Enlarged Prostate Gland

Prostate Gland Enlargement

PKGhatak,MD

Prostate gland enlargement is due to excessive growth of normal prostate tissue. It is a common problem in elderly men. About 90% of elderly over 80 years of age will have some degree of prostatic enlargement. In the same population cancer of the prostate gland is also common.

Some doctors are gentle with patients when examining the prostate. Your gentle doctor will ask you to lie on your side on the examination table, ask you to pull your knees to your chest. Then he will put on a pair of gloves, gently insert a finger in your anal canal and feel the prostate gland. You may be embarrassed but will not feel any pain. Others are rough, ask you to drop your pants and bend over the examination table and then insert a gloved finger and do the examination. It is not only a crude way to examine but very much unnecessary. Ask for a gentle prostate examination when you go for an examination next time.

Why prostate enlarges:

It grows in proportion to the general growth since birth. At puberty, it grows rapidly and then returns to the usual growth pattern until men reach age 45. Then it starts to grow again. The reason for the second growth is not precisely known. It is postulated that when the blood levels of testosterone begin to fall at age 45, the gland begins to grow again. Others have suggested that the blood levels of testosterone might be below but in the prostate tissue the concentration of Dihydrotestosterone (DHT), derived from testosterone, a more potent agent for prostate growth, remains high and that causes prostate enlargement.

Cancer of the prostate is another cause of prostate enlargement.

Symptoms of Prostate enlargement or Benign Prostatic Hyperplasia (BPH):

Going to the toilet frequently, getting up at night multiple times to go to the toilet, cannot wait when has to go and then wetting underpants, feeling that the bladder did not empty fully, having difficulty in initiating urination, standing too long for starting urination, urine comes in drips and drops, blood in urine and painful urination from infection are symptoms of BPH

Cancer of the prostate usually produces the same symptoms and the two conditions may present at the same time.

How doctors know an enlargement is cancer:

There are no symptoms that are specific to cancer, but fresh blood in the urine and pain and discomfort in the genital area are more common in cancer.

Going to the doctor:

After an examination, the doctor may say the gland is not only large but hard and has lumps. But that is not diagnostic of cancer. A blood test – PSA level may be elevated but that is not enough. An ultrasound test through the rectum may show the irregular pattern of growth and nodules in the gland. But ultrasound test is not diagnostic either. An MRI of the prostate provides better information. A needle biopsy of the prostate is necessary for the diagnosis of cancer.

PSA test:

A protein secreted by the prostate cells known as Prostate Specific Antigen (PSA), is present in blood in free and bound forms.

The PSA test was introduced as a surveillance tool for detecting the recurrence of cancer in patients treated successfully. PSA levels fall to zero and remain zero following cancer treatment; the reappearance of PSA in the blood is an indication of cancer recurrence. Subsequently, it was used as a screening tool for prostate cancer. Later studies showed many patients were unnecessarily subjected to prostate biopsies and treatment on the basis of elevated levels of PSA. PSA is present in blood in free and bound forms. When total PSA is over the normal limits - 25 % or more of free PSA in relation to total PSA is associated with a low probability of cancer; whereas, a 10% or lower ratio of free PSA/ bound PSA is considered as positive for cancer. A rising level of PSA over time, a high ratio of PSA in relation to the prostate volume, and a sharp rise in the level over the previous year were considered as the presence of cancer. But none of these tests are not full proof, both false positive and false negative results are common.

A normal level of PSA is age specific. Blood levels of  2 to 4 ng/ml are generally accepted as normal for people between 45 and 79 years of age. For people 80 or over, a level up to 5.5 ng/ml is taken as normal.

At present, a routine PSA test for people over 80 years of age is not recommended.

Besides BPH and cancer, other causes of elevated PSA levels are - prostate infection, injury to the prostate, prostate examination, recent sexual activities, and urinary tract infection.

Prostate Biopsy:

The prostate gland is accessed through the wall of the rectum. Local or general anesthesia is used. It is still a painful procedure. 6 to 12 pieces of tissue are obtained during the biopsy. Prostate cancer grows at different rates at different sites and varies in the degree of abnormality from one side to the other, that is why multiple tissue samples are taken from different sites.

Based on the degree of abnormality of cells and the distortion of architecture of the glands, when examined under a microscope, a biopsy report is given a score from 2 to 10 on the Gleason score. A score of 10, being the most aggressive, and a core of 2 is atypical growth but not cancer.

 All 12 biopsy samples are individually assessed and graded on a 1 to 5 scale based on the degree of cancerous changes and architectural distortions. Only two samples with the highest grade are selected and reported and this is the basis of reporting on Gleason's score.

Like the interpretation of PSA tests, the prostate biopsy reports and interpretations are confusing. Quite often, Pathologists disagree among themselves when examining the same tissue sample.

If digital examination of the prostate gland, PSA, and ultrasound are indicative of a low chance of cancer, the doctor may recommend regular follow up with PSA tests before suggesting a biopsy or on the other hand, if the possibility of cancer is high then a biopsy will be recommended.

For treatment of BPH, the doctor may prescribe one of the two types of medications: 

One that decreases the frequency of urination and urgency:

They are called alpha-blockers. Urinary bladder contracts in response to alpha stimulation of the sympathetic nervous system. The neck of the bladder is rich in alpha receptors and alpha blockers block receptors and thereby interfere with bladder contraction and help relaxation of the bladder.

The other group of drugs is called 5- alpha reductase inhibitors.
These drugs block the action of 5-alpha reductase on testosterone and prevent the formation of Dihydrotestosterone (DHT), thus preventing prostate cell proliferation and gland growth. And when used on a long term it actually reduces cell volume and prostate size.

A combination of these two groups of drugs is available as tablets and is often prescribed.

Complications and surgery:

Common complications are- infection of urine and the prostate, acute urinary retention and backpressure in the bladder leading to a decrease in renal function.

Infections of the prostate and urinary bladder are treated with antibiotics and are followed by preventive therapy that includes surgery of the prostate.
Acute retention is relieved by inserting a catheter into the urinary bladder and may require to drain the bladder for a prolonged period by Foley catheters.

To relieve obstruction at the bladder neck by the enlarged prostate, the extra gland tissue is shaved off by instruments inserted through the urinary passage. The procedure is called Transurethral Resection of the Prostate (TURP), a modified version is called Transurethral Incision of the Prostate (TUIP), and by Open Prostatectomy

Other modalities like Laser, Radiofrequency Ablation, Microwave, Hyperthermia are also used. Still, other methods are in the developmental stages.

Health food stores sell herbal products claiming these promote “prostate health” and prevent BPH. It may be true for some of these products but the potency of these pills varies according to country of origin, seasonal variation of plant growth producing a different concentration of active ingredients and may be contaminated with pesticides. There are no federal regulations certifying the safety of these products.

Other tests and procedures at the time of evaluating BPH are:

Cystoscopy of the urinary bladder, MRI. IVP, urinalysis, urine culture, cystometrogram, and urodynamic profile, etc. are not required to make a diagnosis of BPH but to detect associated complications.

It is important to note: BPH does not cause cancer, but cancer may coexist with an enlarged gland.

 

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Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

      PKGhatak,MD

Chronic Myeloid Leukemia (CML), also called chronic myelogenous leukemia, develops due to an acquired abnormality of a chromosome and has become an important milestone in medicine in more than one way.

In 1959 Dr. Peter Nowell, a pathologist at the University of Pennsylvania, PA, while microscopically examining the blood of a Leukemic patient, detected an abnormal chromosome. Dr. David Hungerford, a Zoologist working on his Ph.D. at the Fox Chase hospital in Philadelphia, corroborated with Dr. Nowell. They established that the abnormality was on chromosome 22. They named this abnormal chromosome as Philadelphia Chromosome (Ph Chromosome). The Ph chromosome is present in all CML cases. It is also present in 20% of acute lymphatic leukemia and 2% of mixed types of leukemia.

The long arm of chromosome 9 breaks away at ABL (Abelson Leukemia virus) and the broken piece gets attached to the breakpoint BRC (Breakpoint Cluster Region) of chromosome 22. This results in a fusion gene called the BCC-ABL gene. The broken piece from chromosome 22 attaches to chromosome 9. The process of swapping genetic materials between two chromosomes is called Reciprocal Translocation.
This discovery was the first of a Chromosomal abnormality as the cause of human leukemia, and the abnormal chromosome was visible on blood smears. This discovery generated a lot of interest in research in finding genetic mutations in the development of malignancy.
In 1973 Dr. Janet Rowling at the University of Chicago identified the mechanism behind reciprocal translocation.
The scientific notation for this translocation is t (9;22) (q34.1; q11.2)

t stands for translocation; 9 and 22 within the parentheses are chromosomes no. 9 and no. 22. In the next parentheses, q stands for the long arm of chromosomes and the two digits are for the band location on Chromosomes.

The normal ABL gene carries instructions for the synthesis of a protein called Tyrosine Kinase (TK). TK speeds up the rate of cell division and also repairs corrupt DNA. The rate of synthesis of TK is auto-regulated. When ABL is fused with the BCR gene, this fusion gene loses its auto-regularity property and begins producing an excess quantity of TK. Some myelocytes contain this fusion gene.  An excessive number of white cells appear in the blood, and only a small fraction of granulocytes carries this Ph gene in their nucleus. The protein produced by BCR-ABL is named according to the molecular weight and location (p120 to p180). The protein p230 is associated with CML.

The normal BCR gene regulates cell movement and cell functions. It may work as an on and off molecular switch within the cell.

Clinical Features of CML:

CML patients present in three distinct phases of the illness-

Chronic phase CML, Accelerated phase CML and Acute Blast phase or Acute leukemic phase.

Chronic CML:

The patients are generally symptom free. The disease is detected in a routine blood test done for other reasons. The white cell counts (WBC) over 50,000/mcL are usual. Further, tests detect the Ph chromosome. A bone marrow biopsy is required to establish a CML diagnosis.

When patients develop symptoms, they are likely to complain of night sweats, lack of energy, low grade fever, left sided abdominal pain, joint pain and increased WBC counts of 100,000/mcL or more. Enlargement of the spleen is usually detected. And a ratio of BCR-ABL / ABL (abnormal over normal gene ratio), detected by PCR test (polymerase chain ratio), of the white cells and bone marrow shows a ratio over 0.01(the range of 0.02 to 0.25). This ratio helps to determine when to start treatment. It is also an important indicator of the effect of therapy and adjustment of medications.

When mature white cell numbers fall, viral or bacterial infections result. When the WBC count reaches 150,000/mcL or higher, the blood becomes thick and blocks capillaries of the retina and blurred vision results. A segmental visual field loss is the rule. Similarly, obstruction of brain vessels may occur and produce strokes.

About 18 years ago Imatinib, an oral medication, was introduced to treat CML. It blocks the uncontrolled production of Tyrosine Kinase by the fusion BCR-ABL gene. Since then, the outlook of patients with CML has changed dramatically. About 98% of CML patients respond to this drug and patients remain in stable condition for 10-15 years or more. Some patients may even be taken off the medication and are observed with blood tests only.

However, a minority of patients either do not respond to Imatinib or develop resistance to medication. The BCR- ABL/ABL ratio increases, so also the WBC count. In these cases, other TK inhibitors - Nilotinib, Dasatinib and Bosutinib are effective.

The accelerated phase of CML:

Those patients who do not respond to Tyrosine Kinase Inhibitors (TKI) or develop further mutation of BCR-ABL gene, develop worsening of fatigue, weight loss, weakness, fever, gum bleeding, and pain in the abdomen and joints. Anemia and an enlarged liver may be present on examination. An increase in WBC count over 200,000/mcL, 10 to 19% basophils in blood, an increase in BCR-ABL/ABL ratio and an increase in blast cells in blood and bone marrow are present. A new mutation in the BCR-ABL gene may be detected. T315I mutation is resistant to several TKI drugs.

Patients generally respond to increasing dose of TKI or switching to different TKI and at the time a combination of two TKI drugs are used. Those patients who still do not respond are treated with a new TKI drug, Ponatinib, with a good response. Some young patients may be considered for allogenic Stem Cell Transplantation but transplant results are mixed.

Acute Blast Phase or Blast Crisis:

Patients are sick with increased intensity of all existing symptoms. Increasing weight loss, high fever diarrhea, sepsis, high blood sugar, and pain over bones and joints, nose bleeding, cerebral bleeding, and abdominal pain usually develop.

Anemia and a very high WBC count and decreased platelet count, blast cells over 20% in the peripheral blood, and 20% or more blast cells in bone marrow are usual. Internal organs show blast cell infiltration. Testing for mutation of BCR-ABL gene is mandatory before treatment is initiated because the selection of medications depends on the detection of the correct mutation. Acute Lymphoblastic Leukemia develops in 20% of cases. Acute myeloblastic leukemia in 2% and mixed Acute Leukemia are also seen.

Treatment of Myeloid blast crisis consists of administrating one or two TKI drugs and multiple chemotherapeutic agents to induce remission. Afterward, suitable TKI drug or drugs are continued. Omacetaxine, a non-TKI drug is approved for use in the blast and accelerated stages of CML. It may produce severe bone marrow depression, cerebral hemorrhage, elevated liver enzymes, and diarrhea.

Early allogenic stem cell (stem cells obtained from a donor) transplantation is recommended in blast crisis. But the results are not that impressive.

The introduction of tyrosine kinase inhibitors has changed the outlook of over 90% of CML patients. The majority of them can expect to live their lives normally. Peripheral blood PCR test helps an accurate evaluation of the disease progression and early detection of the emergence of resistance and modification of treatment are possible before more serious complications could develop.

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The Otherside of Transplant

                                             The Other Side of Transplant

                                                     PKGhatak,MD

                                           

                                       
Many diseases fail to respond to the best possible treatment and usually end in organ failure. Research and advances in medicine have made it possible to extend life by the use of Mechanical Ventilators, Renal Dialysis Machines, Artificial Heart Pacemakers, and Mechanical Heart Pumps. These devices are life-extenders but far from a cure. Implanting a functioning organ from a recently deceased person came next, and kidneys from living donors and a portion of the liver are also accepted. Transplants are now standard practice for end-stage organ failure. But a shortage of available organs and rejection of the transplanted organs by the recipient's body, lead to further refinements of patient selection, organ harvest, post-transplant immunosuppression medications, and prevention of infections.

After the patient's specialist recommends transplantation, the patient is interviewed and thoroughly examined by a transplant team. The team is made up of surgeons, physicians, immunologists, nurses, pharmacists, psychologists, social workers and others. The patient is well advised about risks, future complications, and the requirement of strict compliance with the treatment regimen. Once selected for transplant, then the patient waits and waits - till the day an organ is available. For most patients, this period is long but is full of hope and sweet dreams - a promise to return to a normal life.

Shortly after successful transplantation, the initial elation is replaced by anxiety. Fear of catching an infection, and concerns about rejection become unconscious preoccupations. Some of those are discussed here:

Rejection:
Lung transplant patients have the most frequent rejection incidents, and the kidney the least, liver, pancreas, and heart are in between. The rejections are of two types- Acute and Chronic. About 50 to 80 % of transplant patients will have at least one episode of rejection in the post-transplant period.

Acute Rejection: This usually happens within a year of transplantation. In a kidney transplant, the incidence is 10 % in patients who have undergone the pre- transplant immunosuppressant therapy, in non- treatment group the incidence is 20 -30 %. In Lung transplants the rejection incidence is over 50% for one episode, often multiple incidences occur and lead to bronchiolitis obliterate – a fatal disease. In cases of heart, the incidence is over 50% and 2 to 3 incidences occur in the same patient. In liver transplant cases, the first incidence of rejection often occurs within 2 weeks.
To reverse the acute rejection the patient needs to be hospitalized. Laboratory blood, urine tests, X-rays, scans, ultrasound tests, etc. may not be enough to make a diagnosis. A biopsy of the transplant organ is usually required for each episode of rejection. The procedure is painful and has associated risks.
The treatment of acute rejection includes biological agents. These are:
  
Polyclonal Antibodies:    Administered via a central vein. Chills, high fever, joint pain are common and symptoms of acute serum sickness may develop, occasionally anaphylaxis is seen.
Monoclonal Antibodies: Can be given via a peripheral vein. The side effects are milder than polyclonal antibodies.
Alemtuzumab, Belatacept, Rituximab and other agents are in the process of development.

Chronic Rejection: This may occur at any time for the life of the transplant organ. The incidents vary according to the organ transplanted. The symptoms of chronic rejection are mild and deterioration of the function of the transplant organ is the usual sign. A biopsy of the organ may be required. Chronic rejection is a progressive insidious process and is due to atrophy of the transplant organ and fibrosis.
To prevent chronic rejection patients are placed on immunosuppressant therapy which consists of several drugs -

Drugs used:
Usually, more than one drug is used, often requiring a change of medications and a close follow up for the rest of patients' lives. The following drugs are commonly used. -
Glucocorticoids: Initially given in large dosages by intravenously then switched orally. The dosage is tapered slowly over time and the maintenance dose is around 10 mg a day. This drug has significant side effects – Osteoporosis, compression fractures of the spine and hip fractures, cataracts, and fungal infections.
Cyclosporine: administered orally. It is toxic to kidneys, decreases renal function over time, gum hyperplasia, increases blood potassium and elevates blood sugar are commonly seen. Increase hair growth often occurs. Dose adjustments are made based on the blood levels of the drug.
Tacrolimus: It is also toxic to kidneys. It increases blood sugar. It is given orally. Dosage adjustments are made on blood levels.
Sirolimus: It is given orally and has no renal toxicity. It increases blood lipids, causes oral ulcers and anemia. Blood levels are obtained for dosage adjustment.
Azathioprine (Imuran): It may produce bone marrow suppression. It is administered orally.
Mycophenolic Acid: It causes GI disturbances, nausea, abdominal pain and low white cell and platelet counts. It is available as pills.
Drug Interactions:
Cyclosporin and Tacrolimus are metabolized faster by Anti TB drugs and blood levels fall below the therapeutic range, whereas, blood levels reach toxic levels when used with calcium channel blockers, antifungal drugs, erythromycin and clarithromycin. Cyclosporin and Tacrolimus are nephrotoxic and should not be combined. Cyclosporin and sirolimus should be given at least 6 hrs. apart to prevent excessive blood levels of sirolimus. Mycophenolic acid blood levels are higher when used with tacrolimus or sirolimus concurrently.


Infection:
Cytomegalovirus (CMV): The infection is often due to the reactivation of an old infection. If the transplant organ is seropositive for CMV, implanted in a seronegative recipient then it becomes a serious problem and multi system failure may occur.
Hepatitis B virus (HBV): Patients receiving a liver transplant as a consequence of previous HBV infection are properly monitored and treated to prevent reactivation of infection, otherwise, fulminate hepatitis and liver failure would follow. If a patient is seropositive for HBV, then he becomes ineligible for transplant of organ other than liver.
Hepatitis C Virus (MCV): Risks are similar to HBV infection but the symptoms are milder and the disease progresses slowly.
Ebstein-Barr Virus (EBV): Infections may lead to the development of Lymphoma.
Human Herpes Viruses: (HHV): Infections may lead to renal graft loss and kidney failure.
Fungal Infections: Mucormycosis, Aspergella, Candida infections are common due to immunosuppression.
Cryptococcus: Infection to the brain and meninges lead to a serious situation.

Infection Prophylaxis:
Appropriate medications are given, short or long term, to prevent infections against CMV, HHV, Pneumocystis, Nocardia, and in endemic countries against Tuberculosis.

Malignancy:
The incidence of carcinoma of the skin and lips is high and accounts for 50% of all malignancies in transplant recipients. The incidence of lung cancer, Kaposi sarcoma, renal cell carcinoma, urogenital carcinoma is higher than the general population.
Non-Hodgkin lymphoma accounts for about 25% of all malignancies and is about 40-fold higher than the general population.

Immunization:
Pneumococcal vaccines, Hepatitis B vaccines, yearly Influenza vaccine and Varicella-Zoster vaccine are recommended. Recipients of transplants should never receive any live vaccine.

Organ transplantation should be done only in transplant centers. A transplant team is essential and only dedicated centers can attract and retain the highly qualified and technically super-gifted people. All tests must be done in house and results must be available instantly. A good outcome of implantation depends on patients' full compliance with the medical advice, and such centers have people and follow up protocols for tracking each patient for a very long time.

Transplant of bone marrow, stem cells, cord blood cells, skin, face, fecal, beta cells of the pancreas, and small intestine, etc. are also done but these are not discussed here.

 

 

 

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