Friday, May 9, 2014

Carcinoma In Situ of the Bladder: Beware of this Non-Invasive Cancer

Approximately 75,000 people are diagnosed with urothelial cancer of the bladder each year.[1]  It is estimated that nearly 300,000 people are walking around right now with bladder cancer in a variety of stages.  Fortunately, most people -- approximately 70% -- have non-invasive urothelial cancers or cancers that do not invade the detrusor muscle of the bladder.[2]  In general, non-invasive urothelial cancers are, in their own right, not dangerous.  However, even non-invasive high-grade cancers can progress to invasive disease and therefore have the potential to be fatal.
Bladder Cancer Staging.

Non-invasive cancers are stratified into stage Ta (70%) or confined to the lining of the bladder (i.e. urothelium), T1 (20%) invading the lamina propria (superficial layer of the bladder) or carcinoma in situ (CIS, 10%).[2]  CIS is a high-grade urothelial malignancy that is confined to the superficial-most layers of the bladder.  Although CIS is considered a non-invasive malignancy, it should not be considered a benign or indolent cancer.

Here we review some of the data regarding CIS.

CLINICAL PRESENTATION

While many bladder cancers (13-34%) present with gross hematuria (visible blood in the urine);[3,4] CIS is notorious for presenting with irritative voiding symptoms.[5]  Upwards of 80% of patients with CIS will present with irritative voiding symptoms.[6]

RISK OF PROGRESSION

In many cancers, CIS is considered a "pre-malignant" lesion.  This is NOT true for bladder cancer.  In fact, CIS of the bladder should be thought of as a flat, high-grade cancer and a precursor to invasive disease.  This is supported by a number of studies and findings:

  • The subsequent risk of CIS to progress to muscle-invasive or metastatic urothelial cancer is 40% or greater, especially if concomitant papillary tumors are present.[7,8]  
  • Of patients who undergo cystectomy for CIS alone, upwards of 20% will be found to have invasive cancer at final pathology.[9]  
  • Patients with T1 disease who undergo cystectomy have a 6% risk of upstaging at final pathology; however patients with T1 disease and concomitant CIS have a 55% risk of upstaging.[10]
  • In a number of surgical series, CIS is one of the most important prognostic characteristics after tumor grade.[11,12]
  • 20% of patients with CIS alone will die at 10 years.[13]

MANAGEMENT OF CARCINOMA IN SITU

CIS can be difficult to manage as it cannot be resected in the same sense as a papillary tumor as CIS is often flat, difficult to visualize and multifocal.  In addition, CIS can be very difficult to find.  In patients with irritative symptoms and/or positive high-grade cytology, a number of strategies can be employed to evaluate the bladder for the presence of CIS including (1) random, cold-cup bladder biopsies or (2) fluorescence cystoscopy.

Once diagnosed, CIS is best treated with intravesical BCG (please see prior blog entries BCG For Bladder Cancer: Why it Works, How it Works and Success Rates for Intravesical BCG Treatments for Bladder Cancer).  BCG is approved by the FDA (Food & Drug Administration) for the treatment of CIS and is the preferred initial intravesical treatment for CIS according to the AUA (American Urological Association) Guideline for the Management of Nonmuscle Invasive Bladder Cancer.

  • The initial tumor-free response after induction BCG is as high as 84%.[14,15]
  • Approximately 50% of patients experience a durable response for 4 years or longer.
    • Approximately 30% of patients experience a response for 10 years.[16]

However, patients who do not respond to BCG have an incredibly high rate of progression; 95% of patients who do not respond to an induction course of BCG will progress to worse disease.[17,18]

There are a number of other chemotherapies that can be used for the treatment of CIS including adriamycin, gemcitabine and thiotepa.  In North America, BCG is used most frequently due to a higher response rate (68% complete response for CIS vs. 49% for other chemotherapies) in a number of studies.[19,20]

Many patients with CIS will be refractory to an initial course of intravesical treatment.  If first-line treatment fails, especially if the first line was chemotherapy, a second course of BCG can be given as 30-50% of patients will respond to this second course.[21,22]  More than two courses of any medication are not recommended as 80% of patients who fail two courses will fail a third, and can be a harbinger of rapidly progressive, dangerous disease.

Patients with CIS who fail BCG should strongly consider an "early" cystectomy.  While removal of the bladder for non-invasive disease can be considered drastic:

  • 50% of patients with non-muscle invasive disease will be found to have muscle-invasion at cystectomy
    • 15% of muscle-invasive cancers will have micrometastatic disease [23]
  • The long-term survival for patients with non-muscle invasive disease approaches 90%, which is significantly higher than patients with muscle-invasive cancers.[24,25]


SUMMARY


  • Carcinoma in situ (CIS) is a high-grade, flat cancer of the bladder with potentially aggressive behavior
  • The first line treatment for CIS in intravesical BCG treatment
  • Patients who do not respond to intravesical treatment should strongly consider cystectomy due to the high rates of progression to advanced disease.


For additional information regarding BCG treatments check out the following blog entries:
BCG For Bladder Cancer: Why it Works, How it Works
Success Rates for Intravesical BCG Treatments for Bladder Cancer


This blog was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology at the Brady Urological Institute at Johns Hopkins.










[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Ro JY, Staerkel GA, Ayala AG,et al: Cytologic and histologic features of superficial bladder cancer. Urol Clin North Am 1992; 19: 435-453
[3] Lee LW, Davis E: Gross urinary hemorrhage: a symptom, not a disease. JAMA 1953; 153: 782-784
[4] Varkarakis MJ, Gaeta J, Moore RH,et al: Superficial bladder tumor: aspects of clinical progression. Urology 1974; 4: 414-420
[5] Mohr DN, Offord KP, Owen RA,et al: Asymptomatic microhematuria and urologic disease: a population-based study. JAMA 1986; 256: 224-229
[6] Zincke H, Utz DC, Farrow GM,et al: Review of Mayo Clinic experience with carcinoma in situ. Urology 1985; 26: 39-46
[7] Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. Urol Clin North Am 2003;30:765–6.
[8] Althausen AF, Prout GR, Daly JJ,et al: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116: 575-580
[9] Farrow GM, Utz DC, Rife CC,et al: Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Res 1976; 36: 2495-2501
[10] Masood S, Sriprasad S, Palmer JH,et al: T1G3 bladder cancer—indications for early cystectomy. Int Urol Nephrol 2004; 36: 41-44
[11] Koch MO, Smith JA: Natural history and surgical management of superficial bladder cancer (stages Ta/T1/Tis). In Vogelzang N, Miles BJ(eds)Comprehensive textbook of genitourinary oncology. Baltimore: Lippincott Williams & Wilkins, 1996, pp.405-415
[12] Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J,et al: Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol 2000; 163: 73-78
[13] Herr HW, Badalament RA, Amato DA,et al: Superficial bladder cancer treated with bacillus Calmette-Guérin: a multivariate analysis of factors affecting tumor progression. J Urol 1989; 141: 22-29
[14] Lamm DL, Blumenstein BA, Crissman JD,et al: Maintenance bacillus Calmette-Guérin immunotherapy for recurrent Ta,T1 and carcinoma in situ TCC of the bladder: a randomized SWOG study. J Urol 2000; 163: 1124-1129
[15] Lamm DL, Riggs DR, Bugaj M,et al: Prophylaxis in bladder cancer: a meta-analysis. J Urol 2000; 163: 151
[16] Herr HW, Wartinger DD, Fair WR,et al: Bacillus Calmette-Guérin therapy for superficial bladder cancer: a 10-year follow-up. J Urol 1992; 147: 1020-1023
[17] Coplen DE, Marcus MD, Myers JA,et al: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guérin: analysis of possible predictors of response free of tumor. J Urol 1990; 144: 652-657
[18] Harland SJ, Charig CR, Highman W,et al: Outcome in carcinoma in situ of bladder treatment with intravesical bacille Calmette-Guérin. Br J Urol 1992; 70: 271
[19] O'Donnell MA: Advances in the management of superficial bladder cancer. Semin Oncol 2007; 34: 85-97
[20] Sylvester RJ, van der Meijden A, Witjes JA,et al: High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 2005; 66: 90-107
[21] Brake M, Loertzer H, Horsch R,et al: Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer. Urology 2000; 55: 673-678
[22] Pansadoro V, De Paula F: Intravesical bacillus Calmette-Guérin in the treatment of superficial transitional cell carcinoma of the bladder. J Urol 1987; 138: 299-301
[23] Chang SS, Cookson MS: Radical cystectomy for bladder cancer: the case for early intervention. Urol Clin North Am 2005; 32: 147-155
[24] Amling C, Thraser J, Frazier H,et al: Radical cystectomy for stages Ta, Tis, and T1 transitional cell carcinoma of the bladder. J Urol 1994; 151: 31
[25] Freeman JA, Esrig D, Stein JP,et al: Radical cystectomy for high-risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995; 76: 833-839

12 comments:

  1. Really awesome blog. Your blog is really useful for me. Thanks for sharing this informative blog. Keep update your blog.Plz visit us:
    Best Urologist in Delhi

    ReplyDelete
  2. Everyone here i think would have gotten a piece of their share from cancer, with some being able to survive and others dying even with the high efforts of oncologists. I had lungs cancer due to the fact that i was a hardcore smoker Due to the terrain in Alaska. I started to have symptoms in 2008 and i was diagnosed in April 2009. Several therapies of treatment were prescribed but none seemed to help me. I had just less than a year to live. Less than 6 months to go i read about Doctor Roland who is a herbal doctor that treats cancer. At first i doubted because my case was chronic and even if he could help it was already late. I had nothing to lose so i contacted him and he was very encouraging even in my condition and i placed an order for the herbal medicine which i used for 3 months. Even before i was done using it i felt strong and after it all i went for diagnosis and i tested negative. This is a permanent cure because it's been three years from my supposed death and i am still very strong and alive. Do not give up soon on yourself just reach him on (dr.rolandoscar@gmail.com) i am positive that if i can be cured you too can. I pray for all cancer patients worldwide.

    ReplyDelete
  3. Excellent blog very nice and unique information related to Beclovent. Thanks for sharing this information.Urologist in Delhi

    ReplyDelete
  4. As a sign of gratitude for how my wife was saved from CANCER, i decided to reach out to those still suffering from this.
    My wife suffered cancer in the year 2013 and it was really tough and heartbreaking for me because she was my all and the symptoms were terrible, she always complain of abnormal vaginal bleeding, and she always have pain during sexual intercourse. . we tried various therapies prescribed by our neurologist but none could cure her. I searched for a cure and i saw a testimony by someone who was cured and so many other with similar body problem, and he left the contact of the doctor who had the cure to cancer . I never imagined cancer. has a natural cure not until i contacted him and he assured me my wife will be fine. I got the herbal medication he recommended and my wife used it and in one months time she was fully okay even up till this moment she is so full of life. cancer. has a cure and it is a herbal cure contact the doctor for more info on drwilliams098675@gmail.com on how to get the medication. Thanks for reading my testimony.

    ReplyDelete
  5. I have being on blog Sites for a while now and today I felt like I should share my story because I was a victim too. I had HIV for 6 years and i never thought I would ever get a cure I had and this made it impossible for me to get married to the man I was supposed to get married to even after 2 years of relationship he broke up with me when he finds out I was HIV positive. So I got to know about Dr. Itua on Blog Site who treated someone and the person shared a story of how she got a cured and let her contact details, I contacted Dr. Itua and he actually confirmed it and I decided to give a try too and use his herbal medicine that was how my burden ended completely. My son will be 2 soon and I am grateful to God and thankful to his medicine too.Dr Itua Can As Well Cure The Following Disease…Alzheimer’s disease,Bechet’s disease,Crohn’s disease,Parkinson's disease,Schizophrenia,Lung Cancer,Breast Cancer,Colo-Rectal Cancer,Blood Cancer,Prostate Cancer,siva.Fatal Familial Insomnia Factor V Leiden Mutation ,Epilepsy Dupuytren's disease,Desmoplastic small-round-cell tumor Diabetes ,Coeliac disease,Creutzfeldt–Jakob disease,Cerebral Amyloid Angiopathy, Ataxia,Arthritis,Amyotrophic Lateral Scoliosis,Fibromyalgia,Fluoroquinolone Toxicity
    Syndrome Fibrodysplasia Ossificans ProgresSclerosis,Seizures,Alzheimer's disease,Adrenocortical carcinoma.Asthma,Allergic diseases.Hiv_ Aids,Herpe ,Copd,Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Lung disease.Enlarged prostate,Osteoporosis.Alzheimer's disease,
    Dementia.
    ,Cushing’s disease,Heart failure,Multiple Sclerosis,Hypertension,Colo_Rectal Cancer,Lyme Disease,Blood Cancer,Brain Cancer,Breast Cancer,Lung Cancer,Kidney Cancer, HIV, Herpes,Hepatitis B, Liver Inflammatory,Diabetes,Fibroid, Get Your Ex Back, If you have (A just reach him on drituaherbalcenter@gmail.com / info@drituaherbalcenter.com Or Whatsapp Number.+2348149277967)He can also advise you on how to handle some marital's issues. He's a good man.

    ReplyDelete
  6. I have long felt a special connection with herbal medicine. First, it's natural, Charlie attended the same small college in Southern California - Claremont Men's College - although he dropped out of school to enroll in the Julliard School of Performing Arts in New York. York. Had he been to Claremont, he would have been senior the year I started there; I often thought that was the reason he was gone when he discovered that I had herpes. So, my life was lonely, all day, I could not stand the pain of the outbreak, and then Tasha introduced me to Dr. Itua who uses her herbal medicines to cure her two weeks of consumption. I place an order for him and he hands it to my post office, then I pick it up and use it for two weeks. All my wound is completely healed no more epidemic. I tell you honestly that this man is a great man, I trust him Herbal medicine so much that I share this to show my gratitude and also to let sick people know that there is hope with Dr. Itua. Herbal Phytotherapy.Dr Itua Contact Email.drituaherbalcenter@gmail.com/ info@drituaherbalcenter.com. Whatsapp ... 2348149277967
    He cures.
    Herpes,
    Breast Cancer
    Brain Cancer
    CEREBRAL VASCULAR ACCIDENT.
    Hepatitis,Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Lung disease.Enlarged prostate,Osteoporosis.Alzheimer's disease,
    Dementia.Tach Disease,Shingles,
    Lung Cancer
    H.P.V TYPE 1 TYPE 2 TYPE 3 AND TYPE 4. TYPE 5.
    HIV,Arthritis,Amyotrophic Lateral Scoliosis,Fibromyalgia,Fluoroquinolone Toxicity
    Cervical Cancer
    Colo-rectal Cancer
    Blood Cancer
    SYPHILIS.
    Diabetes
    Liver / Inflammatory kidney
    Epilepsy

    ReplyDelete
  7. My husband was diagnosed with MND ALS (amyotrophic lateral sclerosis) when he was 69 years old 6 years ago. The Rilutek (riluzole) did very little to help him. The medical team did even less. His decline was rapid and devastating. The psychological support from the medical center was non-existent and if it were not for totalcureherbsfoundation .c om and the sensitive cure of their herbal formula he would have been not been alive today,there was significant improvement in the first 4 weeks of usage that gave us hope that he will be alive,His doctor put him on riluzole, letting us know there was no cure until we gave try on total cure herbal supplement that cure him totally from this disease after 15 weeks of his usage. There is nothing positive about cure ALS condition except for their herbal treatment .

    ReplyDelete
  8. HOW I GOT CURED OF HERPES VIRUS.

    Hello everyone out there, i am here to give my testimony about a herbalist called dr imoloa. i was infected with herpes simplex virus 2 in 2013, i went to many hospitals for cure but there was no solution, so i was thinking on how i can get a solution out so that my body can be okay. one day i was in the pool side browsing and thinking of where i can get a solution. i go through many website were i saw so many testimonies about dr imoloa on how he cured them. i did not believe but i decided to give him a try, i contacted him and he prepared the herpes for me which i received through DHL courier service. i took it for two weeks after then he instructed me to go for check up, after the test i was confirmed herpes negative. am so free and happy. so, if you have problem or you are infected with any disease kindly contact him on email drimolaherbalmademedicine@gmail.com. or / whatssapp --+2347081986098.
    This testimony serve as an expression of my gratitude. he also have
    herbal cure for, LUPUS DISEASE, JOINT PAIN, POLIO DISEASE, PARKINSON'S DISEASE, ALZHEIMER'S DISEASE, CYSTIC FIBROSIS, SCHIZOPHRENIA, CORNEAL ULCER, EPILEPSY, FETAL ALCOHOL SPECTRUM, LICHEN PLANUS, COLD SORE, SHINGLES, CANCER, HEPATITIS A, B. DIABETES 1/2, HIV/AIDS, CHRONIC PANCERATIC, CHLAMYDIA, ZIKA VIRUS, EMPHYSEMA, LOW SPERM COUNT, ENZYMA, COUGH, ULCER, ARTHRITIS, LEUKAEMIA, LYME DISEASE, ASTHMA, IMPOTENCE, BARENESS/INFERTILITY, WEAK ERECTION, PENIS ENLARGEMENT. AND SO ON.

    ReplyDelete
  9. Γεια σε όλους εδώ στο φόρουμ αυτό είμαι τόσο ευτυχής που έχω αυτή τη μεγάλη ευκαιρία να έρθω εδώ και να μοιραστώ τη μαρτυρία μου για το πώς ο Δρ Isiramen ήταν σε θέση να με θεραπεύσει εντελώς από την ασθένεια του έρπητα, έχω πάσχει από αυτή την ασθένεια για περίπου 4 χρόνια τώρα , έχω δοκιμάσει διάφορους τρόπους για να απαλλαγούμε από αυτό τον ιό από το σώμα μου, έχω επίσης αγορά για ιατρική περίθαλψη από το γιατρό μου, αλλά όλοι απέτυχαν, κάποτε πίσω από αυτή τη στιγμή, ενώ περιηγούσα στο Διαδίκτυο βρήκα κάποια καλή παρατήρηση σχετικά με τον Dr Isiramen Herbal Η ιατρική και το πώς το χρησιμοποίησε για να σώσει ψυχές από διαφορετικές ασθένειες, συμπεριλαμβανομένου του καρκίνου, κάποιος είπε επίσης ότι είχε θεραπευτεί από έρπητα από το φάρμακό του και έδωσαν τα στοιχεία επικοινωνίας σε περίπτωση που κάποιος χρειάζεται τη βοήθειά του, αποφάσισα να έρθω σε επαφή με τον Dr Ο Isiramen και του είπα για την ασθένεια του έρπητα μου είπε να μην ανησυχώ ότι επρόκειτο να μου στείλει το φυτικό φάρμακο του μόνο που έπρεπε να κάνω είναι να του στείλω τα προσωπικά μου στοιχεία και επίσης τη διεύθυνση του σπιτιού μου, , μετα Χριστον Τον έκανα ό, τι απαιτούσε αυτός ο άνθρωπος, πήρα το φάρμακο ακριβώς όπως συνταγογραφήθηκε από τον ίδιο, μου είπε να πάω για έλεγχο στο νοσοκομείο που έκανα και για μεγάλη μου έκπληξη ο γιατρός μου μου είπε ο έρπης Ο ιός δεν ήταν πια εκεί έχω πάει ακόμα σε άλλο νοσοκομείο για καλύτερη επιβεβαίωση ότι ήταν ακόμα το ίδιο πράγμα Σήμερα είμαι τόσο χαρούμενος που είμαι Αρνητικός πάλι, ο Δρ Isiramen μου έχει δώσει λόγους να μοιραστώ τα δάκρυα της Χαράς, μπορείτε να φτάσετε στον Δρ Isiramen με το ηλεκτρονικό του ταχυδρομείο απευθυνθείτε στο (oyimeanelisiramen@gmail.com) ή καλέστε τον αριθμό του WhatsApp +2 {34} 8117963221 ευχαριστεί και πάλι το DR Isiramen Θεός να σας ευλογεί και την οικογένειά σας.

    ReplyDelete
  10. Hello Everyone Here,
    My Name is Elizabeth Knox, I'm from UK and I was once a Vaginal Cancer patent.
    Until one day I watched Dr Itua Herbal Remedy on TV Channel on how he uses Herbal medicines to cure all kind of disease, I was very inst rested on his herbal remedy because I was very sick at that moment and I was diagnosed of Brain Tumor and Vaginal Cancer. I took the risk to take his treatment after watching his documentary,
    I contacted him on Email and explain my situation to him, he kindly told me how it works also how I can purchase his herbal product which I did.
    A week later the herbal medicines was ship to me through courier service, I drank his herbal medicines for three weeks and I was healed, cured from Brain Tumor/Vaginal Cancer.
    It was so marvelous even my friends with Breast/Prostate Cancer also contacted this Dr Itua for herbal product and they are all cured as well with Dr Itua Herbal Medicines, I do not how many Sick people are here today or whom are not yet read this. I pray god should let you see this to know there is a wellness for you. He guaranties me that he can cure the listed diseases below______Bladder cancer,Brain cancer,Hiv,Herpes,
    Esophageal cancer,Gallbladder cancer,Gestational trophoblastic disease,Head and neck cancer,Hodgkin lymphoma
    Intestinal cancer,Kidney cancer,Hpv,Tach Diseases,Leukemia,Liver cancer,Lung cancer,Melanoma,Mesothelioma,Multiple myeloma,Neuroendocrine tumors
    Non-Hodgkin lymphoma,Oral cancer,Ovarian cancer,Sinus cancer,Hepatitis A,B/C,Skin cancer,Soft tissue sarcoma,Spinal cancer,Stomach cancer
    Testicular cancer,Throat cancer,Thyroid Cancer,Uterine cancer,Fibroid,Angiopathy, Ataxia,Arthritis,Amyotrophic Lateral Scoliosis,Brain Tumor,Fibromyalgia,Fluoroquinolone Toxicity
    Syndrome Fibrodysplasia Ossificans ProgresSclerosis,Alzheimer's disease,Chronic Diarrhea,Copd,Parkinson,Als,Adrenocortical carcinoma  Infectious mononucleosis. Vaginal cancer,Vulvar cancer
    Dr Itua Herbal Center Contact,Email: drituaherbalcenter@gmail.com Or WhatsApp:+2348149277967

    ReplyDelete
  11. I am a 51 year old female that just found out I have Motor Neuron Disease Parkinson's about a year and half, but I have been having signs of it for years, tremors, depression, body weakness. ECT. I honestly don't think my doctor was reading the signs because of my gender and age. A few years ago I had my shoulder lock up on me and I was sent to a P.T since x-rays didn't show any physical damage. My shaking was getting worse and I began falling. Only when my speech became so bad that it brought concern to my dentist was Parkinson's even considered. He phoned my doctor with his concerns about my shaking and balance problems. By this time I was forgoing shots in the back of my neck for back and neck pain to which once again I was sent to a P.T (although x-rays showed no damage) I was told I had a few spurs which were most likely causing the pain. Here I was feeling like my whole body was falling apart and doctor could not find anything wrong, maybe in was all in my head? My doctor even seemed annoyed with me and things just kept progressing and I just kept it to myself, why bother going through testing and them finding nothing? Well, it was after my second P.T called my doctor about the weakness in my legs and arms, by this time I have developed a gait in my walk and I fell more frequently. Only then did my doctor send me to a specialist and it was found that I had Parkinson's, and that I have had it for awhile. I think because I was a woman that my signs and symptoms weren't taken seriously and therefor left untreated for so long,I was taking pramipexole dihydrochloride three times daily, I Was on carbidopa levodopa but only lasted 90 minutes then wore off.I found that none of the current medications worked effective for me.I got tired of using those medication so I decided to apply natural herbs formula that was prescribed to me by my second P.T, i purchase the herbal formula from totalcureherbsfoundation. com, There has been huge progression ever since I start the treatment plan which will last for 15 weeks usage.all the symptoms and sign has begin to disappear .

    ReplyDelete