69 yo with bloody diarrhea

1
69 yo with bloody diarrhea

• Jason Hemming, M.D.
• Case Conference
• Oct 5,2007

2
HPI

• 60 F with h/o metastatic melanoma
• cc bloody diarrhea
• 3-4 days of progressive loose stools
• gt10 BM/day
• Initially dark then grossly bloody
• No recent travel or sick contacts

3
ROS

• LQ discomfort
• Decreased appetite
• Nausea without vomiting
• Weakness
• Fatigue

• No F/C/S
• Tolerating PO
• No dysphagia
• No odynophagia
• No CP / SOB

4
Medical History

• Metastatic Melanoma
• Atrial fibrillation
• CAD
• Hypothyroidism
• Prolapsed uterus

5
Oncologic History

• Diagnosed 1993 - s/p local resection
• Metastatic LN 2006
• Pulmonary and CNS mets
• sterotactic XRT no IL-2
• Progression of disease
• Ipilimumab (CTLA-4 Ab)
• 2 cycles (last 7/1/07)

6
Medications

• Digoxin
• HCTZ
• Metoprolol
• Levothyroxine
• Detrol
• Celebrex
• Capoten

• ASA 81mg
• Warfarin
• Amitriptyline
• Lomotil
• Imodium

7
Social History

• Married with children
• Retired business executive
• Social EtOH
• No Tob or Illicit drug use
• No recent travel or sick contacts

8
Family History

• Parents with CAD
• Brother with prostate CA
• Sister with CAD at 60 yo
• No IBD or colon cancer

9
Emergency Department

• VS 99.3, 89, 115/59, 98 RA
• fatigued, NAD
• anicteric, MMM, OP wnl
• Irr/Irr, 1/6 SEM
• CTAB
• Soft , ND, diffuse TTP, NABS, no HSM
• dark, non-bloody but OB stool

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Initial Data
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Admission

• Oncology Service
• Stool Cultures
• GI Consult
• c/o frequent bloody diarrhea, abd pain
• PE, labs unchanged from ED

12
Differential?

• Next Step?

13
Stool Studies

• Routine Cx negative
• C.diff negative times 2
• Norovirus negative
• Rotavirus negative

14
Sigmoidoscopy

• Diffuse erythema and edema
• Exudative
• Rectum to Sigmoid
• Random Biopsies

15
Pathology
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Pathology

• Marked acute and chronic inflammation
• Acute cryptitis and focal surface erosion
• No architectural distortion
• No basal lymphoplasmacytosis
• No malignancy

19
Ipilimumab induced colitis
20
Treatment

• Solumedrol 2 mg/kg
• Sxs improved
• Discharged 7/18/07
• One month prednisone taper

21
Follow Up

• Readmitted with FTT (8/9/07)
• c/o worsening abd pain and diarrhea
• Afeb, tachycardic, normotensive
• PE distended, tender abd (no peritoneal signs)
• Surgery consult

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Abd CT
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Abd CT

• Extensive intraperitoneal free air
• compresses/displaces bowel
• No source of free air
• No bowel obstruction
• No extravasation of contrast

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Exploratory Laparotomy

• Mildly distended small bowel
• Distended colon with fixed omentum
• Mobilization revealed stool spillage
• Perforation in transverse and sigmoid colon
• Extremely friable sigmoid
• Subtotal colectomy and End-ileostomy

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Gross
27
Gross
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Gross Pathology

• Hyperemic serosa with purulent and fibrinous
  exudate
• Multiple area of deep ulcerations
• up to 10cm
• 3 areas of perforation
• Focal areas of hemorrhage

29
Micro Pathology

• Severe mucosal ulceration
• Marked neutrophilic and mild lymphocytic
  infiltrates
• No obvious infection, IBD, ischemia

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Hospital Course

• Long course broad spectrum ABx
• Repeated ex-laps for washout and LOA
• PEG placement
• D/C to rehab one month later

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Cytotoxic T lymphocyte antigen-4 (CTLA-4)

• T-cell receptor
• CD25CD4 Tcells (Treg)
• Down regulatory role in T-cell activation
• Binds members B7 family
• competes against CD28 (upregulation)
• CTLA-4-/- deadly lymphoproliferation
• Role in tolerance against self antigen

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CTLA-4 Oncology

• Manipulation with goal to enhance cancer
  immunotherapies
• Blockade increased regression of immunogenic
  tumors
• Enhanced effect of IL-2

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Ipilimumab

• Antimurine CTLA-4 ab
• Induce anti-tumor activity
• regression in melanoma, RCC, Prostate
• 22 response in conjunction with IL-2 (I/II)
• Immune-related adverse events
• GI, skin, pituitary (Phase I/II 14)
• ? represent a breakdown of tolerance to self-Ag
• Mild, and Grade III/IV usually reversible

Maker AV. Ann Surg Oncol Dec 12 (12) 1005-1016
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Enterocolitis

• 198 pt with MM or RCC (2002-2005)
• 41 pts with grade 3/4 enterocolitis (21)
• Not related to total dosage or number
• Diarrhea most common Sx (40/41)
• 37/41 developed Sx within 21days (median 11d)
• Endoscopic evaluation
• 23/36 with erythema or ulcerations
• 39/41 histologically proven colitis
• 4 cases of perforation (700 total treated)

Beck K. Journ Clin Onc. 2006 15 2283-2289 Weber
J. Oncologist. 2007 12 864-872
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Histologically

• Neutrophilic (46)
• cryptitis and abscesses
• Lymphocytic (15)
• crypts with prominent eosinophils

Beck K. Journ Clin Onc. 2006 15 2283-2289
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Treatment

• High dose methylprednisolone
• Slow prednisone taper
• 30-45 days
• Infliximab 5mg/kg

Weber J. Oncologist. 2007 12 864-872
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CTLA-4 and IBD

• Acute and chronic inflammatory changes
• Role of CD25CD4 regulatory Tcells
• high levels of CTLA-4
• transferred Treg cells resolve immune-mediated
  colitis
• CTLA-4 polymorphism linked to Graves disease,
  DMI and possibly UC
• Phase III trial CTLA-4-Ig (abatacept) in IBD

Read S. Journ Immun. 2006 177 4376-4383 Kim G.
Journ Immun. 2007 178 5563-5570 Zhonghua N.
2004 Mar 43(3)191-4
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Selective References

• Maker AV. Ann Surg Oncol Dec 12 (12) 1005-1016
• Inagaki-Ohara K. Gut. 2006 55 212-219
• Izcue A. Immuno Rev. 2006 212 256-271
• Beck K. Journ Clin Onc. 2006 15 2283-2289
• Weber J. Oncologist. 2007 12 864-872
• Zhonghua N. 2004 Mar 43(3)191-4
• Kim G. Journ Immun. 2007 178 5563-5570
• Read S. Journ Immun. 2006 177 4376-4383