Archive for December, 2007.
This is the histologic appearance of the clear cell carcinomas. It’s obvious why this tumor is called a clear cell carcinoma. You look at the morphology of the cells and the nuclei here. Compare that with this slide where there is a granular appearance. This is basically the same type of a tumor. So both this appearance and the clear cell appearance, that I just showed you, are considered to be the run-of-the-mill, garden variety, renal cell carcinoma. So that the tumors, the majority of the renal cell carcinomas that you see, can have either that clear cell appearance or this granular appearance. And as you see, the morphology of these cells is very similar, except that the cytoplasm stains pinkish. But the morphology of the nuclei is very similar, the morphology of the cells is very similar. There used to be a distinction between these two but these are really both classified as clear cell carcinomas. And are treated in the same fashion.
This is a histologic example of papillary carcinoma and you can see the papillary fronds of the tumor. And there is some debate as to whether papillary carcinomas represent a better prognosis or about the same prognosis as the more common clear cell carcinomas. This was from a report in 2006 where they found that in their review, papillary carcinomas tended to present at an earlier stage and the survival for the earlier stages was better than those for what they are calling conventional renal cell carcinomas. This was true not only for stage I but across stages as well, it seemed like survival was better. Like I said, there is some controversy about this but there are some authors who feel that the papillary carcinomas have a better prognosis.
This is simply a slide of a chromophobe renal cell carcinoma. I just included it for completeness. I don’t really have a lot to say about this minor variant. This is a transitional cell carcinoma which will arise in the renal pelvis. And the most important thing about this tumor is that you remember to treat it as if it was a bladder carcinoma, with respect to chemotherapy. These tumors I do not treat with immunotherapy but I do treat them with MVAC-type regimens. The tumor arises in the transitional epithelium in the pelvis so it makes a lot of logical sense and as well, as it turns out, clinical sense to treat these tumors in that fashion.
Renal cell carcinoma constitutes about 3% of all malignancies, so it’s not a common tumor. There’s about 25,000 cases annually in the United States that that results in about 10,000 deaths. There’s a male to female predominance of 2:1 and there’s a similar incidence in both black and white populations. It is a disease of the elderly; most of the cases present in ages 50-70, although certainly presentations in younger patients occur. The youngest patient I’ve had is somebody who is 16-years-old when he developed a renal cell carcinoma. There is an increased risk associated with cigarette smoking and the disease occurs in sporadic and familial forms.
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Now the von Hippel-Lindau syndrome is not a major health problem in the United States but it was useful in defining the genetic abnormalities that occur in both an inherited form of renal cell carcinoma as well as an acquired form. In general, those abnormalities occur on chromosome 3. This just summarizes some of the features of the von Hippel-Lindau syndrome. A multi-focal, bilateral clear cell carcinoma of the kidney occurs in about 35% of the patients with this syndrome. In your hand-out there’s a diagram of where the genetic abnormalities occur on chromosome 3 in VHL. Chromosomal abnormalities in the same area occur in patients with acquired clear cell carcinomas of the kidney as well. There is also a hereditary form of renal cell carcinoma which manifests as papillary tumors. These chromosomal abnormalities are on chromosome 8 and the median age of patients with this tumor is 52-years. Now there is a third, what I would consider hereditary, form of renal cell carcinoma and this is a much rarer form of the disease. These are renal medullary carcinomas and they occur in young patients with the sickle cell trait. Advanced presentation is typical and these tumors typically pursue a very aggressive course. The median survival is 15 weeks. As these things go, I saw three cases of this syndrome in the space of about four months when I was at the Lombardi Cancer Center and then didn’t see any others for the remaining time that I was there. So it is a fairly uncommon presentation but if you have a young patient, especially if they are African-American, it might be useful to check them for sickle cell trait; especially if they have a medullary-type of histology.
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These are the subtypes of renal cell carcinoma. The majority of the renal cell carcinomas are what we call clear cell carcinomas. About 70% of patients. The papillary version, which is also referred to as a chromophilic tumor, occurs in about 20% of the patients. Chromophobics are 5% and then other histology’s, including the renal medullary carcinomas and the transitional cell carcinomas and the collecting duct tumors, represent the other 5%. There’s a sarcomatoid variant which I’ll talk about in a little bit, which is actually a variant of the clear cell carcinomas.
Complications of radical prostatectomy are well-known and the most bothersome ones are impotence and incontinence. There is also a risk of mortality because this is a surgical procedure. For that interest I think radiation therapy will offer some alternatives. The complications are different for the two procedures. Surgery, as we said, has an immediate mortality; incontinence and impotence. Radiation therapy causes irritation to the rectum and bladder, which usually gets better over time, although you can have some scarring. Both of them can actually produce impotence and fatigue. Impotence following radiation therapy is usually more slow to develop. It develops gradually over time but it is there as a complication. Whereas in surgery it’s an immediate, one-time issue. There have been improvements in therapy, in both radiation and surgical areas. Surgeons are interested in so-called nerve-sparing prostatectomies, which lower the risks of impotence in these patients. Cryosurgery has been done in both modalities, neo-adjuvant hormonal therapy, which I will come to in a minute - has also been done. Radiation therapy has undergone improvements also. We now have better radiation planning and radiation implants for low stage patients with needles be put into the prostate, rather than external beam radiation.
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The optimal strategy then for localized disease remains somewhat controversial. I think that the data that we have so far suggests that radical prostatectomy is the best proven method for disease-free survival. However, I think neither of these techniques - again, very analogous to breast cancer where they are dealing with radiation or surgery - neither of them are going to have an optimal impact on overall mortality until you can get something to go in systemically for the patients who have microscopic metastases. Remember the slide I showed you earlier, it showed that upwards of 30-50% of these people are going to have occult lymph node involvement even with clinically localized disease. These people are not going to be salvaged by whatever you do for local therapy. There is some data and a great deal of interest now starting to emerge in using adjuvant or neo-adjuvant androgen depletion in these patients. This shows data from patients who underwent prostatectomy alone or prostatectomy with orchiectomy and you can see the improved survival in this group of patients. So we are now very interested in using somewhere between 6 and 9 months of anti-androgen therapy in addition to local treatment for patients who have high risk tumors. Female pink viagra
With regard to metastatic prostate cancer, in the last couple of slides, the major therapy is related to androgen depletion. This can be done by orchiectomy. This can be done by using estrogens, which are seldom used today because of the complications of estrogen. It’s done most popularly today by using gonadotropin releasing hormone analogs and these have all been shown to be of equal efficacy. There has been some interest in using flutamide, which is an androgen receptor blockade, to provide so-called total androgen blockade. The data with that has, I think, been somewhat controversial. This cartoon I think reflects the problem. This is of course the testicle and the testosterone being reduced by blocking the gonadotropin releasing hormone to cut down on testicular testosterone. You still have the adrenal gland _ which can convert it to 5-alpha reductase to DHT so by blocking this or by blocking the androgen receptor you can have more complete androgenic blockade. Despite the fact that this looks good theoretically and the fact that this early study did show a slight survival advantage for total androgenic blockade, it looks now that there is really minimal, you know, slim to none, none to minimal advantage of using both gonadotropin releasing hormone agonist, and probably gonadotropin releasing hormone agonist alone is adequate therapy for metastatic disease.
The final slide I will show you for prostatism is that there are chemoprevention efforts that are getting under way using the retinoids, using the 5-alpha reductase inhibitors and looking at low fat diets to see whether we can modify incidence of disease, not just deal with it from screening positivity. So thank you very much.
Now these are the stages, the staging distribution that you will find by and large. I think this is slightly out of date by this time in the sense that the A-lesions, because of the A-3 increase in PSA determinations are going be higher, but you can see that about 60% of patients who localized, about a quarter of the patients are going to have metastatic disease. And this is a fairly representative distribution of a series of patients with this. Except, as I said, for probably an increase in the A’s and a decrease in the B’s.
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I already alluded to this and that is the problem of early diagnosis. There are several problems posed by early diagnosis which really basically equates with someone who has a PSA level that’s elevated, gets worked up and is found to have the disease. The issues of early diagnosis are: first of all, does it really improve survival? This has been argued about. As I said, the data presented at this year suggests that there is a mortality reduction with PSA screening, but not surprisingly that study was jumped on as soon as it was out of the box and attacked by many statisticians as being seriously flawed. I think that usually until you have a second study that reproduces positive data it’s hard to be certain that a single trial is definitive. So I think there are still issues about whether these lesions that are found in PSA elevation only will translate into improved survival with treatment. Therefore we have still this year one of the most accurate measurements for early detection, given the specificity issues with PSA. Can we distinguish clinically significant disease from that which is not significant? And finally, what is the most effective form of therapy for these early stage patients? Particularly those found by PSA? One of the things that turns out to be very useful in assessing what you are dealing with is the use of tumor grading. And there are multiple ways you can grade these tumors. You can look at flow psychometry, you can get flow levels, you can look at nuclear morphology but the architectural formation, the so-called Gleason system I think has been the most useful to date in establishing the grade of the tumors. This cartoon shows you what the Gleason system is all about. Basically what we have in the Gleason system. You can see this is a Gleason grade 1, this is a Gleason grade 5. These are well differentiated that look much like normal prostatic tissue. You can see various degrees of un-differentiation. So what they do is they look at two areas of the tumor and they grade the dominant area and the less dominant area because there are often discordances and they give each of those two areas of Gleason scores. So you can have as low as a 2 or as high as a 10, in terms of grade. We know that patients who have a low Gleason score - and I’m talking particularly about these PSA level determination patients, or patients with very small amounts of tumor involving prostatic chips - if you’ve got a low PSA level under 10, a low Gleason score and a small volume tumor, the rate of progression over the next ten years is very very low. It is in the low single digits. So if you are looking at a 75-year-old man with those characteristics you might proceed one way, whereas if you are looking at a 50-year-old man with a Gleason grade of 6 and A-2 tumor, that patient clearly is at risk before a normal life span passes needs therapy. So the Gleason grade is a very useful thing in assessing when to walk or when to run to the nearest exit. I think that if you combine the Gleason score with the PSA levels over or under 10 and measure tumor volume, gives you a fairly useful construct for thinking about management.
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Again, before we had the Gleason score and the PSA level, we just looked at volume of disease. You can see that these are the patients detected by TURP chips, small amounts of tumor involved. Much better prognosis than more extensive disease. These are all people with no palpable disease. This is multiple chips involved. Much higher rate of progression.
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So if you have prostate cancer, these are the choices that you have available to you. You have observations, surgical radical prostatectomy, external radiation, radiation implants, androgen depletion, some combinations of the above. As I’ve already said, patients who have favorable characteristics might be good candidates for observation only. With regard to the other therapies, we have some data, although it tends not to be randomized and prospected. This is pooled data from series that have either done prostatectomy or radiation therapy. You can see these are from B-1, that is nodules that are palpable under 1.5 cm, for survival up to 10 years looks the same with either radiation or a radical prostatectomy. Again, this is some surgical data looking at B-1’s B-2’s and you can see that with surgery, you are going to have about half of the patients living and cancer free 10 years after therapy. And again, the radiation data looks pretty similar to this. You are talking about an 80-90% five year, and about 50% ten years. That is significant because it means there is going to be some drop off in survival even after the fifth year from this disease. Some of it is due to co-morbidities as these are often older patients but there is some continuing mortality from the disease as time goes by.
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If you get a positive diagnosis of cancer as the result of these biopsies, the patient, like other types of malignancies, will undergo some type of staging evaluation. There’s a staging system for prostate cancer which is an ABCD system which is still probably the most common that’s used, and there are certain subtypes within it. A-disease in prostate cancer means you have nothing palpable. A-disease used to be found by patients who were undergoing a transurethral prostatectomy for prostatism and then fragments of prostate tissue were reamed out in the procedure and they were looked at under a microscope. If they found tumor that was low grade or involved three or fewer fragments of tissue, the patient was a so-called A-1. If they found disease in the tissue diffusely with multiple chips involved, the patient was an A-2. Today there is a different category as well. An additional category called A-3 and that is prostate cancer that is diagnosed only because biopsies were done in the face of an elevated PSA level and not surprisingly, A-3 is the fastest or most rapidly rising diagnostic category today as more and PSA levels are used. B-disease in prostatic cancer means that there is a palpable lump. It can either be smaller, which is a B-1 less than 1.5 cm or a larger nodule but still confined to the prostate would be B-2. C-disease is extracapsular extension and again this depends on the size of the lesion whether it extends to the pelvic side wall and these were smaller or larger lesions. D-disease is metastatic prostate cancer. D-1 disease is confined to pelvic lymph nodes. D-2 disease usually means bony metastasis. So that’s the staging system one would employ after making a diagnosis.
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You can somewhat predict what you are going to get based on what is present on the prostatic exam. If the patient has a nodule, particularly if it is a large nodule or extracapsular extension, this is very predictive that there has been spread to at least lymph nodes. The disease mechanism of spread is to the lymph nodes in the absence of perivertebral plexus and to bones, primarily of the pelvis and spine. The bone lesions are almost always sclerotic. You can have lytic lesions in prostate cancer but they represent a small minority of the bone lesions. In the patient who has a prostate nodule and lytic bone lesions might well have localized prostatic cancer and metastatic malignancy of a different type. Often staining tissue from a histologically lytic bone lesion from PSA would help to determine whether or not this is metastatic prostate cancer or if a patient with, let’s say, with a prostate tumor localized and metastatic lung cancer at the same time.
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This just shows the status of lymph nodes at laparotomy in patients with palpable and non-palpable lesions. As you can see - and these are patients done by transurethral resection and nothing palpable - this is the proportion of lymph node metastases when you actually go in and sample pelvic nodes. What you can see here is that this very much increases in patients who either have diffuse disease or larger nodules or extracapsular extension. So if we have localized disease here there is a fairly high incidence of nodal involvement in pelvic nodes. The only groups really with low involvement are small nodules or patients with very small numbers of chips involved. If you look at the other stage of tests that we talked about, usually a CT-scan is a good way to stage pelvic lymph nodes. This is a large pelvic lymph node and here again are the bony metastases which are almost _ and show up as very very hot on bone scans, because bone scans of course measure osteoblastic activity.
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Remember also that cancer is not usually associated with symptoms of BPH. Symptoms of BPH result from having hypertrophy of the glandular tissue in the periurethral area and cancer usually involves the posterior lobes. So most people with cancer and having symptoms of prostatism simply have both. They don’t have prostatism symptoms as a result of having the malignancy.
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This would be one algorithm for screening that I think is reasonable. Now there has been a lot of argument about PSA level for screening and particularly whether it actually translates into any mortality advantage. There is no question that it is a sensitive test but what does it all mean? A large study from Canada that appeared to show a mortality reduction through the use of PSA screening in Canadian men. If we assume for the moment that there is a value to PSA screening in terms of how you would use this test, I would recommend something like this algorithm. That is, once you are going to start screening patients, and that would vary perhaps with the age and risk that a patient has. If you are going to start screening and the patient is normal risk without a family history, you could probably start screening - if you were going to do this and you believe in it - at about age 50. For patients who have a family history and are at high risk probably start a screening type of algorithm at perhaps age 40. The combination again of digital rectal exam and PSA I think is the way to go. Clearly if both of these are normal you would just simply re-screen the patient a year later. What more often happens is you have a normal rectal exam but the PSA is abnormal. In that situation I think a transrectal ultrasound can be a very useful way to look at the prostate. When you do that you may find that the ultrasound is normal and in that case if the PSA elevation is limited you may choose either random biopsies or further observation to see what’s going on and whether the PSA velocity or density is changing much over the observation period. If the ultrasound is normal but the PSA level is very high, probably biopsies would be indicated. In situations where the ultrasound is abnormal, obviously biopsy is necessary. In the situations where the digital exam is abnormal and the PSA is abnormal also, you would go on to biopsy. So the key thing here is to use these two things together and then if the PSA is abnormal, move on to an ultrasound and move accordingly from that. If the rectal exam and PSA are abnormal, move directly on to a biopsy type of procedure. Again, I think if you were going to screen, you would probably begin this sort of protocol at about age 50 in a normal risk person and perhaps age 40 in a high risk individual.
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Prostatic ultrasound. Here is the needle being put into an area of malignancy. It’s a nice technique for doing guided biopsies. I think ultrasound screening is not an appropriate first level test. I think the ultrasound should be reserved for evaluating abnormalities in either the PSA or digital rectal exam and shouldn’t be part of the first step in screening patients for this disease.