% and the OS rate was 82%.⁷

Nilotinib is approved for use in patients with Ph-positive chronic phase or accelerated phase CML who are resistant to or intolerant of imatinib.
Recommendations
Given the strong evidence demonstrating benefit with BCR-ABL TKIs in patients with CML, NCCN Clinical Practice Guidelines recommends their use in patients with CML with confirmed BCR-ABL transcripts in bone marrow or evidence of translocation on cytogenetics. Treatment-naive patients with chronic phase CML should be started on imatinib, or dasatinib or nilotinib if resistant to or intolerant of imatinib. Patients in accelerated phase should be started on dasatanib or nilotinib, and patients in blast phase should be started on dasatinib.¹¹

Importantly, if patients are BCR-ABL negative or Ph-negative, the diagnosis of CML should be reconsidered.¹¹

Testing for the Genetic Mutation

Two different methods are used to test for the BCR-ABL mutation. Cytogenetic studies of the BCR-ABL gene fusion use fluorescence in situ hybridization (FISH) and DNA probes for the ABL and BCR genes to quantify nonproliferating neoplastic cells with the BCR-ABL fusion. With this method, response to therapy is calculated based on the percentage of Ph-positive cells in metaphase in the bone marrow.

The second method quantifies BCR-ABL transcripts in the marrow. With this method, response to therapy is calculated based on the volume decrease in transcripts, measured in logs.

Overview

Approximately 30% of malignant breast cancers demonstrate overamplification of the human epidermal receptor type 2 (HER2) gene, resulting in  an overexpression of the HER2 receptor, a transmembrane tyrosine kinase receptor within the epidermal growth factor receptor (EGFR) family. Activation of this class of cellular receptors is known to result in increased activity of a variety of molecular pathways associated with tumor growth and progression. Extensive published pre-clinical and clinical data have demonstrated that patients whose cancers overexpress HER2 have a relatively poor prognosis independent of other clinical features (eg, age, stage, tumor grade).¹

Clinical Implications of the Genetic Mutation

Trastuzumab (Herceptin), a humanized recombinant monoclonal antibody specifically directed against the HER2 receptor, has been shown to be biologically active and of considerable clinical utility in breast cancer patients with documented HER2 amplification. Trastuzumab mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2, and lacks effect on cells not overexpressing HER2.

Clinical trials have shown that the addition of trastuzumab to a combination chemotherapy regimen in the adjuvant and the metastatic settings significantly improves outcomes and survival measures.^2,3 In a phase III trial of 469 women with chemo-naïve, HER2-positive, metastatic breast cancer, patients randomized to trastuzumab plus chemotherapy (doxorubicin or epirubicin + cyclophosphamide or paclitaxel) demonstrated a significantly higher rate of overall response (50% vs. 32%, P < 0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P < 0.001), a longer time to treatment failure (median, 6.9 vs. 4.5 months; P < 0.001), and a significantly lower rate of death (22% vs. 33%; P = 0.008) compared with those randomized to chemotherapy alone. Overall survival was significantly different between the groups(25.1 months vs. 20.3 months; P = 0.046), and trastuzumab reduced the relative risk of death by 18% to 20% at a median follow-up of 30 months.² It should be noted that the overall survival results in the chemotherapy alone arm included patients who received open-label trastuzumab after progression on this protocol. Therefore, use of the agent in this setting may have favorably impacted the ultimate survival outcome in this population.

In the adjuvant setting, results from two phase III trials comparing trastuzumab + chemotherapy (doxorubicin + cyclophosphamide followed by paclitaxel) vs. chemotherapy alone were combined for analysis. Patients in both trials had surgically removed, HER2-positive breast cancers that were node-positive or that were node-negative but considered at high risk for progression due to size (ie, > 2 cm in diameter) or hormone receptor status (ie, both estrogen and progesterone negative). Data from the 3351 patients who had at least one follow-up evaluation demonstrated a significant improvement in disease-free survival (85.3% vs. 67.1% at four years; P < 0.0001) as well as a significant improvement in overall survival (91.4% vs. 86.6% at four years; P = 0.015) in the trastuzumab group vs. chemotherapy alone.³

Lapatinib (Tykerb), a 4-anililoquinazoline kinase that inhibits intracellular tyrosine kinase domains of EGFR (ErbB1) and HER2 (ErbB2),  has also been shown to improve time to progression when combined with chemotherapy in the management of advanced breast cancer.⁴ In a phase III trial, 324 patients with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomized to lapatinib plus capecitabine or capecitabine alone.  Patients randomized to lapatinib + capecitabine demonstrated significant improvements in both median time to progression (8.4 months vs. 4.4 months; P < 0.001) and median progression-free survival (8.4 months vs. 4.1 months; P < 0.001).⁴

Based on data from these and other randomized phase III clinical trials, in the absence of a medical contraindication, high-risk, HER2-positive breast cancers should be treated with a HER2 inhibitor (eg, trastuzumab, lapatinib) in addition to cytotoxic chemotherapy.

NCCN Clinical Practice Guidelines recommend adjuvant use of this class of agents in combination with chemotherapy for patients with node-positive, HER2-positive breast cancers > 1 cm, and suggest consideration of its use in patients with HER2-positive, node-negative breast cancers between 0.6 and 1.0 cm.⁵

In patients with HER2-positive, metastatic breast cancer, the Guidelines recommend the use of trastuzumab or lapatinib in combination with chemotherapy or as a single agent in the first line as well as continuation of trastuzumab in patients whose cancers progress despite treatment with a trastuzumab-containing regimen in the adjuvant setting.⁵

Testing for the Genetic Mutation

The goal of laboratory-based analysis for HER2 is to document the presence of HER2 gene amplification or receptor overexpression within the malignant cell population.

It is critical that any laboratory providing clinical testing for HER2 have considerable experience with the measurement of this molecular marker. Two types of tests are generally available: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).⁶ IHC is a semi-quantitative method that measures overexpression of the HER2 receptor, with the degree of staining graded on a scale from 0 to 3+. Patients with breast cancers with intensive staining (3+) should definitely receive anti-HER2 therapy; the clinical relevance of 2+ staining is uncertain.

FISH is a far more quantitative and reproducible method, as it directly measures the number of copies of the HER2 gene. However, FISH testing is associated with greater cost and takes more time than an analysis employing IHC.

Resources

More information about breast cancer, HER2, and targeted treatments for HER2-overexpressing breast cancer can be found in Medscape’s Breast Cancer Resource Center and the Cancer: Biologic Therapies Resource Center as well as in the eMedicine article on Breast Cancer.

İlk olaraq 1920-ci ildə təyin olunan hemofiliya, irsi faktorlara (soyaçekim) bağlı olaraq inkişaf edən ciddi qanamalara yolaçan bir xəstəlikdir. Lakin Hemofiliya xəstələrinin təxminən %30 unun ailəsində Hemofiliya yoxdur. Çünki genlərdə meydana gələn mutasiyalardan qaynaqlanar. Hemofilide problem qanamada deyil qanama müddətinin uzanmasında yəni qanın daha keç laxtalanmasındadır.
Cəmiyyətdə görülmə sıxlığı çoxdur. Hər 4 min kişidə bir ortaya çıxar. Kişilərdə görülmə sıxlığı qadınlara görə çox daha çoxdur. Qadınlarda görülməsi çox nadir bir vəziyyətdir.
1985 ‘deyil əvvəl bədəninə faktor 8 enjekte edilən bir çox xəstə HIV ilə enfekte olmuş və AIDS inkişaf etmişdir. Lakin son zamanlarda qan saxlama üsulları ilə bu risk azaldılmışdır.

HEMOFİLİYANIN TİPLƏRİ VƏ SƏBƏBİ

Hemofiliyanın səbəbi, qanın laxtalanmasını təmin edən faktorların əskik olmasıdır. İki tip Hemofiliya vardır: Hemofiliya A və Hemofiliya B.

Bu adlandırma qanda əskik olan zülala görə edilər. Hemofiliya A-da faktor 8 zülalı əskikdir. Hemofiliya Bə görə daha çox görülər. Hemofiliya xəstələrinin % 80i bu qrupdadır. Bu faktor 8 zülalın qanda olması lazım olan miqdarın yarısının altına düşdüyündə Hemofiliya ortaya çıxar. Nə qədər az isə xəstəlik o qədər şiddətlidir.

Hemofiliya B isə faktor 9 zülalın əksikliyindən qaynaqlanmaqdadır. Xəstəliyin klinika əlamətləri Hemofiliya Adan seçilmir. Əlamət vermədən irəliləyə bildiyindən diaqnoz qandakı faktor səviyyələrinin təyin olunmasıyla ortaya qoyular.

HEMOFİLİYANIN ƏLAMƏTLƏRİ

Hemofiliyanın ifadə olunan şiddəti, qanda olan faktorların nə qədər əskik olduğuna bağlıdır.

Əlaməti qanamadır. Uşaqlıq çağında ortaya çıxan beyin qanaması, ölümə səbəb ola bilər. Ümumiyyətlə bu yaşdakı qanamalar yaralanmalara bağlı olaraq görülər. Uşaq, ağızını ya da burnunu bir yerə vurduğunda qan itkisi görülər. Ayrıca oyun çağında, çox yaralanan uşaqda, qanama oynaq içinə ola bilər. Bu sıx təkrarlasa, ciddi probemlere gətirib çıxarar. Oynağın hərəkətlərini məhdudlaşdırar hətta tamamilə ortadan qaldıra bilər. Sümüklərin qaynaşmasına səbəb olar.

Ayrıca qanamalar qaraciyər, böyrək kimi iç orqanlarda da ortaya çıxar. Yaş irəlilədikcə xəstəliyin fərqinə varan adam, daha diqqətli bir həyat sürər. Beləcə uzun illər həyatını davam etdirə bilər. Lakin kiçik yaralarda ya da çarpmalarda belə bədəndə bənövşəyiliklər görülə bilər. Xəstəliyin, yaş irəlilədikcə necə seyr edəcəyini təxmin etmək çətindir. Kiçik qanamalardan sonra durdurulamayan qan itkinləri meydana gələ bilər.

HEMOFİLİya NECƏ YOXLANILAR?

Hemofiliya diaqnozu həyatın hər dövründə təyin edilə bilər. Yeni doğulan uşaqda da bu xəstəlik təsbit edilər. Lakin, hemofiliya xəstələrində, qanamanın nə vaxt görüləcəyi bilinmədiyindən, diaqnoz üçün həkimə müraciət etmə zamanı da gecikər.

həkimə getdiyinizdə, sizə ailədə belə bir hadisənin daha əvvəl olub olmadığı soruşulacaq. Xəstəliyin keçişində, anadan gələn genlər əhəmiyyətli olduğundan, ananın qardaşlarında ya da qardaşlarının uşaqlarında hemofiliya xəstəsi olub olmadığı araşdırılar.

Ayrıca edilən qan təhlilləriylə, qan laxtalanmasına baxılar. Qəti diaqnoz, bu testlərdən sonra qoyular. Hemofiliya müalicəsi uzun sürər və bundan sonra xəstəni və ailəsini ciddi və uzun bir müddət gözləməkdədir.

HEMOFİLİ XƏSTƏLİYİNİN MÜALİCƏSİ

Hemofilinin müalicəsi ömür boyu sürər. Çünki bu xəstəlik genetik bir xəstəlikdir və hələ müalicələr bu mərhələyə gəlməmişdir. Xəstəlikdə əskik olan faktorlar ( zülallar ) enjeksiyonla yerinə qoyular. Bu şəkildə, xəstədə qanama olduğunda laxtalanmanın meydana gəlməsi təmin edilər. Lakin bu qalıcı bir müalicə şəkli deyil. Davamlı və nizamlı bir şəkildə tətbiq olunması lazımdır. Bir müddət sonra xəstədə bu qalıcı faktorlar yenə azalacaq və köhnə səviyyəsinə enəcək.

Xəstəliyin diaqnozu erkən qoyulduğunda, bu üsulla adam, gündəlik həyatını digər insanlardan fərqsiz bir şəkildə davam etdirə bilməkdədir. Bu xəstəliyin müalicəsi üçün işlər davam etməkdədir. Xüsusilə Amerikada 40 könüllü xəstə üzərində gen müalicəsi tətbiq olunmaqdadır. Xəstələrə zəiflədilmiş virus verilməkdə və bu virus qaraciyərə yerləşərək, faktor 8 çıxarmaqdadır. Çox miqdarda verilmədiyindən, hələ yan təsiri görülməmişdir. Məqsəd, xəstəliyi tamamilə ortadan qaldırmaqdır.

Ayrıca xəstənin idman etməsi, əzələlərin güclənməsi, sağlam bir həyat sürməsi üçün lazımlıdır. Üzmə, stolüstü tennis, gediş hemofiliya xəstələri üçün faydalıdır. Yalnız irəli dərəcədə hemofiliya xəstəsi olanlar, həkimin təklif etdiyi məşq proqramını tətbiqləri daha faydalıdır. Bəzi idmanlar bu xəstələr üçün risk meydana gətirə bilər.