b. Use protective apparel, eyewear, mask, and gloves. c. Cover spills with disposable absorbent towels. d. Decontaminate the area with 10% bleach solutio n, or other appropriate disinfectant suitable for decontamination, allowing appr oximately a 20-minute contact time. e. Dispose of all waste and protective apparel as infectious biohazardous waste and incinerate according to institutional policy and according to local, state, and federal regulations. 19. Immediately report spills and accidents resu lting in overt exposure to recombinant DNA molecules to the Institutional Biosafety Committee and NIH/OSP (Office of Science Policy). Send reports to the Office of Science Policy, National Institutes of Health, 6705 Rockledge Drive, Suite 750, MSC 7985, Bethesda, MD 20892-7985. Phone (301) 496-9838. Provide medical evaluation, surveillance, and treatment as appropriate an d maintain written records of the event. For more information about biohazard risk gr oup classification and biohazard safety levels: xNIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines). See current version at: http://osp.od.nih.gov/sites/def ault/files/NIH_Guidelines.html xBiosafety in Microbiological and Biomedical Laboratories; U. S. Department of Health and Human Services Centers for Disease Control and Prevention and National Institutes of Health. See current edition at: http://www.cdc.gov/biosafety/publications/index.htm Precautions for Healthcare Workers Recombinant vaccinia virus transmission risk to exposed healthcare workers is unknown. To date, no reports of transmission to healthcare personnel from vaccine recipients have been published. If appropriate infection control precautions are obser ved (such as covering the vaccination site and washing hands after contact with the vaccinat ion site or bandages), healthcare workers are probably at less risk of infecti on than laboratory workers because of the smaller volume and lower titers of virus in clinical specimens as compared with laboratory material. However, because of the potential risk for transmission, healthcare personnel who prepare or administer doses of recombinant vaccinia vaccine or have direct contact with contaminated dressings or other infectious material from participants in clinical studies must adhere to appropriate infection control measures and should be offered vaccination with the licensed vaccinia vaccine. Do not administer routine, non-emergency vaccination with the licensed vaccinia vaccine to healthcare workers, if they, or for at least three weeks after vaccina tion, their close household contacts (close household contacts are those who share housing or have close physical contact): xhave active eczema or a history of eczema or atopic dermatitis, or Darier’s disease. xhave other acute, chronic, or exfoliative skin conditions (e.g., burns, imp etigo, varicella zoster, severe acne, or other open rashes or wounds), until the condition resolves. xare pregnant or intend to become pregnant within 4 weeks of vaccination or are breast-feeding. xare immunodeficient or immunocompromised (b y disease or therapy), including HIV infection. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 61Additionally, do not administer routine, non-emer gency vaccination with the licensed vaccinia vaccine to healthcare workers if the vaccinee: xhas a moderate or severe acute illness, until the illness resolves. xis less than 18 years of age, unless specifically indicated. xis undergoing topical steroid therapy for inflamma tory eye diseases or undergoing therapy with systemic steroids; potential immune suppression increases ri sk for vaccinia-related complications. xhas a history of allergy or serious reaction to pr ior vaccinia vaccination or any of the vaccine’s components. xAs a precaution, the CDC recommends that indi viduals with known cardiac disease (e.g., previous MI, angina, CHF, cardiomyopathy, stroke or TIA) or who have > 3 known risk factors for cardiac disease (e.g., hypertension, hyperc holesterolemia, diabetes, first degree relative with onset of cardiac complications prior to age 50, smoker), not receive routine, non- emergency, prophylactic vaccination with the licensed vaccinia vaccine while a possible causal relationship between vaccination and cardiac events is being evaluated. Avoid exposure to the recombinant vaccinia vaccine, any contaminated dressings, or other infectious materials from patients, or the patient’s inoculation site if you are pregnant or breast- feeding; have a history or presence of active eczema or atopic dermatitis; have acute, chronic or exfoliative skin conditions; or, are immunocom promised. More information on vaccinia precautions for healthcare workers can be obtained from http://www.cdc.gov/mmwr/pre view/mmwrhtml/rr5010a1.htm#tab2 and http://www.cdc.gov/mmwr/PDF/rr/rr5207.pdf . The CDC is the only source of the licensed vaccinia vaccine. The CDC will provide vaccinia vaccine to protect laboratory and other healthcare personnel, whose occupati ons place them at risk of exposure to vaccinia and other closely re lated orthopoxviruses, including vaccinia recombinants. The vaccine should be administered under the supervision of a physician selected by the study institution. Revaccination is reco mmended every 10 years. For instructions on obtaining the licensed vaccinia vaccine, contact Drug Services, National Center for Infectious Diseases, CDC at (404) 639-3670. Recombinant Vaccinia Vaccine Patient Care Implications, Contraindications and Potential Complications Patient Care Implications and ContraindicationsCover vaccination sites with a sterile dry dressing ( e.g., Telfa pad). Instruct patients on proper hand- hygiene, sterile dressing care, bathing, laundering of clothing, etc. Treat patient bandages or dressings removed from the vaccination site as infectious wa ste and dispose in appropriate biohazard containers. Do not administer the recombinant vaccinia vaccine if the recipient, or for at least three weeks after vaccination, their close househol d contacts (close household cont acts are those who share housing or have close ph ysical contact): xhave active eczema or a history of eczema or atopic dermatitis, or Darier’s disease. xhave other acute, chronic, or exfoliative skin conditions ( e.g., burns, impetigo, varicella zoster, severe acne, contact dermatitis, psoriasis, herp es or other open rashes or wounds), until the condition resolves. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 62xare pregnant or intend to become pregnant (due to the potential risk of fetal vaccinia); or are breast-feeding (due to the potential risk of c ontact transmission and in advertent inoculation). It is currently unknown if vaccinia virus or antibodies are excreted in breast milk. Patients (i.e., vaccinees) should avoid fathering a child for at least 4 months following completion of therapy with the recombinant vaccine. xare in close contact with children less than 3 years of age (due to the potential risk of contact transmission and inadve rtent inoculation). xare immunodeficient or immunocompromised (by di sease or therapy), including individuals with HIV infection. Additionally, do not administer the recombinant vaccinia vaccine if the vaccinee: xhas a moderate or severe acute illness, until the illness resolves. xis undergoing topical steroid th erapy for inflammatory eye di seases, or undergoing therapy with systemic steroids; poten tial immune suppression increases risk for vaccinia-related complications. xAt this time, until a more definitive causal relationship is determined, it is recommended that patients with known CHF or clinically significant cardiomyopathy, not be vaccinated with recombinant vaccinia-based vaccines, due to the potential for development of myocarditis and/or pericarditis. Although the CDC believes that there is no eviden ce to conclude that the licensed vaccinia vaccine used in the Smallpox Vaccination Program causes angina or heart attacks, it acknowledges a possible causal relationship between the vaccina tion and heart inflammation. The CDC continues to study the relationship, but in the meantime, recommends excluding individuals with underlying heart disease from participation in the current Smallpox Vaccination Program. Patients are being immunized with recombinant vaccinia vaccines with therapeutic intent and will be evaluated for cardiovascular risk factors and recent or symptomatic cardiac events per protocol eligibility criteria. Patients will be encouraged to minimize cardiovascular disease risks and encouraged to follow risk reduction according to standard medical practice. Due to the method of manufacturing (virus gr own in primary chicken embryo dermal cells), do not administer the recombinant vaccinia vaccine to patients with a history of allergy to eggs or egg products. Do not administer the r ecombinant vaccinia vaccine to patients with a history of allergy or serious react ion to prior vaccinia vaccination ( e.g., smallpox vaccination). Potential Complications Associated With Recombinant Vaccinia VaccinationWhen vaccinia vaccine is administered by scarification for vaccination against smallpox, expected local reactions in individuals that have not previously been vaccinated with vaccinia include the appearance of a red papule in 3-4 days, followe d by vesiculation in 5-6 days, and then the formation of a pustule on days 8-9. A large area of erythema may surround the vesicle and pustule. A crusted scab usually forms by the second week and sloughs by the third week, leaving a well- formed scar. Maximal viral shedding occurs from days 4-14, but can continue until the scab is shed from the skin. Other normal local reactions can include development of local satellite lesions, regional lymphadenopathy that can persist for weeks following healing of the skin lesion, considerable local edema, and intense inflammation from the vaccination ( i.e., viral cellulites), which may be confused with bacterial cellulites. Systemic symptoms typically occur between 8- Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 6310 days post-vaccination and include fever, malaise, headache, chills, nausea, myalgia, local lymphadenopathy, soreness and intense eryt hema surrounding the vaccination site. When administered by scarification in individuals that have previously been vaccinated with vaccinia, expected local reactions include the appearance of a clear cut pustule 6-8 days following vaccination or the development of an area of de finite induration around a central lesion that may be an ulcer or scab 6-8 days following vaccination. The response to re-vaccination depends on the degree of residual immunity following previous vaccination. Similar systemic symptoms may occur, but typically at a lower frequency. When recombinant vaccinia vaccines are administere d by intradermal, intralesional, subcutaneous or intramuscular routes of injection, milder lo cal reactions are expect ed, but similar systemic symptoms may occur.There have been a number of complications reported in the literature associated with vaccinia vaccination for smallpox. Reported complications from vaccinia vaccine when given by scarification include: a) auto-inoculation of other sites with vaccinia, b) generalized vaccinia, c) eczema vaccinatum, d) progressive vaccinia (vaccinia necrosum), or e) post-vaccinial encephalitis. In a 1968 ten-state survey, cases of these complications per million vaccinations in adult recipients (> 20 years of age) of vaccinia primary vaccination and revaccination were: Primary Vaccination Revaccination auto-inoculation 606.1 25 generalized vaccinia 212.1 9.1 eczema vaccinatum 30.3 4.5 progressive vaccinia none reported 6.8 postvaccinial encephalitis none reported 4.5 Based on a 1968 national survey, the number of deat hs in primary vaccinees was approximately 1 per million and the number of deaths in recipien ts of revaccination was approximately 0.25 per million. Deaths were most often th e result of postvaccinial encepha litis or progressive vaccinia. Information has been reported by the US Department of Defense (DoD) during the post-vaccination surveillance assessment of adve rse events in military personnel following implementation of a Smallpox Vaccination Program from the period of December 13, 2002 through May 28, 2003. Although not directly comparable to historical numbers, due todifferences in multiple population variables, estimated cases (number of cases per million vaccinations based on vaccination of 450,293 pers onnel, with a median age of 26 years and 70.5% as primary vaccinees) of these same complications per million vaccinations were: auto-inoculation 107 generalized vaccinia 80 eczema vaccinatum none reported progressive vaccinia none reported postvaccinial encephalitis 2.2 Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 64Generally, self-limited adverse reactions that can be serious, but not life-threatening include autoinoculation, erythematous and urticarial rashes, and ge neralized vaccini a. More serious life-threatening complications include progre ssive vaccinia, eczema vaccinatum, and post- vaccinial encephalitis/encephalomyelitis. The complications of vaccinia vaccination may involve a number of different reactions: 1.Non-specific erythematous or urticarial rashes: These rashes can appear approximately 10 days after vaccination and may sometimes be confused with generalized vaccinia, but are generally self-limiting. Patients are usually afebrile and these benign rashes usually resolve spontaneously within 2-4 days. Erythema multiforme can present as different types of lesions, including macules, papules, urti caria, and bull’s eye lesions (dark papule or vesicle surrounded by a pale zone and an area of erythema). These lesions may be extremely pruritic, lasting up to four weeks. Rarely, more serious bullous erythema multiforme (Stevens-Johnson syndrome) may oc cur, requiring hospitalization. Vaccinia Immune Globulin (VIG) therapy is not indicat ed to treat these rashes. Supportive care measures are warranted since these rashes ar e likely manifestations of an immune response or hypersensitivity reaction to the vaccine and are not likely to contain vaccinia virus. 2.Bacterial Infection: Vaccination site infection, most likely due to staphylococcus and streptococcus normal skin flora, is rare. Onset is approximately 5 days post-vaccination and is more common in children. Appropriate antibiotic therapy is required. 3.Inadvertent Inoculation : This can occur in the vaccinee (autoinoculation) as well as in close contacts (contact transmission). Accidental infection is the most common complication of vaccinia vaccination, ac counting for approximately 50% of all complications associated with vaccination and revaccination. This usually results from autoinoculation of vaccinia virus transferred from the site of the vaccination. Sites typically involved include the face, eyelids, nose, mout h, genitalia, or rectum, but can also involve the arms, legs, and trunk. Contact transmission of vaccinia, with accompanying toxicities, may occur when a recently vaccinated individual has contact with a susceptible individual. In a 1968 ten-state survey, contact transmissions were reported to occur at a rate of 27 infections per million vaccinations. The age group in which contact transmission occurred most commonly was in children d 5 years. Eczema vaccinatum as a result of contact transmission may result in a more severe syndrome than that seen in vaccinees, perhaps because of multiple simultane ous inoculations. About 30% of eczema vaccinatum cases reported in the 1968 ten-state survey were a resu lt of contact transmission. It is possible that the number of cases of contact transmi ssion would be greater in today’s population, due to a largely unvaccinated patient population against sma llpox. Contact transmission rarely results in postvaccinial encephalitis or progressive vaccinia. Most cases of inadvertent inoculation usually resolve without specific therapy and resolution of lesions follow the same course as the vaccination s ite in immunocompetent individuals. VIG can be used for severe cases involving extensive lesions or if comorbid conditions exist. VIG is contraindicated in the presence of isolated keratitis due to the risk of increased corneal scarring. VIG use can be considered in cases of ocular implanta tion, with keratitis, if vision-threatening or if other life-threatening vaccinia-related complications exist that require VIG therapy. 4.Generalized vaccinia: Generalized vaccinia (GV) is characterized by a disseminated maculopapular or vesicular rash of varying extent on any part of the body and typically Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 65develops 6-9 days after vaccination. The lesions follow the same course as the vaccination site lesion. The lesions are he matogenously spread and may contain vaccinia virus. In immunocompetent individuals, the rash is generally self-limiting and requires supportive care therapy. VIG treatment can be used in severe cases for patients who are systemically ill and whose condition might be toxic or w ho have serious underl ying immunosuppressive illnesses.The differential diagnosis of GV includes eczema vaccinatum, erythema multiforme, inadvertent inoculation at multiple sites, and uncommonly, early stages of progressive vaccinia or other vesicular diseases ( e.g., severe chickenpox or disseminated herpes). Several publications have inve stigated the reporting of GV among those individuals who received smallpox vaccinations during 2003. Out of 38,440 vaccine recipients, 29 reports of possible GV during January 2003–Decembe r 2003 were identified but only 2 reports met the case definition. More than 75% of the reports received a final diagnosis of hypersensitivity reaction or nonspecific rash af ter review by dermatologists or because laboratory results were negative for vaccini a and other orthopoxviruses. Of 74 cases investigated in 753,226 smallpox vaccina tions administered in December 2002 to December 2004, 50 (67.6%) met the case definition of possible GV. Cases occurred more frequently in primary vaccinees (rate, 81 per 1 million vaccinees) than in those revaccinated (rate, 32 per 1 million vaccinees). However, none met the case definition of probable or confirmed GV, including 15 with vi rologically negative laboratory evaluations (e.g., culture, polymerase chain reaction, or skin biopsy). Twenty-one reports of postscab lesions were made between January and August 2003 among 37,542 smallpox vaccinees. The lesions (scab and/or fluid) of seven patients were tested for vaccinia virus by use of polymerase chain reaction and/or immunohistoche mistry; all were found to be negative. In addition, the postscab lesions of four of th e patients were biopsied. The results from two of the biopsies suggested an allergic c ontact dermatitis, and results of one each demonstrated chronic dermatitis and squamous cell carcinoma. None of the four biopsied lesions had histologic evidence of viropathic changes and no evidence supported smallpox vaccination as a cause for any of the lesions. 5.Eczema vaccinatum: Eczema vaccinatum is a serious complication in persons with eczema and other types of chronic or exfoliative skin conditions. It can also occur among eczematous contacts of recently vaccinated persons. Vaccinial lesions (generalized papular, vesicular or pustular le sions) develop on areas of the skin that are, or had at one time been, eczematous. These areas become highly inflamed and lesions may spread to healthy skin. The rash is often accompanied by fever and individuals are systemically ill. The fatality rate for untreated cases (prior to availability of VIG) has been reported from 30-40%. Following availability of VIG, mortality was reduced to approximately 7%. Early diagnosis and prompt treatment with VI G is necessary to reduce mortality. 6.Progressive vaccinia: Progressive vaccinia is the most serious cutaneous complication, occurring when the local vaccination lesion fails to heal and develops progressive necrosis, with destruction of large areas of skin, su bcutaneous tissue, and underlying structures. Progressive lesions may spread to other skin su rfaces and to bone and viscera. Progressive vaccinia is associated with a high mortality rate. This complication has been seen in patients with a compromised immune system due to a congenital deficiency, lymphoproliferative disease, immunosuppressive treatment, or HIV infection.Management should include aggressive VIG therapy. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 667.Post-Vaccinial Encephalitis/Encephalomyelitis : Vaccinial complications affecting the CNS are unpredictable. Post-vaccinial encephaliti s typically affects children < 2 years of age and is characterized by an onset of sy mptoms 6-10 days following vaccination, which include seizures, hemiplegia, aphasia, and transient amnesia. Histopathological changes include generalized cerebral edema, mild ly mphocytic meningeal infiltration, ganglion degenerative changes and perivascular hemorrh ages. Older children and adults can develop encephalitis or encephalomyelitis characterized by an onset of symptoms 11-15 days following vaccination, which include fever, vomiting, headache, mala ise, and anorexia, progressing to loss of consciousness, amnesi a, confusion, disorientation, restlessness, delirium, drowsiness, seizures and coma. Histopathological changes include demyelination with lymphocytic infiltration, but limited cerebral edema.