<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Endovascular aneurysm repair and can you explain it in depth? [/INST] Endovascular aneurysm repair (EVAR) is a type of minimally-invasive endovascular surgery used to treat pathology of the aorta, most commonly an abdominal aortic aneurysm (AAA). When used to treat thoracic aortic disease, the procedure is then specifically termed TEVAR for "thoracic endovascular aortic/aneurysm repair." EVAR involves the placement of an expandable stent graft within the aorta to treat aortic disease without operating directly on the aorta. In 2003, EVAR surpassed open aortic surgery as the most common technique for repair of AAA, and in 2010, EVAR accounted for 78% of all intact AAA repair in the United States.

Medical uses
Standard EVAR is appropriate for aneurysms that begin below the renal arteries, where there exists an adequate length of normal aorta (the "proximal aortic neck") for reliable attachment of the endograft without leakage of blood around the device ("endoleak"). If the proximal aortic neck is also involved with the aneurysm, the patient may be a candidate for complex visceral EVAR with a fenestrated or branched EVAR.
Patients with aneurysms require elective repair of their aneurysm when it reaches a diameter large enough (typically greater than 5.5 cm) such that the risk of rupture is greater than the risk of surgery. Repair is also warranted for aneurysms that rapidly enlarge or those that have been the source of emboli (debris from the aneurysm that dislodges and travel into other arteries). Lastly, the repair is also indicated for aneurysms that are the source of pain and tenderness, which may indicate impending rupture. The options for repair include traditional open aortic surgery or endovascular repair.Endovascular procedures aim to reduce the morbidity and mortality of treating arterial disease in a patient population that is increasingly older and less fit than when major open repairs were developed and popularized. Even in the early days, significant risks were accepted in the understanding that the large open operation was the only option. That is not the case in most patients today.Studies that assign aneurysm patients to treatment with EVAR or traditional open surgery have demonstrated fewer early complications with the minimally invasive approach. Some studies have also observed a lower mortality rate with EVAR. The reduction in death, however, does not persist long-term. After a few years, the survival after repair is similar to EVAR or open surgery. This observation may be the result of durability problems with early endograft, with a corresponding need for additional procedures to repair endoleaks and other device-related issues. Newer, improved technology may reduce the need for such secondary procedures. If so, the results of EVAR may improve to the point where long-term survival benefit becomes evident.EVAR is also used for rupture of the abdominal and descending thoracic aorta, and in rare cases used to treat pathology of the ascending aorta.

Aortic dissection
Endografts have been used in patients with aortic dissection, noting the extremely complex nature of open surgical repair in these patients. In uncomplicated aortic dissections, no benefit has been demonstrated over medical management alone.
In uncomplicated type B aortic dissection, TEVAR does not seem either to improve or compromise 2-year survival and adverse event rates. Its use in complicated aortic dissection is under investigation. In the Clinical Practice Guidelines of the European Society for Vascular Surgery, it is recommended that in patients with complicated acute type B aortic dissection, endovascular repair with thoracic endografting should be the first line intervention.Before people are deemed to be suitable candidates for this treatment, they have to go through a rigorous set of tests.  These include a CT scan of the complete thorax/abdomen/pelvis and blood tests.  The CT scan gives precise measurements of the aneurysm and the surrounding anatomy. In particular, the calibre/tortuosity of the iliac arteries and the relationship of the neck of the aneurysm to the renal arteries are important determinants of whether the aneurysm is amenable to endoluminal repair. In certain occasions where the renal arteries are too close to the aneurysm, the custom-made fenestrated graft stent is now an accepted alternative to doing open surgery.

Relative contraindications
A patients anatomy can be unsuitable for EVAR in several ways. Most commonly, in an infrarenal aneurysm, a potential EVAR candidate lacks adequate length of the normal-diameter aorta between the aneurysm and the takeoff of the renal arteries, the "infra-renal neck". Another relative contraindications include prohibitively small iliac arteries, aneurysmal iliac arteries, prohibitively small femoral arteries, or circumferential calcification of the femoral or iliac arteries.In addition to a short proximal aortic neck, the neck may be angulated, large in diameter, or shaped like a funnel (conical) where the neck diameter at the top is larger than the neck diameter at the bottom. Along with a short proximal aortic neck, necks with any of these characteristics are called "hostile necks" and endovascular repair can be either contraindicated or associated with early-late complications of endoleak, or endograft migration, or both.Many of the advances in EVAR technique aim to adapt EVAR for these situations, and advanced techniques allow EVAR to be employed in patients who previously were not candidates.

Technique
The procedure is carried out in a sterile environment under fluoroscopic guidance.  It is usually carried out by a vascular surgeon, interventional radiologist or cardiac surgeon, and occasionally, general surgeon or interventional cardiologist. The procedure can be performed under general, regional (spinal or epidural) or even local anesthesia. Access to the patients femoral arteries can be with surgical incisions or percutaneously in the groin on both sides. Vascular sheaths are introduced into the patients femoral arteries, through which guidewires, catheters, and the endograft are passed.Diagnostic angiography images are captured of the aorta to determine the location of the patients renal arteries, so the stent-graft can be deployed without blocking these. Failure to achieve this will cause kidney failure. With most devices, the "main body" of the endograft is placed first, followed by the "limbs" which join the main body and extend to the iliac arteries, effectively protecting the aneurysm sac from blood pressure.The abdominal aneurysm extends down to the common iliac arteries in about 25%-30% of patients. In such cases, the iliac limbs can be extended into the external iliac artery to bypass a common iliac aneurysm. Alternatively, a specially designed endograft, (an iliac branch device) can be used to preserve flow to the internal iliac arteries. The preservation of the hypogastric (internal iliac) arteries is important to prevent buttock claudication and impotence, and every effort should be made to preserve flow to at least one hypogastric artery.The endograft acts as an artificial lumen for blood to flow through, protecting the surrounding aneurysm sac. This reduces the pressure in the aneurysm, which itself will usually thrombose and shrink in size over time.Staging such procedures is common, particularly to address aortic branch points near the diseased aortic segment. One example in the treatment of thoracic aortic disease is revascularization of the left common carotid artery and/or the left subclavian artery from the innominate artery or the right common carotid artery to allow treatment of a thoracic aortic aneurysm that encroaches proximally into the aortic arch. These "extra-anatomic bypasses" can be performed without an invasive thoracotomy. Another example in the abdominal aorta is the embolization of the internal iliac artery on one side prior to coverage by an iliac limb device. Continued improvement in stent-graft design, including branched endografts, will reduce but not eliminate multi-stage procedures.

Percutaneous EVAR
Standard EVAR involves a surgical cut-down on either the femoral or iliac arteries, with the creation of a 4–6 cm incision. Like many surgical procedures, EVAR has advanced to a more minimally invasive technique, by accessing the femoral arteries percutaneously In percutaneous EVAR (PEVAR), small, sub-centimeter incisions are made over the femoral artery, and endovascular techniques are used to place the device over a wire. Percutaneous EVAR has been systematically compared to the standard EVAR cut-down femoral artery approach. Moderate quality evidence suggests that there are no differences in short-term mortality, aneurysm sealing, long and short-term complications, or infections at the wound site. Higher quality evidence suggests that there are no differences in post-repair bleeding complications or haematoma between the two approaches. The percutaneous approach may have reduced surgical time.

Fenestrated EVAR
In certain circumstances, a specially designed custom-made graft, which has holes, or fenestrations, on the graft body to maintain the patency of the visceral arteries, is used for the procedure, which is called FEVAR (fenestrated endovascular aortic/aneurysm repair). When the aneurysm begins close to the renal arteries, standard EVAR may be contraindicated since there will be an inadequate length of suitable aorta for the endograft attachment. In these cases, a fenestrated endograft may be useful, where the attachment of the endograft to the aorta may be placed above the renal arteries with each fenestration aligned with a renal artery so that blood flow to the kidneys is maintained. Fenestrated EVAR has been in use in the United Kingdom for over a decade and early results were published in Jun 2012.

Branched EVAR
Thoracoabdominal aortic aneurysms (TAAA) involve the aorta in the chest and abdomen. As such, major branch arteries to the head, arms, spinal cord, intestines, and kidneys may originate from the aneurysm. An endovascular repair of a TAAA is only possible if blood flow to these critical arteries is preserved. Hybrid procedures offer one option, but a more direct approach involves the use of a branched endograft. However, the complex anatomy associated with the supra-aortic vessels is particularly difficult to accommodate with branched endograft devices. Dr. Timothy Chuter pioneered this approach, with a completely endovascular solution. After partial deployment of the main body of an endograft, separate endograft limbs are deployed from the main body to each major aortic branch. This procedure is long, technically difficult, and currently only performed in a few centers.
When the aneurysm begins above the renal arteries, neither fenestrated endografts nor "EndoAnchoring" of an infrarenal endograft is useful (an open surgical repair may be necessary). Alternatively, a "branched" endograft may be used. A branched endograft has graft limbs that branch off of the main portion of the device to directly provide blood flow to the kidneys or the visceral arteries.

Hybrid procedures
On occasion, there is inadequate length or quality of the proximal or distal aortic neck. In these cases, a fully minimally invasive option is not possible. One solution, however, is a hybrid repair, which combines an open surgical bypass with EVAR or TEVAR. In hybrid procedures, the endograft is positioned over major aortic branches. While such a position would normally cause problems from disruption of blood flow to the covered branches (renal, visceral, or branches to the head or arms), the prior placement of bypass grafts to these critical vessels allowed the deployment of the endograft at a level that would otherwise not be possible.If a patient has calcified or narrow femoral arteries that prohibit the introduction of the endograft transfemorally, an iliac conduit may be used. This is typically a piece of PTFE that is sewn directly to the iliac arteries, which are exposed via an open retroperitoneal approach. The endograft is then introduced into the aorta through the conduit.In patients with thoracic aortic disease involving the arch and descending aorta, it is not always possible to perform a completely endovascular repair. This is because head vessels of the aortic arch supplying blood to the brain cannot be covered and for this reason, there is often an inadequate landing zone for stent-graft delivery. A hybrid repair strategy offers a reasonable choice for treating such patients. A commonly used hybrid repair procedure is the "frozen elephant trunk repair". This technique involves midline sternotomy. The aortic arch is transected and the stent-graft device is delivered in an ante-grade fashion in the descending aorta. The aortic arch is subsequently reconstructed and the proximal portion of the stent-graft device is then directly sutured into the surgical graft. Patients with anomalies of the arch and some disease extension into the descending aorta are often ideal candidates. Studies have reported successful use of hybrid techniques for treating Kommerell diverticulum and descending aneurysms in patients with previous coarctation repairs.In addition, hybrid techniques combining both open and endovascular repair are also used in managing emergency complications in the aortic arch, such as retrograde ascending dissection and endoleaks from previous stent grafting of descending aorta. A "reverse frozen elephant trunk repair" is shown to be particularly effective.

Adjunctive procedures
Snorkel: A covered stent placed into a visceral vessel adjacent to the main body of the EVAR device. The aortic lumen of the visceral stent is directed superiorly, resembling a snorkel.
Chimney: In TEVAR, a covered stent placed from the ascending aorta to a great vessel (e.g., innominate artery) and adjacent to the main body of the EVAR is termed a chimney. In anatomic position, blood flows superiorly through a chimney-stent graft into the great vessel, just as smoke flows up a chimney.
Periscope: Like a snorkel, a periscope stent graft provides flow to a visceral vessel, but in a retrograde fashion, with the aortic lumen inferior to the main body of the EVAR device.
Stents: Large bare-metal stents have been used to treat proximal endoleaks, as have aortic extension cuffs to treat endograft migration.
Glue: Trans-catheter embolic glue has been used to treat type I endoleaks, with inconsistent success.
EndoAnchors: Small, helically shaped devices are screwed through the endograft and into the aortic wall. EndoAnchors have been used successfully to treat endoleaks and, in concert with an aortic extension endograft, to treat migration of the original endograft. Rigorous evaluations and long-term outcomes of this technique are not yet available.

Risks
The complications of EVAR can be divided into those that are related to the repair procedure and those related to the endograft device. For example, a myocardial infarction that occurs immediately after the repair is normally related to the procedure and not the device. By contrast, the development of an endoleak from degeneration of endograft fabric would be a device-related complication.Durability and problems such as endoleaks may require careful surveillance and adjuvant procedures to ensure the success of the EVAR or EVAR/hybrid procedure. CT angiography (CTA) imaging has, in particular, made a key contribution to planning, success, durability in this complex area of vascular surgery.A major cause of complications in EVAR is the failure of the seal between the proximal, infra-renal aneurysm neck and the endovascular graft. Risk of this form of failure is especially elevated in adverse or challenging proximal neck anatomies, where this seal could be compromised by unsuitable geometric fit between the graft and vessel wall, as well as instability of the anatomy. New recent techniques have been introduced to address these risks by utilizing a segment of the supra-renal portion of the aorta to increase the sealing zone, such as with fenestrated EVAR, chimneys and snorkels. These techniques may be suitable in certain patients with qualifying factors, e.g., configuration of renal arteries, renal function.  However, these are more complex procedures than standard EVAR and may be subject to further complications.An approach that directly augments the fixation and sealing between the graft and aorta to mimic the stability of a surgical anastomosis is EndoAnchoring. EndoAnchors are small, helically shaped implants that directly lock the graft to the aortic wall with the goal to prevent complications of the seal, especially in adverse neck anatomies. These EndoAnchors may also be used to treat identified leaks between the graft and proximal neck.

Procedure-related
Arterial dissection, contrast-induced kidney failure, thromboembolizaton, ischemic colitis, groin hematoma, wound infection, type II endoleaks, myocardial infarction, congestive heart failure, cardiac arrhythmias, respiratory failure.

Device-related
Endograft migration, aneurysm rupture, graft limb stenosis/kinking, type I/III/IV endoleaks, stent graft thrombosis, or infection.

Endoleaks
An endoleak is a leak into the aneurysm sac after endovascular repair. Five types of endoleaks exist:
Type I - Perigraft leakage at proximal or distal graft attachment sites (near the renal and iliac arteries)
Type II - Retrograde flow to the aneurysm sac from branches such as the lumbar and inferior mesenteric arteries. Type II endoleaks are the most common, and least serious type of endoleak. Type II endoleaks do not require immediate treatment, as a portion will resolve spontaneously.
Type III - Leakage between overlapping parts of the stent (i.e., the connection between overlapping components) or rupture through graft material.
Type IV - Leakage through the graft wall due to the quality (porosity) of the graft material. As seen in first-generation grafts, changes in graft material in modern devices have decreased the prevalence of type IV leaks.
Type V - Expansion of the aneurysm sac without an identifiable leak. Also called "endotension".Type I and III leaks are considered high-pressure leaks and are more concerning than other leak types. Depending on the aortic anatomy, they may require further intervention to treat. Type 2 leaks are common and often can be left untreated unless the aneurysm sac continues to expand after EVAR.

Spinal cord injury
Spinal cord injury is a devastating complication after aortic surgery, specifically for thoracoabdominal aortic aneurysm repair; severe injury could lead to urine and fecal incontinence, paresthesia and even paraplegia. The risk varies between studies with two metanalysis demonstrating a pooled incidence of spinal cord injury 2.2% and 11%. Predictive factors include increasing extent of coverage, hypogastric artery occlusion, prior aortic repair and perioperative hypotension. Spinal cord injury related to aortic repair occurs due to impaired blood flow to the spine after coverage of blood vessels, important to the blood circulation of the spine, namely intercostal- and lumbar arteries. A few methods exist for potentially reversing spinal cord injury, if it arises, elevated blood pressure, increased oxygenation, blood transfusion and cerebrospinal fluid drainage.

Cerebrospinal fluid drainage
Cerebrospinal fluid drainage is one of the adjunct methods used to reverse spinal cord injury. With increased drainage of spinal fluid, the intrathecal pressure decreases which allows for increase blood perfusion to the spine, possibly reversing the ischemic injury of the spinal tissue due to lessened blood supply. The benefits of this procedure have been established in open aortic repair and suggested in endovascular aortic repair.

Recovery after EVAR
Unlike traditional aortic repair, standard recovery after EVAR is remarkably straightforward. Patients who have undergone EVAR typically spend one night in the hospital to be monitored, although it has been suggested that EVAR can be performed as a same-day procedure.Patients are advised to slowly return to normal activity </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Centrifugal abdominal lipodystrophy and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hutchinsons triad and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Non-small-cell lung carcinoma and can you explain it in depth? [/INST] Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively (neoadjuvant chemotherapy) and postoperatively (adjuvant chemotherapy).

Types
The most common types of NSCLC are squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma, but several other types occur less frequently. A few of the less common types are pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma. All types can occur in unusual histologic variants and as mixed cell-type combinations. Nonsquamous-cell carcinoma almost occupies the half of NSCLC. In the tissue classification, the central type contains about one-ninth.Sometimes, the phrase "not otherwise specified" (NOS) is used generically, usually when a more specific diagnosis cannot be made. This is most often the case when a pathologist examines a small number of malignant cells or tissue in a cytology or biopsy specimen.Lung cancer in people who have never smoked is almost universally NSCLC, with a sizeable majority being adenocarcinoma.On relatively rare occasions, malignant lung tumors are found to contain components of both SCLC and NSCLC. In these cases, the tumors are classified as combined small-cell lung carcinoma (c-SCLC), and are (usually) treated as "pure" SCLC.

Lung adenocarcinoma
Adenocarcinoma of the lung is currently the most common type of lung cancer in "never smokers" (lifelong nonsmokers). Adenocarcinomas account for about 40% of lung cancers. Historically, adenocarcinoma was more often seen peripherally in the lungs than SCLC and squamous-cell lung cancer, both of which tended to be more often centrally located. Recent studies, though, suggest that the "ratio of centrally to peripherally occurring" lesions may be converging toward unity for both adenocarcinoma and squamous-cell carcinoma.

Squamous-cell lung carcinoma
Squamous-cell carcinoma (SCC) of the lung is more common in men than in women. It is closely correlated with a history of tobacco smoking, more so than most other types of lung cancer. According to the Nurses Health Study, the relative risk of SCC is around 5.5, both among those with a previous duration of smoking of 1 to 20 years, and those with 20 to 30 years, compared to "never smokers" (lifelong nonsmokers). The relative risk increases to about 16 with a previous smoking duration of 30 to 40 years, and roughly 22 with more than 40 years.

Large-cell lung carcinoma
Large-cell lung carcinoma (LCLC) is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung. LCLCs have typically comprised around 10% of all NSCLC in the past, although newer diagnostic techniques seem to be reducing the incidence of diagnosis of "classic" LCLC in favor of more poorly differentiated SCCs and adenocarcinomas. LCLC is, in effect, a "diagnosis of exclusion", in that the tumor cells lack light microscopic characteristics that would classify the neoplasm as a small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma, or other more specific histologic type of lung cancer. LCLC is differentiated from SCLC primarily by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of "salt-and-pepper" chromatin.

Symptoms
Many of the symptoms of NSCLC can be signs of other diseases, but having chronic or overlapping symptoms may be a signal of the presence of the disease. Some symptoms are indicators of less advanced cases, while some may signal that the cancer has spread. Some of the symptoms of less advanced cancer include chronic cough, coughing up blood, hoarseness, shortness of breath, wheezing, chest pain, weight loss, and loss of appetite. A few more symptoms associated with the early progression of the disease are feeling weak, being very tired, having trouble swallowing, swelling in the face or neck, and continuous or recurring infections such as bronchitis or pneumonia. Signs of more advanced cases include bone pain, nervous-system changes (headache, weakness, dizziness, balance problems, seizures), jaundice, lumps near the surface of the body, numbness of extremities due to Pancoast syndrome, and nausea, vomiting, and constipation brought on by hypercalcemia. Some more of the symptoms that indicate further progression of the cancer include shortness of breath, superior vena cava syndrome, trouble swallowing, large amounts of mucus, weakness, fatigue, and hoarseness.

Cause
Smoking is by far the leading risk factor for lung cancer. Cigarette smoke contains more than 6,000 components, many of which lead to DNA damage (see table of tobacco-related DNA damages in Tobacco smoking).
Other causes include radon, exposure to secondhand smoke, exposure to substances such as asbestos, chromium, nickel, beryllium, soot, or tar, family history of lung cancer, and air pollution.Genetics can also play a role as a family history of lung cancer can contribute to an increased risk of developing the disease. Furthermore, research has revealed specific chromosome regions associated with increased risks of developing lung cancer. In general, DNA damage appears to be the primary underlying cause of cancer. Though most DNA damages are repairable, leftover unrepaired DNA damages from cigarette smoke are the likely cause of NSCLC.
DNA replication past an unrepaired damage can give rise to a mutation because of inaccurate translesion synthesis.  In addition, during repair of DNA double-strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can lead to epigenetic gene silencing.

DNA repair deficiency in NSCLC
Deficiencies in DNA repair underlie many forms of cancer. If DNA repair is deficient, the frequency of unrepaired DNA damages increases, and these tend to cause inaccurate translesion synthesis leading to mutation.  Furthermore, increased damages can elevate incomplete repair, leading to epigenetic alterations.As indicated as in the article Carcinogenesis, mutations in DNA repair genes occasionally occur in cancer, but deficiencies of DNA repair due to epigenetic alterations that reduce or silence DNA repair-gene expression occur much more frequently in cancer.Epigenetic gene silencing of DNA repair genes occurs frequently in NSCLC.  At least nine DNA repair genes that normally function in relatively accurate DNA repair pathways are often repressed by promoter hypermethylation in NSCLC.  One DNA repair gene, FEN1, that functions in an inaccurate DNA repair pathway, is expressed at an increased level due to hypo-, rather than hyper-, methylation of its promoter region (deficiency of promoter methylation) in NSCLC.
The frequent deficiencies in accurate DNA repair, and the increase in inaccurate repair, likely cause the high level of mutation in lung cancer cells of more than 100,000 mutations per genome (see Whole genome sequencing).

Staging
Staging is a formal procedure to determine how developed the cancer is, which determines treatment options.
The American Joint Committee on Cancer and the International Union Against Cancer recommend TNM staging, using a uniform scheme for NSCLC, SCLC, and bronchopulmonary carcinoid tumors. With TNM staging, the cancer is classified based on the size of the tumor and spread to lymph nodes and other organs. As the tumor grows in size and the areas affected become larger, the staging of the cancer becomes more advanced as well.
Several components of NSCLC staging then influence physicians treatment strategies. The lung tumor itself is typically assessed both radiographically for overall size and by a pathologist under the microscope to identify specific genetic markers or to see if invasion into important structures within the chest (e.g., bronchus or pleural cavity) has occurred.  Next, the patients nearby lymph nodes within the chest cavity, known as the mediastinum, are checked for disease involvement.  Finally, the patient is evaluated for more distant sites of metastatic disease, most typically with brain imaging and or scans of the bones.

Five-year survival rates
The survival rates for stages I through IV decrease significantly due to the advancement of the disease. For stage I, the five-year survival rate is 47%, stage II is 30%, stage III is 10%, and stage IV is 1%.

Treatment
More than one kind of treatment is often used, depending on the stage of the cancer, the individuals overall health, age, response to chemotherapy, and other factors such as the likely side effects of the treatment.  After full staging, the NSCLC patient can typically be classified in one of three different categories: patients with early, nonmetastatic disease (stages I and II, and select type III tumors), patients with locally advanced disease confined to the thoracic cavity (e.g., large tumors, tumors involving critical chest structures, or patients with positive mediastinal lymph nodes), or patients with distant metastasis outside of the thoracic cavity.

Early/nonmetastatic NSCLC
NSCLCs are usually not very sensitive to chemotherapy and/or radiation, so surgery (lung resection to remove the tumor) remains the treatment of choice if patients are diagnosed at an early stage.If the persons have a small, but inoperable tumor, they may undergo highly targeted, high-intensity radiation therapy.  New methods of giving radiation treatment allow doctors to be more accurate in treating lung cancers. This means less radiation affects nearby healthy tissues. New methods include Cyberknife and stereotactic body radiation therapy.  Certain people who are deemed to be higher risk may also receive adjuvant (ancillary) chemotherapy after initial surgery or radiation therapy.  A number of possible chemotherapy agents can be selected, but most involve the platinum-based chemotherapy drug called cisplatin.Other treatments include percutaneous ablation and chemoembolization. The most widely used ablation techniques for lung cancer are radiofrequency ablation (RFA), cryoablation, and microwave ablation. Ablation may be an option for patients whose tumors are near the outer edge of the lungs. Nodules less than 1 cm from the trachea, main bronchi, oesophagus, and central vessels should be excluded from RFA given high risk of complications and frequent incomplete ablation. Additionally, lesions greater than 5 cm should be excluded and lesions 3 to 5 cm should be considered with caution given high risk of recurrence. As a minimally invasive procedure, it can be a safer alternative for patients who are poor candidates for surgery due to comorbidities or limited lung function. A study comparing thermal ablation to sublobar resection as treatment for early stage NSCLC in older people found no difference in overall survival of the patients. It is possible that RFA followed by radiation therapy has a survival benefit due to synergism of the two mechanisms of cell destruction.

Advanced/metastatic NSCLC
The treatment approach for people who have advanced NSCLC is first aimed at relieving pain and distress (palliative), but a wide variety of chemotherapy options exists. These agents include both traditional chemotherapies, such as cisplatin, which indiscriminately target all rapidly dividing cells, and newer targeted agents, which are more tailored to specific genetic aberrations found within a persons tumor. When choosing an appropriate chemotherapy approach, the toxicity profile (side effects of the drug) should be taken into account and balanced with the persons comorbidities (other conditions or side effects that the person is experiencing). Carboplatin is a chemotherapy agent that has a similar effect on a persons survival when compared to cisplatin, and has a different toxicity profile from cisplatin. Carboplatin may be associated with a higher risk of thrombocytopenia. Cisplatin may cause more nausea or vomiting when compared to carboplatin treatment.At present, two genetic markers are routinely profiled in NSCLC tumors to guide further treatment decision-making - mutations within epidermal growth factor (EGFR) and anaplastic lymphoma kinase. Also, a number of additional genetic markers are known to be mutated within NSCLC and may impact treatment in the future, including BRAF, HER2/neu, and KRAS. For advanced NSCLC, a combined chemotherapy treatment approach that includes cetuximab, an antibody that targets the EGFR signalling pathway, is more effective at improving a persons overall survival when compared to standard chemotherapy alone.Thermal ablations, i.e. RFA, cryoablation, and microwave ablation, are appropriate for palliative treatment of tumor-related symptoms or recurrences within treatment fields. People with severe pulmonary fibrosis and severe emphysema with a life expectancy less than a year should be considered poor candidates for this treatment.

EGFR mutations
Roughly 10–35% of people who have NSCLC will have drug-sensitizing mutations of the EGFR. The distribution of these mutations has been found to be race-dependent, with one study estimating that 10% of Caucasians, but 50% of Asians, will be found to have such tumor markers. A number of different EGFR mutations have been discovered, but certain aberrations result in hyperactive forms of the protein.  People with these mutations are more likely to have adenocarcinoma histology and be nonsmokers or light smokers.  These people have been shown to be sensitized to certain medications that block the EGFR protein known as tyrosine kinase inhibitors specifically, erlotinib, gefitinib, afatinib, or osimertinib.
Reliable identification of mutations in lung cancer needs careful consideration due to the variable sensitivity of diagnostic techniques.

ALK gene rearrangements
Up to 7% of NSCLC patients have EML4-ALK translocations or mutations in the ROS1 gene; these patients may benefit from ALK inhibitors, which are now approved for this subset of patients. Crizotinib, which gained FDA approval in August 2011, is an inhibitor of several kinases, specifically ALK, ROS1, and MET.  Crizotinib has been shown in clinical studies to have response rates around 60% if patients are shown to have ALK-positive disease </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Umbilical granuloma and can you explain it in depth? [/INST] Umbilical granuloma is the most common umbilical abnormality in newborn children or neonates, causing inflammation and drainage. It may appear in the first few weeks of newborn infants during the healing process of the umbilical cord due to an umbilical mass. It is the overgrowth of the umbilical tissue. It develops in about 1 out of 500 newborns. With appropriate treatment, it is expected to heal in 1~2 weeks.

Causes
Following umbilical cord clamping during delivery, the umbilicus base will spontaneously separate  within 7-15 days. With routine cord care and proper hygienic conditions, the remaining umbilical base will heal and new skin tissue will form. In some instances, a mass of tissue, or granuloma, will form at the base.Umbilical granulomas occur after umbilical cord removal when the remaining ring of the umbilicus undergoes incomplete wound healing and there is excessive healing tissue, also known as granulation tissue.Delayed cord separation, mild infections and hygienic conditions are all factors which may contribute to the incidence of umbilical granuloma. Although the exact cause of umbilical granulomas is unknown, it is hypothesized that inflammation of the remaining umbilical stump drives skin cell division, resulting in a tissue mass, rather than proper healing at the site.

Histophysiology
An umbilical granuloma is a physiological response which surpasses the normal processes of skin restoration following umbilical cord clamping. Once the skin lesion is formed, there is an excess of fibroblast production. These fibroblasts, or connective tissue cells, are responsible for the production of collagen and additional fibers, resulting in the excess tissue mass found in the granuloma. Additional histological studies reveal an increase of cell division of vascular endothelial cells. These cells line our blood vessels and are further responsible for the growth and development of tissue and the formation of new blood vessels within the granuloma.

Pathophysiology
Inflammatory saprophytic microorganisms, involved with decomposition, may delay the healing process, and can lead to overproduction of fibroblasts that are involved in normal skin restoration. These microorganisms can interfere with the skin’s normal flora, and lead to increased pathogenic inflammation that leads to delayed epithelialization and the formation of granulomas with excessive blood vessels, fibroblasts, and mucus.

Signs and symptoms
Umbilical granulomas appear as round, pink lumps found at the base of the umbilicus after the removal of the umbilical cord. It appears small, pink/red, and moist due to cord separation. They are usually 1-10 mm in size, however grow in size if they are not treated. Umbilical granulomas are also painless since they do not contain nerve fibers. In some cases, they may contain an odorless discharge, or may be covered in a clear mucus. The surrounding skin of the infants umbilicus site will appear normal. Umbilical granulomas can become entry points for infectious agents. Symptoms such as edema, redness around the umbilical site, pain or discomfort when the area is touched, accompanied by a fever and purulent discharge, may indicate sepsis or a serious infection at the umbilicus site.

Diagnosis
Umbilical granuloma can be diagnosed from physical examination. If there is a discharge around the navel and the granulation tissue is large enough to be visible with the open eye, umbilical granuloma is the first to be suspected. Open eye inspection and/or dermoscopy is commonly used to recognize the granular tissue at the site. If the granuloma is not visible with the open eye, gentle pressure on the surrounding site or a surgical tweezer can be used to expose the small granuloma hidden within the umbilical pit. An otoscope may also be used by physicians in order to expose a small, sessile granuloma. Other additional tests are usually not required, but if continued, ultrasonography (US) can be used for initial diagnosis of umbilical lesions.

Treatment
Topical
Although there is no singular method of treatment for umbilical granulomas, some treatment options available include common salt, silver nitrate, corticosteroids, and cleaning with alcohol. Home care following treatments include gentle cleaning the navel area with soap and sterile water, followed by open exposure of the belly button to air.

Silver nitrate
Silver nitrate is the most common treatment and practiced worldwide. Neonatology textbooks suggest silver nitrate as a first-line treatment option. The application of silver nitrate to granulomas was first noted in early 1800s as a cauterizing agent.Silver nitrate can be used as an antiseptic, an astringent, and as a caustic agent, depending on the indication. Its application requires medical personnel for treatment and may have unfavorable adverse effects if applied improperly. In the treatment of umbilical granulomas, silver nitrate is applied to the umbilical site to burn off the excess tissue. The absence of nerve endings within the granuloma make this a painless treatment for the newborn. While painless, contact of silver nitrate to the adjacent, healthy, normal tissue may result in burns. Silver nitrate application to the infected site should not exceed three applications with an interval of 3-4 days. In this event, alternative treatments should be considered Following treatment with silver nitrate, the granuloma is expected to shrink and resolve within 7 days.

Double-ligature treatment
In cases with deeply located umbilical granulomas, the double-ligature technique can be utilized to ligate the base of the granuloma. The procedure involves prepping and sterilizing the umbilical area with iodine solution, placing a silk suture around the base of the lesion to keep in place, and finally placing a more exact ligature around the granuloma. Much like the normal process of umbilical cord residue healing, the ligated granuloma will necrose due to lack of blood supply and will fall off naturally within 1 to 2 weeks. Minor complications of this technique include minimal bleeding and possibly requiring more ligatures than the original double ligation.

Cryocautery
Cryocautery can be utilized to freeze the umbilical granuloma by using cryogenic nitrous oxide along with other equipment. During cryocautery procedures, the umbilical site is first cleaned. The physician will then hold a cyroprobe with nitrous oxide as a refrigerant directly to the granuloma for 3 minutes. One risk of utilizing this technique is burning the skin surrounding the granuloma. Following the procedure, the naval site is cleansed, left exposed to the air and the infant is discharged. Cyrocautery is more commonly used for freezing for post hysterectomy granulation tissue </s>