• Patients must have a histopathologically confirmed diagnosis of an aggressive B-cell non-Hodgkin lymphoma that is recurrent or refractory to standard therapy.
• For the purpose of this study, aggressive B-cell NHL will be deemed any lymphoma belonging to one of the following groups according to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms (Swerdlow et al., 2016).
• For the purposes of stratification, diagnoses are grouped into 2 categories:
• Category A
  • Burkitt lymphoma;
  • Burkitt-like lymphoma with 11q aberration;
  • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements;
  • High-grade B-cell lymphoma, NOS.
• Category B
  • Diffuse large B-cell lymphoma (DLBCL), NOS;
  • Diffuse large B-cell lymphoma (DLBCL), NOS; Germinal center B-cell type;
  • Diffuse large B-cell lymphoma (DLBCL), NOS; Activated B-cell type;
  • Large B-cell lymphoma with IRF4 rearrangement;
  • T-cell/histiocyte-rich large B-cell lymphoma;
  • Primary DLBCL of the central nervous system (CNS);
  • Primary cutaneous DLBCL, leg type;
  • EBV+ DLBCL, NOS;
  • EBV+ mucocutaneous ulcer;
  • DLBCL associated with chronic inflammation;
  • Lymphomatoid granulomatosis;
  • Primary mediastinal (thymic) large B-cell lymphoma;
  • Intravascular large B-cell lymphoma;
  • ALK+ large B-cell lymphoma ;
  • Plasmablastic lymphoma;
  • Primary effusion lymphoma;
  • HHV-8+ DLBCL, NOS;
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma. 
• Patients must have measurable disease, defined as at least one lesion that is > 15 mm (1.5 cm) in the longest axis on cross-sectional imaging and measureable in two perpendicular dimensions per computed tomography (spiral CT), PET-CT or MRI.
• Patients must have disease that has relapsed after or is refractory to at least 2 lines of standard therapy; the remaining standard treatment options are unlikely to be effective in the opinion of the treating physician, or patient is felt to be ineligible for such therapies or the patient refuses such therapies; patients who have undergone autologous stem cell transplant are eligible as long as they meet all other criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
• Life expectancy of greater than 12 weeks
• White blood cell (WBC) ≥ 2000/mm^3.
• Absolute neutrophil count (ANC) ≥ 1500/mm^3.
• Platelet count ≥ 100,000/mm^3.
• Hemoglobin > 9.0 g/dL.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL). 
• Aspartate transaminase (aspartate aminotransferase [AST]) ≤ 2.5 x ULN. 
• Calculated creatinine clearance (CrCl) ≥ 50 mL/min (if using the Cockcroft-Gault formula). 
• Negative urine or serum pregnancy test result for females of child bearing potential; females of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 23 weeks after the last dose of study drug; males who are the sexual partners of a female of child-bearing potential must use any contraceptive method with a failure rate of less than 1% per year for the duration of study participation and for a period of 31 weeks after the last dose of study drug; these periods of required use of contraception have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that females of child-bearing potential use contraception for 5 half-lives plus 30 days and males who are the sexual partners of females of child-bearing potential use contraception for 5 half-lives plus 90 days.
• Females must not be breast-feeding. 
• Females of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab.
• A female of child-bearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.; menopause is defined clinically as 12 months of amenorrhea in a female over 45 in the absence of other biological or physiological causes; in addition, females under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.
• Females who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic males do not require contraception. 
• Should a female of child-bearing potential become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or at least 5 half-lives, whichever is longer, prior to entering the study. 
• Palliative (limited-field) radiation therapy is permitted, if all of the following criteria are met. 
• Repeat imaging demonstrates no new sites of bone metastases. 
• The lesion being considered for palliative radiation is not a target lesion. 
• Patients who have not recovered to grade 1 or less from any adverse events due to agents administered more than 4 weeks earlier (excluding alopecia).
• Patients who are receiving any other investigational agents. 
• * Patients should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. 
• Patients who have received autologous stem cell transplant (ASCT) =< 12 weeks prior to the first dose of study drug. 
• Patients with a prior history of allogeneic stem cell or solid organ transplantation. 
• Patients with evidence of active disease in the central nervous system (CNS) defined as either the presence of active lesions on MRI obtained within 4 weeks of registration or progressive neurological decline. 
• Patients with primary CNS lymphoma who develop systemic recurrence following standard therapy may be included as long as no active CNS disease is present at the time or enrollment; similarly, patients with secondary involvement of the CNS from a systemic lymphoma may be included as long as the CNS disease has been optimally treated and they demonstrate no evidence of active CNS disease. 
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CDX-1127 (varlilumab) and/or nivolumab.
• History of severe hypersensitivity reaction to any monoclonal antibody. 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with CDX-1127 (varlilumab) or nivolumab .
• Patients with human immunodeficiency virus (HIV) are eligible for the study provided they meet the other protocol criteria in addition to the following: 
  • Undetectable HIV load by standard polymerase chain reaction (PCR) clinical assay; 
  • Absolute CD4 count of >= 200 mm^3;
  • Willing to maintain adherence to combination antiretroviral therapy; 
  • No history of acquired immunodeficiency syndrome (AIDS) defining condition (other than lymphoma or CD4 cell count < 200 mm^3); 
  • Likely to have near normal lifespan if not for the presence of relapsed/refractory lymphoma:
    • Patients with evidence of hepatitis B virus (HBV) are eligible provided there is minimal hepatic injury and the patient has undetectable HBV on suppressive HBV therapy; patient must be willing to maintain adherence to HBV therapy; 
    • Patients with previously treated and eradicated hepatitis C virus (HCV) who have minimal hepatic injury are eligible. 
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible. 
• Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event). 
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted. 
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study. 
• Patients with other active malignancy =< 3 years prior to registration for which active treatment is required must be excluded; patients with composite lymphomas that have a non-B-cell component must be excluded.
  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.

Inclusion Criteria
•Pre-Registration:

• Smoking history of ≥ 30 pack‐years AND either current smoker (still smoking or quit < 1 year prior to pre‐registration) OR former smoker (quit 1‐15 years prior to pre‐registration).
  • Note: Pack years is determined by multiplying the number of packs smoked per day by the number of years smoked.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Computed tomography (CT) scan of the chest done ≤ 6 months prior to pre‐registration showing either negative findings (no nodules) or solid or part‐solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung‐Reporting and Data Systems [RADs] version 1.0).
• Willingness to employ adequate contraception, if applicable; Note: women of child‐bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

Inclusion Criteria
•Registration:

• Leukocytes (white blood cell [WBC]) ≥ 3,000/microliter.
• Neutrophils (absolute neutrophil count [ANC]) ≥ 1,500/microliter.
• Platelets ≥ 100,000/microliter.
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) Note: Higher total bilirubin levels (≤ 3 mg/dL) can be allowed if due to known benign liver condition; i.e. Gilbert''s.
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ≤ 1.5 x institutional upper limit of normal (ULN).
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 1.5 x institutional upper limit of normal (ULN).
• Creatinine ≤ institutional upper limit of normal (ULN).

Exclusion Criteria
•Pre-Registration:

• History of any malignancy; exceptions: non‐melanoma skin cancer or carcinoma in situ (CIS) of the cervix.
• Known hepatitis B or C.
• Receiving any other investigational agents.
• Any prior investigational immune therapy, such as for lung cancer prevention or treatment or for CIS of the cervix.
• Use of oral or systemic steroids or other systemic anti‐immune therapy ≤ 90 days prior to pre-registration.
  • Note: Use of inhaled/nasal steroids and local steroid injections for pain control are not exclusionary.
• Known human immunodeficiency virus (HIV).
• Known autoimmune disease.
• Known non‐alcoholic steatohepatitis (NASH) or non‐alcoholic fatty liver disease (NAFLD).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MUC1/Poly‐ICLC
  •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Exclusion Criteria
•Registration:

•  Any positive antinuclear antibody (ANA) titer above 1:160, even in an asymptomatic individual.
  • Note: Weakly positive ANA defined as ANA titers up to 1:160 maximum (≤ 1:160) will be acceptable in an asymptomatic individual who is otherwise eligible for the study.
• Pregnant or breast feeding.
  • Note: Pregnant women are excluded from this study because the MUC1/Poly-ICLC vaccine may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with MUC1/Poly-ICLC vaccine, breastfeeding should be discontinued if the mother is treated with the vaccine

• Age ≥ 18 years old
• Histological confirmation of melanoma of any mucosal site including (but not limited to) anus/rectum, vulvar/vaginal, sinonasal.
  • NOTE: Melanomas of cutaneous origin and/or ocular origin are ineligible.
• R0 or R1 resection of primary melanoma tumor (no gross disease can be left behind, but microscopically positive margins are acceptable).
• Surgery within ≤ 90 days of registration.
• ECOG Performance Status (PS) ≤ 1.
• The following laboratory values obtained ≤ 14 days prior to registration:
• Hematological
  • Absolute Neutrophil Count (ANC) ≥ 1500/mm^;3
  • Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused);
  • Platelet (Plt) 100,000/mm^3.
• Renal
  • Serum Creatinine ≤ 1.5 x ULN.
• Hepatic
  • Alkaline Phosphatase (Alk Phos) ≤ 1.5 x upper limit of normal (ULN);
  • Total and Direct Bilirubin ≤ 1.5 × (ULN);
  • Aspartate aminotransferase (AST) ≤ 1.5 × ULN.
• Negative pregnancy test done within 7 days prior to registration, for women of childbearing potential only.
  • NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• Written informed consent and HIPAA authorization for release of personal health information prior to registration.
  • NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Willing to return to enrolling institution for follow-up.
• Willing to provide archival tissue prior to C1D1 if available and blood samples for correlative research purposes

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and subjects known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Subjects known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 3 years prior to registration.
  • EXCEPTIONS: Malignancies with a very low (< 5%) risk of recurrence such as non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Active autoimmune disease -including but not limited to:
  • Subjects with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease;
  • Subjects with a history of symptomatic autoimmune disease requiring systemic treatment within the past 2 years with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs:
  • rheumatoid arthritis;
  • systemic progressive sclerosis (scleroderma);
  • systemic lupus erythematosus;
  • psoriasis;
  • autoimmune vasculitis (e.g., Wegener’s Granulomatosis);
  • CNS or motor neuropathy considered of autoimmune origin (e.g., GuillainBarre Syndrome and Myasthenia Gravis, multiple sclerosis).
    • EXCEPTION: autoimmune conditions that are only requiring replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Any radiation within 2 weeks prior to study initiation. Neoadjuvant and adjuvant radiation are allowed, but must be completed > 2 weeks prior to registration.
• Any prior systemic therapy for melanoma (chemotherapy, immunotherapy, targeted therapy).
• Women of childbearing potential (WOCBP) must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent until 5 months after the last dose of study drug. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Examples include: intrauterine device (IUD), vasectomy of a female subject’s male partner, contraceptive rod implanted into the skin, or use of two of the following: diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive.

*Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• NOTE: Male subjects are not required to utilize contraception. The study regimen is not genotoxic and systemic concentrations sufficient to produce a risk of fetal toxicity are not expected in WOCBP partners from exposure to a male participant’s seminal fluid.
• Pregnant or breastfeeding.
  • NOTE: breast milk cannot be stored for future use while the mother is being treated on study.

• Participants must have histologically confirmed intracranial glioblastoma or gliosarcoma following maximum surgical resection. Tumors primarily localized in the infratentorial compartment will be excluded.
• Participants may have had prior surgery for glioblastoma or gliosarcoma but no systemic or radiation therapy.
• Age ≥ 18 years.
• Karnofsky performance status ≥60
• Participants must have normal organ and marrow function as defined below:
  • Leukocytes ≥3,000/mL
  • Absolute neutrophil count ≥1,500/mL
  • Platelets ≥100,000/mL
  • Hemoglobin ≥ 9g/dl
  • Total bilirubin within normal institutional limits (except for participant's with Gilbert's disease)
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal
  • Creatinine ≤ institutional upper limit of normal OR
  • Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
  • Potassium within normal institutional range, or correctable with supplements
  • Serum amylase ≤ 1.5 x institutional upper limit of normal
  • Serum lipase ≤ 1.5 x institutional upper limit of normal
  • INR < 2.0
  • PTT ≤ institutional upper limit of normal, unless receiving therapeutic low molecular weight heparin
• Must be able to swallow pills.
• Participants must plan to begin radiation therapy 14-42 days after surgical resection.
• Immunohistochemically negative for IDH1 R132H mutation.
• Evidence that the tumor MGMT promoter is unmethylated by standard of care assays.
• Genotyping data available or in process (data must be available at time of initial registration if randomization probabilities differ across biomarker subgroups as determined by the DFCI Coordinating Center) to assign biomarker subgroups through whole exome sequencing, whole genome copy number analysis, or a combination as described in Section 9.1.
• MRI with gadolinium should be obtained within 21 days prior to beginning treatment. Patients without measurable disease are eligible. Participants must be able to undergo MRIs (CTs are not allowed for response assessment on study).
• The effects of the experimental agents used in this study on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (women who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation unless otherwise specified in sub-study that the participant is randomized to. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• For women of child bearing potential (women who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) a negative serum pregnancy test must be documented prior to initial registration.
• Ability to understand and the willingness to sign a written informed consent document.

• Participants will not be eligible if the original diagnosis was a lower grade glioma and a subsequent histologic diagnosis revealed glioblastoma.
• Planned major surgery.
• Participants who are receiving any other investigational agents.
• Participants who have had any prior cranial radiotherapy.
• Planned use of Optune™.
• History of a different malignancy, unless (a) have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, and/or (b) malignancy was cervical cancer in situ, superficial bladder cancer or basal cell or squamous cell carcinoma of the skin, and malignancy has been treated. Patients who meet the above listed criteria and are only on preventative treatment will be deemed eligible.
• History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician.
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
• Known history of congenital QT prolongation or Torsade de pointes (TdP).
• Complete left bundle branch or bifascicular block.

  --QTc interval > 450 ms for men or > 470 ms for women.

• Persistent or history of clinically meaningful ventricular arrhythmias or atrial fibrillation.
• Unstable pectoris or myocardial infarction ≤ 3 months prior to starting study treatment.
• Uncontrolled hypertension (blood pressure ≥ 160/95 mmHg).
• Other clinically significant heart disease such as congestive heart failure requiring treatment.
• Uncontrolled diabetes mellitus, or subjects with either of the following:
• Fasting blood glucose (FBG defined as fasting for at least 8 hours) ≥ 200 mg/dL (7.0 mmol/L), or
• HbA1c ≥ 8%
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), chronic renal disease, pancreatitis, chronic pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations.
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNS [qualitative] is detected).
• Known acute or chronic pancreatitis.
• Participants with active diarrhea ≥ CTCAE grade 2 despite medical management.
• Active infection requiring antibiotics.
• Pregnant or breastfeeding.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection). Participants with unresolved diarrhea ≥ CTCAE grade 2 will be excluded as previously indicated.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the experimental agents or other agents used in study.
• Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate. Participant must be off any EIAEDs for at least 7 days prior to planned start of study treatment. A list of EIAED and other inducers of CYP3A4 is provided. Among non-EIAED, caution is recommended with use of valproic acid due to potential for drug interaction.
• Participants taking a drug known to be strong inhibitors or inducers of isoenzyme CYP3A. Participant must be off CYP3A inhibitors and inducers for at least 7 days prior to planned start of study treatment. NOTE: participants must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to planned start of study treatment and during the entire study treatment period due to potential CYP3A4 interaction.
• Current use of herbal preparations/medications, including but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. Participants should stop using these herbal medications 7 days prior to planned start of study treatment.
• Current use of warfarin sodium or any other coumadin-derivative anticoagulant. Participant must be off Coumadin-derivative anticoagulants for at least 7 days prior to planned start of study treatment. Low molecular weight heparin and factor Xa inhibitors are allowed.

ELIGIBILITY CRITERIA FOR PREREGISTRATION (STEP 0): 

• Preoperative biopsy for confirmation of renal cell carcinoma (RCC) must be performed within four (4) months prior to randomization. 
• If biopsy was performed as part of patients standard care, and will not be performed during step 0 proceed directly to randomization.

ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): 

• Patients with newly diagnosed higher risk RCC of any histology including sarcomatoid or (if preoperative biopsy was uninformative)
  •"unknown" histology; RCC must have been confirmed by biopsy within 4 months prior to randomization; if the biopsy clearly demonstrated a benign condition or a different type of cancer, the patient is not eligible to be randomized
  •Clinical stage >= T2NxM0 or TanyN+ disease for which radical or partial nephrectomy is planned.
• Patients must have no clinical or radiological evidence of distant metastases (M0.) 
• No concurrent or prior systemic or local anti-cancer therapy for RCC is permitted; examples of these prohibited therapies include: 
  • Radical or partial nephrectomy for prior RCC;
  • Metastectomy for RCC; 
  • Radiation therapy to the renal bed or any distant metastatic sites; 
  • Antineoplastic systemic therapies for RCC: i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or investigational agents for treatment of RCC; 
  • Prior treatment with an anti-programmed cell death 1 (PD-1), anti-programmed cell death-ligand 1 (PD-L1), anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. 
• Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1. 
• Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 
  • Has not undergone a hysterectomy or bilateral oophorectomy; or 
  • Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and effective methods of contraception, as described in the informed consent form (ICF), or to abstain from sexual intercourse for the duration of their participation in the study; women of childbearing potential should use adequate methods to avoid pregnancy for 23 weeks after the last dose of nivolumab; sexually active males should use adequate methods to avoid pregnancy for 31 weeks after the last dose of nivolumab.
• Patient must have no prior history of RCC that was resected with curative intent within the past 5 years.
• Patients must not have other current malignancies: 
  • Adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 3 years prior to the time of registration and they are not receiving any current treatment;
  • Prior or current prostate cancer is excluded;
    • A history of superficial Ta urothelial cancer is permitted (not being currently treated) but T1 or greater disease is excluded.
• No active known or suspected autoimmune disease; the following are permitted: patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune or non-autoimmune condition requiring hormone replacement, asymptomatic hypothyroidism not requiring treatment, psoriasis not requiring systemic treatment, or conditions not expected to recur.
• No ongoing condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications; no treatment with other immunosuppressive agents within 14 days prior to the first dose of study drug; topical, ocular, intra-articular, intranasal, inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.; a brief (less than 3 weeks) course of corticosteroids (any amount) for prophylaxis (for example: contrast dye allergy) or for treatment of non-autoimmune conditions (for example: delayed-type hypersensitivity reaction caused by a contact allergen) is permitted if > 14 days since last dose.'
• No uncontrolled adrenal insufficiency.
• No known chronic active liver disease or evidence of acute or chronic hepatitis B virus (HBV) or hepatitis C (HCV).
• Patients must not have a serious intercurrent illness, including ongoing or active infection requiring parental antibiotics.
• No known evidence of human immunodeficiency virus (HIV) infection.
• No known medical condition (e.g. a condition associated with uncontrolled diarrhea such as ulcerative colitis or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or interfere with the interpretation of safety results.
• No major surgery within 28 days prior to randomization.
• Patients currently enrolled in other clinical trials testing a therapeutic intervention.
• Patients must have the following baseline laboratory values within 4 weeks of randomization:
  • White blood cells >= 2000/uL, within 4 weeks of randomization.
  • Absolute granulocyte count (AGC) >= 1,500/mm^3, within 4 weeks of randomization.
  • Platelet count >= 100,000/mm^3, within 4 weeks of randomization.
  • Hemoglobin >= 9.0 g/dL, within 4 weeks of randomization.
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) >= 40 mL/min, within 4 weeks of randomization.
  • Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 x ULN), within 4 weeks of randomization.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN, within 4 weeks of randomization.
• No history of severe hypersensitivity to a monoclonal antibody.
• Signed, dated informed consent.

• None.

Inclusion Criteria
•Pre Registration:

• Patients must have histologically or cytologically confirmed malignant pleural mesothelioma.
• Patient is willing to submit a tissue sample to test for expression of mesothelin.
  • Note: Tissue sample for mesothelin assay may have been collected prior to, during or after receipt of the frontline chemotherapy; patients will not be required to submit another tissue sample after receipt of the chemotherapy.
• Patients must have received platinum based chemotherapy.

Inclusion Criteria - Registration (Phase 2 Only):

• Patient has measurable disease per RECIST 1.1 for non-pleural disease or modified RECIST 1.1 (mRECIST) for pleural disease. Note: For pleural disease, this is defined as at least one lesion that can be accurately measured perpendicular to the chest wall or mediastinum that is ≥ 10 mm (≥ 1 cm). For extra pleural disease, measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 10 mm (≥ 1 cm) for non-nodal lesions and ≥ 15 mm (≥ 1.5 cm) for nodal lesions with spiral CT scan, MRI, or calipers by clinical exam as per RECIST 1.1.
• Tissue submitted for testing at pre-registration shows moderate or stronger mesothelin expression in ≥ 30% of the tumor cells.

For Phase 1 and 2

• Patients must have received platinum-based therapy with or without bevacizumab.
• Patients age ≥ 18 years old.
  • Note: Because MPM primarily affects older adults and no dosing or adverse event data are currently available on the use of anetumab ravtansine and MK-3475 (pembrolizumab) in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• ECOG performance status < 2 (Karnofsky ≥ 70%).
• Patients must have normal organ and marrow function as defined below:
  • leukocytes ≥ 3,000/mcL;
  • absolute neutrophil count ≥ 1,500/mcL;
  • platelets ≥ 100,000/mcL;
  • total bilirubin Within normal institutional limits;
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal (ULN).
  • creatinine Within normal institutional limits OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN AND partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, unless patient is on stable dose of anti-coagulation therapy in which case patients will be allowed to participate if they have no signs of bleeding or clotting and the INR/PT and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the Investigator’s discretion.
• Negative serum pregnancy test for females of child bearing potential.
• Note: Females are considered to not be of child bearing potential if any of the following apply:
  • Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
  • Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
• Has a congenital or acquired condition that prevents childbearing.
• Negative serum pregnancy test for females of child bearing potential.
  • Note: Females are considered to not be of child bearing potential if any of the following apply:
    • Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
    • Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
    • Has a congenital or acquired condition that prevents childbearing.
• Patient agrees to use one of the following acceptable methods of contraception prior to study entry, during study participation, and for at least six months after receiving the last dose of study treatment.
• Acceptable methods of contraception are:
  • Single method (1 of the following is acceptable):
    • abstinence, if consistently employed as the patient’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and Institutional Review Boards (IRBs);
    • intrauterine device (IUD);
    • vasectomy of a female patient’s male partner;
    • contraceptive rod implanted into the skin.
  • Combination method (requires use of 2 of the following):
    • diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide);
    • cervical cap with spermicide (nulliparous women only);
    • contraceptive sponge (nulliparous women only);
    • male condom or female condom (cannot be used together);
    • hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection.
• Ability to understand and the willingness to sign a written informed consent document, unless patient is of impaired decision making capacity in which case patient may be eligible if they have a Legal Authorized representative or caretaker available.

• Patients who have received any monoclonal antibody therapy within 4 weeks prior to entering the study.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1).
  • Note: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
  • Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Patients who are receiving any other investigational agents.
• Patients with known brain metastases with progressive neurologic dysfunction, requirement of steroids and lack of improvement on head imaging obtained prior to consent to this clinical trial should be excluded because of their poor prognosis and because they would confound the evaluation of neurologic and other adverse events.
• Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging [MRI] or computed tomography [CT] scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
• Patients with carcinomatosis meningitis should also be excluded.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to anetumab ravtansine or MK-3475 (pembrolizumab).
• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4, including herbal preparation containing CYP3A4 inducers (e.g., St. John’s Wort), grapefruit and grapefruit juice (CYP3A4 inhibitor), within 2 weeks before the start of study treatment.
• Patients are prohibited from receiving the following therapies during the screening and treatment phases (including retreatment for post-complete response relapse) of this trial:
  • Antineoplastic systemic chemotherapy or biological therapy;
  • Immunotherapy not specified in this protocol;
  • Chemotherapy not specified in this protocol;
  • Investigational agents other than anetumab ravtansine and MK-3475 (pembrolizumab);
  • Radiation therapy;
    • Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be considered on an exceptional case by case basis after consultation with CTEP. The patient must have clear measurable disease outside the radiated field. Administration of palliative radiation therapy will be considered clinical progression for the purposes of determining PFS.
  • Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Chalmette–Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  • Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the study PI and CTEP.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Women who are pregnant or breastfeeding.
  • Note: Pregnant women are excluded from this study because anetumab ravtansine and MK-3475 (pembrolizumab) are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with anetumab ravtansine and MK-3475 (pembrolizumab), breastfeeding should be discontinued if the mother is treated with anetumab ravtansine or MK-3475 (pembrolizumab).
• HIV-positive patients who do not meet all of the following and/or are on HIV medications considered to be strong inhibitors or inducers of CYP3A4:
  • Undetectable HIV viral load by standard clinical assay within 6 months of registration;
  • Willing to adhere to antiretroviral therapy that has minimal overlapping toxicity or pharmacokinetic interactions with protocol therapy;
  • No AIDS-defining events other within the past 12 months;
  • Near normal life expectancy if not for the presence of the cancer.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• Patients who are known to have a history of or a finding of corneal epitheliopathy at pre-study are excluded because anetumab ravtansine may worsen this condition and reduce vision.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
• Receipt of transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks prior to study treatment.
• Patient with active interstitial lung disease (ILD)/pneumonitis or a prior history of ILD/pneumonitis requiring treatment with steroids.
• Patient has received prior treatment with PD-1, PD-L1 or PD-L2 inhibitor.

1. Age ≥18 years
2. Histologically confirmed diagnosis, according to the World Health Organization (WHO, 2008) classification, of: DLBCL NOS, THRLBCL, EBV-positive DLBCL, composite lymphoma with a DLBCL component with a DLBCL relapse subsequent to DLBCL treatment, disease transformed from an earlier diagnosis of low grade lymphoma (i.e. an indolent pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with a DLBCL relapse subsequent to DLBCL treatment.
3. Fresh tumour tissue for central pathology review must be provided as an adjunct to participation in this study. Should it not be possible to obtain a fresh tumour tissue sample, archival paraffin embedded tumour tissue acquired ≤3 years prior to screening for this protocol must be available for this purpose.
4. Patients must have:
   1. Relapsed or refractory DLBCL
   2. At least one bidimensionally measurable disease site. The lesion must have a greatest transverse diameter of ≥1.5 cm and greatest perpendicular diameter of ≥1.0 cm at baseline. The lesion must be positive on PET scan
   3. Received at least one, but no more than three previous systemic therapy lines for the treatment of DLBCL. At least one previous therapy line must have included a CD20-targeted.
   4. ECOG 0 to 2
5. Patients after failure of ASCT or patients considered in the opinion of the investigator currently not eligible for HDC with subsequent ASCT.
6. Patients must meet the following laboratory criteria at Screening:
   1. ANC ≥1.5 × 109/L (unless secondary to bone marrow involvement by DLBCL)
   2. PLTs ≥90 × 109/L (unless secondary to bone marrow involvement by DLBCL) and absence of active bleeding
   3. Total serum bilirubin ≤2.5 × ULN unless secondary to Gilbert's syndrome (or pattern consistent with Gilbert's) or documented liver involvement by lymphoma. Patients with Gilbert's syndrome or documented liver involvement by lymphoma may be included if their total bilirubin is ≤5 x ULN
   4. ALT, AST and AP ≤3 × ULN or <5 × ULN in cases of documented liver involvement by lymphoma
   5. Serum creatinine ≤2.0 x ULN or creatinine clearance must be ≥40 mL/min calculated using a standard Cockcroft-Gault formula (Cockroft & Gault, 1976)
7. For a female of childbearing potential (FCBP), a negative pregnancy test must be confirmed before enrolment. An FCBP must commit to take highly effective contraceptive precautions without interruption during the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later. An FCBP must refrain from breastfeeding and donating blood or oocytes during the course of the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later. Restrictions concerning blood donations apply as well to females who are not of childbearing potential.
8. Males must use an effective barrier method of contraception without interruption during the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later, if the patient is sexually active with an FCBP. Males must refrain from donating blood or sperm during study participation and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later.
9. In the opinion of the investigator, the patients must:
   1. Be able to comply with all study-related procedures, medication use, and evaluations
   2. Be able to understand and give informed consent
   3. Not be considered to be potentially unreliable and/or not cooperative.

1. Patients who have: any other histological type of lymphoma including, e.g., primary mediastinal (thymic) large B-cell lymphoma (PMBL) or Burkitt's lymphoma, primary refractory DLBCL, patients with known "double/triple hit" DLBCL genetics, CNS lymphoma involvement in present or past medical history
2. Patients who had a major surgery less than 30 days prior to Day 1 dosing
3. Patients who have, within 14 days prior to Day 1 dosing:
   1. Not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma-specific therapy
   2. Received live vaccines
   3. Required parenteral antimicrobial therapy for active, intercurrent systemic infections
4. Patients who:
   1. In the opinion of the investigator, have not recovered sufficiently from the adverse toxic effects of prior therapies, major surgeries or significant traumatic injuries
   2. Were previously treated with CD19-targeted therapy or BEN
   3. Have a history of previous severe allergic reactions to compounds of similar biological or chemical composition to MOR00208, RTX, murine proteins or BEN, or the excipients contained in the study drug formulations
   4. Have undergone ASCT within a period of ≤3 months prior to signing the informed consent form. Patients who have a more distant history of ASCT must exhibit full haematological recovery before enrolment into the study.
   5. Have undergone previous allogeneic stem cell transplantation
   6. Concurrently use other anticancer or experimental treatments
5. Prior history of malignancies other than DLBCL, unless the patient has been free of the disease for ≥3 years prior to Screening. Exceptions to the ≥3-year time limit include history of the following:
   1. Basal cell carcinoma of the skin
   2. Squamous cell carcinoma of the skin
   3. Carcinoma in situ of the cervix, breast and bladder
         f) Incidental histological finding of prostate cancer (Tumour/Node/Metastasis [TNM] stage of T1a or T1b)
6. Patients with:
   1. Positive hepatitis B and/or C serology
   2. Known seropositivity for or history of active viral infection with HIV
   3. Evidence of active, severe uncontrolled systemic infections or sepsis
   4. A history or evidence of severely immunocompromised state
   5. A history or evidence of severe hepatic impairment (total serum bilirubin > 3 mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma
   6. A history or evidence of clinically significant cardiovascular, cerebrovascular, CNS and/or other disease that, in the investigator's opinion, would preclude participation in the study or compromise the patient's ability to give informed consent

Patients presenting with an incipient clinical diagnosis for FSGS/MCD or MN or pediatric participants not previously biopsied, with a clinical diagnosis for FSGS/MCD or MN meeting the following inclusion criteria:

• Documented urinary protein excretion ≥500 mg/24 hours or spot protein: creatinine ratio equivalent at the time of diagnosis or within 3 months of the screening/eligibility visit.
• Scheduled renal biopsy

• Prior solid organ transplant
• A clinical diagnosis of glomerulopathy without diagnostic renal biopsy
• Clinical, serological or histological evidence of systemic lupus erythematosus (SLE) as defined by the ARA criteria. Patients with membranous in combination with SLE will be excluded because this entity is well defined within the International Society of Nephrology/Renal Pathology Society categories of lupus nephritis, and frequently overlaps with other classification categories of SLE nephritis (68)
• Clinical or histological evidence of other renal diseases (Alport, Nail Patella, Diabetic Nephropathy, IgA-nephritis, monoclonal gammopathy (multiple myelomas), genito-urinary malformations with vesico-urethral reflux or renal dysplasia)
• Known systemic disease diagnosis at time of enrollment with a life expectancy less than 6 months
• Unwillingness or inability to give a comprehensive informed consent
• Unwillingness to comply with study procedures and visit schedule
• Institutionalized individuals (e.g., prisoners)

• Age birth-100 years, male or female, any race/ethnicity
• Potential participant shall have a confirmed diagnosis of a mitochondrial disease or a suspected diagnosis based on a review of clinical history by a Mitochondrial Disease Biobank working group member using the clinical criteria listed in the table below
• Selected participants shall have at least two documented conditions contained within the minor clinical criteria
  • Minor Criteria
    • Symptoms compatible with a mitochondrial defect
    • Smaller numbers of RRF or widespread electron microscopy abnormalities of mitochondria
    • Antibody-based demonstration of an mito defect or residual activity of an mito complex 20%–30% in a tissue, 30%–40% in a cell line, or 30%–40% in >2 tissues
    • Fibroblast ATP synthesis rates 2–3 SD below mean, or fibroblasts unable to grow in galactose media
    • Nuclear or mtDNA mutation of probable pathogenicity
    • One or more metabolic indicators of impaired metabolic function
• OR one condition in the major criteria with evidence of a condition in the minor criteria, will be considered for inclusion of a participant of appropriate age
  • Major Criteria
    • Multi-systemic symptoms characteristic of mito disorder
    • Progressive clinical course with episodes of exacerbation
    • A family history strongly indicative of an mtDNA mutation
    • Exclusion of other metabolic or non-metabolic disorders
    • >2% ragged red fibers (RRF) in skeletal muscle
    • Cytochrome c oxidase negative fibers (>2-5%) or residual activity of a mito complex <20% in a tissue; <30% in a cell line, or <30% in >2 tissues
    • Fibroblast ATP synthesis rates >3 SD below mean
    • Nuclear or mtDNA mutation of undisputed pathogenicity
• 1st-degree relatives of affected participants (described above) are also invited to participate in the project.
• In addition, samples from participants with one of the following mitochondrial disease diagnosis will be included:
  • Alpers’ progressive sclerosing poliodystrophy 
  • Barth syndrome 
  • CPEO 
  • Dominant optic atrophy
  • Friedriech’s Ataxia
  • Hereditary paraganglioma 
  • Hereditary spastic paraplegia 
  • Kearns-Sayre syndrome Leber hereditary optic neuroretinopathy
  • Leigh and Leigh-like Syndrome 
  • MELAS 
  • MERRF
  • NARP 
  • Pearson syndrome 
  • Wolfram syndrome 
  • Mitochondrial fatty acid oxidation disorder 
  • Urea cycle defect

• Unwilling to provide informed consent
• Unwilling to consent to providing biospecimens to be stored in the biobank for an indefinite amount of time and to be used in future research studies of as yet unknown design
• Does not have a diagnosis of mitochondrial disease or clinical symptoms that are indicative of a potential mitochondrial disease as determined by a chart review by at least one Individualized Medine Biobank for Mitochondrial Disease working-group member

• Be ≥ 18 years of age
• Have been admitted to hospital
• Have a signed informed consent by participant or surrogate/representative
• Have a local diagnosis (confirmed or suspected) of influenza, or of a targeted non-influenza viral respiratory infection*, resulting in (or extending a previous) hospitalization
  • A list of targeted non-influenza respiratory viruses is maintained on the INSIGHT website.

• Current imprisonment, or compulsory detention (involuntary incarceration) for treat of a psychiatric or physical illness.

Inclusion Criteria  

• Age 18 to 85 years old.
• Equal number of males and females.
• Participants recruited to three experimental groups:
  • Class I-II heart failure patients;
  • Class III-IV heart failure patients;
  • Age, BMI and sex matched healthy control subjects.

Exclusion Criteria  

• Pacemaker dependent.
• If they currently smoke.
• If they are allergic to the CT contrast material.
• If participating in an aim of the study in which an esophageal balloon catheter will be used, subjects will be excluded if:
  • They are allergic to latex; or
  • If they have a history of nose bleeds.                      

Group IA

• Patients with open elbow procedures or trauma which have resulted in arthrofibrosis of the elbow joint  

Group IB

• Patients with normal motion  

Group IIA 

• Patients with established shoulder contractures limiting ADL’s 

Group IIB

• Normal patients 

Group IIIA 

• Patients with knee arthrofibrosis after TKA  

Group IIIB

• Patients without contracture after TKA

• Age less than 18 years
• History of infection in operative extremity
• History of malignancy in operative extremity
• Presence of a condition

Subject Population:

• Heart failure patients and healthy subjects

• Ages 18-90

• Age less than 18

• Age 18-40 years
• No chronic medical conditions other than seasonal or environmental allergies
• On no prescription medications other than second generation antihistamines (Cetirizine, Fexofenadine, Desloratadine, Loratadine, etc), oral contraceptive pills, or intrauterine devices.
• BMI 18.5-35 kg/m2
• Both normotensive and prehypertensive people are eligible and will be studied
• Not a current smoker or tobacco user
• Not pregnant or breast feeding and not intending to become pregnant or breast feed

• The investigators will exclude subjects who have any medical or psychiatric disorders
• History of anxiety or depression, and those taking any medications other than non-sedating antihistamines or oral contraceptives.
• Those found to have depression on a depression screening tool (BDI-II) will be excluded. Current smokers will be excluded.
• All female subjects will undergoing a screening pregnancy test and excluded if positive.
• Subjects found to have significant sleep disorders will be excluded.

• Age ≥ 7 years.
• Biopsy confirmed newly diagnosed or recurrent WHO Grade II or Grade III malignant glioma.
• CT simulation, 18F-DOPA PET imaging, and standard of care pre-RT MRI scans to be performed at Mayo Clinic Rochester.
• Provide informed written consent.

• Patients diagnosed with WHO grade IV malignant glioma.
• Patients previously treated with radiation therapy.
• Unable to undergo MRI scans with contrast (e.g., cardiac pacemaker, defibrillator, kidney failure).
• Unable to undergo an 18F-DOPA PET scan (e.g., Parkinson’s Disease, taking anti-dopaminergic, or dopamine agonist medication or less than 6 half-lives from discontinuance of dopamine agonists.  Other potentially interfering drugs consist of: amoxapine, amphetamine, benztropine, buproprion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, paroxetine, citalopram, and sertraline).
• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.

• Age 18-40 years
• BMI of 18.5-30 kg/m²
• Not a current smoker or tobacco user
• No chronic medical or psychiatric disorders
• On no prescription medications other than second generation antihistamines (cetirizine, fexofenadine, desloratadine, loratadine, etc), oral contraceptive pills, or intrauterine devices
• History of normal sleep patterns, defined as nocturnal sleep duration of 6.5-8 hours per night without regular daytime naps

• The investigators will exclude subjects who have any medical or psychiatric disorders
• History of anxiety or depression
• Those taking any medications other than non-sedating antihistamines or oral contraceptives will be excluded
• Those found to have depression on a depression screening tool (BDI-II) will be excluded
• Current smokers will be excluded
• All female subjects will undergoing a screening pregnancy test and excluded if positive
• Subjects found to have significant sleep disorders will be excluded

Women should meet at least one of the following criteria:

• Abnormal uterine bleeding
• Postmenopausal bleeding
• Thickened endometrial stripe
• Hereditary predisposition to endometrial cancer (e.g. HNPCC)
• Women referred for endometrial biopsy to evaluate suspicion or high risk of endometrial cancer

• Prior hysterectomy
• Pregnant women (There will be a verbal screen by the clinic nurse and the physician about a potential pregnancy and a pregnancy test may be conducted if there is any doubt)
• Prior pelvic radiation

• Elevated serum IgG4 or a clinical or histopathologic diagnosis of IgG4-RD in adult patients

• None

Inclusion Criteria Heart Failure Patients:

• History of Heart Failure with preserved ejection fraction or with reduced ejection fraction
• No history of dangerous arrhythmias
• Body Mass Index less than or equal to 35 kg/m
• Current non-smokers with less than 15 pack year history
• Non-pregnant women
• Individuals who are able to exercise without orthopedic limitations
• All patients will be managed by their primary care physician or cardiologist prior to enrollment to ensure inclusion and exclusion criteria have been satisfied and participation in exercise testing is safe.

Inclusion Criteria Control Participants:

• Will be matched for age, gender, height and weight and will have no history of cardiovascular related abnormalities.
• Body Mass Index less than 35 kg/m
• Current non-smokers with less than 15 pack year history
• Non-pregnant women
• Individuals who are able to exercise without orthopedic limitations

• symptoms of gastroesophageal reflux
• presence of Zenker's diverticulum or cricopharyngeal hypertrophy
• undergoing surgery for Zenker's diverticulum or cricopharyngeal hypertrophy with endoscopic laser cricopharyngeal myotomy
• at least 18 years old

• pregnant women
• children
• prisoners
• adults lacking capacity to consent

• Patients referred for echocardiographic assessment of severe valvular disease and who are referred for valvular surgery. 

• Adults 18 years of age and older
• Healthy subjects without known cardiovascular disease and thyroid disease
• Subjects who are on no medications (except oral contraceptive pill)
• Nonsmokers
• No prior history of caffeine sensitivity or allergy

• Subjects with known cardiovascular and/or thyroid disease
• Subjects currently taking medications other than oral contraceptive pill
• Smokers
• Prior history of caffeine sensitivity or allergy
• Pregnancy

• Both male and female
  • age 18 to 80
  • Healthy volunteers
    OR
  • Patients who are scheduled for clinically indicated liver MRE for fibrosis staging

• Subjects lacking capacity to consent 
• Subjects with unreliable ultrasound or MRE measurements.
• Pregnant women will be excluded.
• Women of child baring potential will be asked by our study coordinator if they are pregnant.
  • If not sure, a urine pregnancy test will be given to screen the subject at no cost to the subject.

• All ages
• Diagnosis of
• Seen at Mayo clinic between 1995 and 2013

CASES: Heavy drinkers with alcoholic hepatitis

Inclusion criteria

1. The diagnosis of AH will be established on published criteria this is based on:
   1. Average daily ethanol consumption of > 40 grams/day for women and > 60 grams/day for men for a minimum of 6 months and within the 6 weeks prior to study enrolment. Judgment regarding daily and yearly alcohol use will be made by the site investigator
   2. Clinical evaluation and appropriate laboratory testing as defined by total bilirubin > 2 mg/dL and AST > 50 U/L. When the diagnosis of AH remains in question, a liver biopsy (if clinically feasible and that subject has no contra-indications) will be required.
   3. Subjects with HBV, HCV and/or HIV will be eligible for enrollment 

Exclusion criteria

1. Evidence of other liver diseases such as autoimmune or drug-induced
2. Significant concomitant medical illnesses such as uncontrolled congestive heart failure or COPD, or multiorgan failure
3. Abstinence of alcohol use > 6 weeks immediately preceding enrollment
4. Hemochromatosis
5. Wilson Disease
6. Active intravenous drug use

CONTROLS: Heavy drinkers without alcoholic hepatitis

Inclusion criteria

1. Average daily ethanol consumption of > 40 grams /day for women and > 60 grams/day for males for a minimum of 6 months and within the 6 weeks prior to study enrollment. In addition, heavy drinkers who have just become abstinent within prior 2 weeks are eligible to be enrolled. Judgment regarding daily and yearly alcohol use will be made by the site investigator
2. AST and ALT ≤ 50 and total bilirubin levels within normal range. If bilirubin is increased due to a suspected Gilbert's Syndrome, patient may be enrolled if the direct bilirubin is within normal limits

Exclusion criteria

1. Evidence of liver disease
2. Significant concomitant medical illnesses such as uncontrolled congestive heart failure or COPD, or multiorgan failure
3. Abstinence of alcohol use > 2 weeks immediately preceding enrollment
4. Hemochromatosis
5. Wilson Disease
6. Active intravenous drug use
7. Prior history of known alcoholic liver disease
8. Presence of hepatosplenomegaly from the physical examination/radiographic imaging or stigmata of liver disease

CASES: Heavy drinkers with alcoholic hepatitis

Inclusion criteria

1. The diagnosis of AH will be established on published criteria this is based on:
   1. Average daily ethanol consumption of > 40 grams/day for women and > 60 grams/day for men for a minimum of 6 months and within the 6 weeks prior to study enrolment. Judgment regarding daily and yearly alcohol use will be made by the site investigator
   2. Clinical evaluation and appropriate laboratory testing as defined by total bilirubin > 2 mg/dL and AST > 50 U/L. When the diagnosis of AH remains in question, a liver biopsy (if clinically feasible and that subject has no contra-indications) will be required.
   3. Subjects with HBV, HCV and/or HIV will be eligible for enrollment 

Exclusion criteria

1. Evidence of other liver diseases such as autoimmune or drug-induced
2. Significant concomitant medical illnesses such as uncontrolled congestive heart failure or COPD, or multiorgan failure
3. Abstinence of alcohol use > 6 weeks immediately preceding enrollment
4. Hemochromatosis
5. Wilson Disease
6. Active intravenous drug use

CONTROLS: Heavy drinkers without alcoholic hepatitis

Inclusion criteria

1. Average daily ethanol consumption of > 40 grams /day for women and > 60 grams/day for males for a minimum of 6 months and within the 6 weeks prior to study enrollment. In addition, heavy drinkers who have just become abstinent within prior 2 weeks are eligible to be enrolled. Judgment regarding daily and yearly alcohol use will be made by the site investigator
2. AST and ALT ≤ 50 and total bilirubin levels within normal range. If bilirubin is increased due to a suspected Gilbert's Syndrome, patient may be enrolled if the direct bilirubin is within normal limits

Exclusion criteria

1. Evidence of liver disease
2. Significant concomitant medical illnesses such as uncontrolled congestive heart failure or COPD, or multiorgan failure
3. Abstinence of alcohol use > 2 weeks immediately preceding enrollment
4. Hemochromatosis
5. Wilson Disease
6. Active intravenous drug use
7. Prior history of known alcoholic liver disease
8. Presence of hepatosplenomegaly from the physical examination/radiographic imaging or stigmata of liver disease

Pediatric patients ages 9-11 years undergoing clinical lipid screening test.

• Patients with an acute viral illness and/or fever > 38C.Acute illness has been shown to result in transient elevation of lipid levels.

• Patients outside the ages of 9-11.

• Female patients who have axillary lymph nodes which may be benign or may have been diagnosed or suspicious for breast cancer will be candidates for enrollment.
• It is anticipated that the majority of these participants will undergo an US guided lymph node biopsy (standard of care). U.S. and CUSE/SDUV data collection from each participant will take place before or 2 weeks after lymph node biopsy/aspiration.  

• Having any condition that does not allow proper use of our imaging devices.

Inclusion Criteria

• A subset of 32 healthy subjects from those participants enrolled in studies IRB 11-002121 and IRB 11-007272
• BMI 18.5-35 kg/m2 
• age 18-40 years
• non-smokers
• free of any chronic medical or psychiatric disorders
• on no medications other than birth control and second generation antihistamines
• will have a history of normal sleep patterns

• Primary hyperoxaluria: Patients diagnosed with type I PH by genetic testing and part of the Rare Kidney Stone Consortium (RKSC) Primary hyperoxaluria registry
• Enteric hyperoxaluria: Patients with Roux-en-Y-gastric-bypass
• Idiopathic CaOx stone : History of passing or having surgically removed a calcium oxalate kidney stone within 5 years of recruitment
• Healthy participants with no history of kidney or bowel disease

• History of kidney or liver transplant
• History of antibiotics use within 6 months of recruitment