Cost Aware Care

Archives of Surgery recently published a study from investigators at UConn and Yale examining the use of a cost card to educate their residents on the costs of various services.

Here's a link to their cost card for services.

The pdf is open access.

Enjoy! SG

Source:
Chandawarkar RY, Taylor S, Abrams P, Duffy A, Voytovich A, Longo WE, Kozol RA. Cost-Aware Care: Critical Core Competency. Arch Surg 2007; 142: 222-226.

McVay Herniorrhaphy

Today we'll talk about the Cooper's Ligament Repair... a nice one to know for femoral hernias and situations where you need to avoid mesh prostheses...

Who was Sir Astley Cooper (1768-1841)?

At the wee age of 16 years old, as a budding surgical apprentice, he developed a groin hernia of his very own, which was managed by a truss. In 1804, he published his works on the Anatomy and Surgical Treatment of Hernia.

What are some of his eponymous anatomical structures?

1. Superior pubic / pectineal ligament
2. Suspensory ligaments of the breast
3. Fascial covering of the spermatic cord

What are the borders of Fruchaud's myopectineal orifice?

medial - rectus abdominus muscle
lateral - iliopsoas muscle
superior - internal oblique and transverse abdominus
inferior - Cooper's ligament and pubis

The inguinal ligament spans and divides the myopectineal orifice, running from the anterior superior iliac spine to the pubic tubercle. The spermatic cord crosses above and the iliac vessels cross below.

The myopectineal orifice is significant as it is a region of aponeurotic fibers that can attenuate, resulting in a groin hernia.

What types of hernias occur in the myopectineal orifice?

1. Direct Inguinal - through transversalis fascia (medial to inferior epigastric)
2. Indirect Inguinal - through inguinal ring (lateral to inferior epigastric)
3. Femoral - through femoral ring

All three types can be addressed using a Cooper's ligament repair...

What are the borders of the inner ring of the femoral canal?

lateral - femoral vein
anteromedial - iliopubic tract
posterior - Cooper's ligament

Who were the first surgeons to utilize Cooper's ligament in herniorrhaphy?

1. Giuseppe Ruggi (1892) - sutured inguinal ligament to Cooper's ligament
2. Georg Lotheissen (1897) - sutured the conjoint tendon to Cooper's ligament
3. Chester McVay (1942)

Chester McVay noted in his doctoral thesis that the normal insertion of the transverse abdominus and the transversalis fascia was on Cooper's ligament, and not the inguinal ligament. His technique for herniorraphy focused on reconstruction of these anatomical relationships.

What are key elements of the McVay Herniorrhaphy?

1. Suturing the transversalis arch to Cooper's ligament, from the pubic tubercle to the femoral vein.
2. Transition sutures to avoid the femoral vein and close the femoral canal, then suturing the transversalis arch laterally to the iliopubic tract.
3. Making a generous relaxing incision to decrease tension to the repair.

Give me details!

1. Begin with an inguinal approach, incising the skin and soft tissues after adequate local anesthesia.
2. Open the external oblique aponeurosis to the external ring.
3. Attempt to preserve the ilioinguinal nerve.
4. Mobilize the spermatic cord. Isolate it with a penrose.
5. Open the internal ring, incising the posterior wall of the inguinal canal towards the pubic tubercle (through the internal oblique aponeurosis and the transversalis fascia.)
6. Retract the spermatic cord superiorly and identify Cooper's ligament. Palpate for the femoral vessels.
7. Define the space between the femoral vein and the pubic tubercle from lateral to medial, with conversion of any femoral hernia sac into an inguinal one.
8. Hernia sacs can be opened to inspect for intraabdominal pathology if strangulation is suspected. Resection may be necessary, otherwise contents can be reduced.
9. Indirect hernia sacs can be isolated from the spermatic cord and transected at the level of the internal ring. Direct hernia sacs can be inverted in the repair.
10. Mobilize the transversus abdominus arch superiorly. Any attenuated transversalis fascia and internal oblique can be excised.
11. Place relaxing incision superior to pubic tubercle at the point of fusion of the external oblique aponeurosis and the anterior rectus sheath. This should extend superiorly for about 4-5 inches.
12. Place patient in Trendelenberg position to minimize intraabdominal injury.
13. The preperitoneal tissues can be carefully imbricated to keep them out of the repair if necessary.
14. Place interupted sutures (10) between the transverse abdominus arch and Cooper's ligament, beginning at the pubic tubercle towards the medial edge of the femoral vein. Place a clamp around the sutures to tie later.
15. Begin placing transition sutures (3) between the transverse abdominus arch, Cooper's ligament, and the iliopubic tract. The medial two of these sutures will be placed so they overlap in between the prior lateral sutures.
16. Continue placing interrupted sutures between the transversus abdominus arch and the iliopubic tract, creating a neo-internal ring.
17. Tie all the sutures from medial to lateral.
18. Return the cord to its natural position.
19. Close the external ring over the cord using a continuous 2-0 Vicryl, creating a neo-external ring.
20. Close skin according to preference.

Here's a picture, just before placement of the transition stitches!

Late... SG

Sources:
Nyhus and Condon's Hernia, 5th ed. (2002)
Hachisuka T. Femoral hernia repair. Surg Clin N Am 2003; 83: 1189-1205.

Intermittent Claudication

This week's edition of NEJM has a sweet little review on Intermittent Claudication. Nice opportunity to discuss this progressively painful topic...

What are risk factors for peripheral artery disease?

Cigarette smoking
Diabetes mellitus
Hypertension
Hyperlipidemia
Hyperhomocysteinemia
Age greater than 50y
Male gender

Remember that peripheral vascular disease and coronary artery disease go hand in hand.

How do patients with intermittent claudication typically present?

leg muscle discomfort on exertion, relieved by rest
leg fatigue
difficulty walking

Pain may be in the calves, thighs, feet, and/or buttocks. It is helpful to document the number of blocks the patient can walk before symptoms arise.

What does claudico (L) mean?

To limp

What are findings commonly seen on physical exam?

abnormal pulses
vascular bruits
low ankle-brachial index

What is the ankle-brachial index (ABI)?

The ratio of systolic blood pressure taken in the arm over the systolic blood pressure taken at the ankle. This indicates severity of lower extremity peripheral vascular disease. Can be taken at rest and after exercise.
>0.9 Normal
0.7-0.9 Mild obstruction
0.4-0.7 Moderate obstruction
<0.4 Severe obstruction - critical ischemia

What are issues with ABI measurements in diabetics?

Diabetics have non-compressible vessels from medial calcification so ABI measurements may not be valid indicators of peripheral vascular disease. An alternative is measuring toe-brachial indices using photoplethysmography.

What is the natural history of intermittent claudication?

The risk of limb loss is low for patients without diabetes (<2%).
The risk of limb loss increases 3X with diabetics requiring drug therapy.
The risk of limb loss increases 20-25% for every 0.1 reduction in ABI.
The risk of cardiovascular events (MI, CVA) is about 5-7%/year.

Peripheral vascular disease is a continuum from intermittent claudication, to rest pain, to gangrene with tissue loss. Only 20-30% of patients with intermittent claudication progress to require some kind of intervention.

What is pseudoclaudication?

Leg pain from non-vascular causes (i.e., osteoarthritis, spinal stenosis, compartment syndrome, sciatica)

What are adjunctive non-invasive studies for further working-up peripheral artery disease?

Doppler probe survey
Duplex ultrasound
Segmental pressure recordings
Pulse-volume recordings

These may help assess the location, presence, and severity of a lesion.

What is a Doppler probe survey?

Using a hand-held continuous-wave Doppler probe unit, the femoral, popliteal, posterior tibial, and dorsalis pedis arterial signals are assessed. With severe stenosis or occlusion the Doppler pulse becomes monophasic and low-pitched.

What is a triphasic arterial signal?

1) High-pitched sound, representing forward systolic blood flow.
2) Low-pitched sound from reversed flow in early diastole
3) Medium-pitched sound, from resumed forward flow.

How does duplex ultrasound evaluate stenoses?

The doppler component allows measurement of blood flow velocity.
20-49% stenosis = increase of peak systolic velocity of 30-100% across lesion.
Critical (>50%) stenosis = increase in peak systolic velocity by greater than 100%
Total occlusion = no flow

Duplex has a 82% sensitivity and 92% specificity in detecting stenoses.

Why is a reduction of only half of the luminal diameter considered a "critical" stenosis?

Reduction in half the diameter represents a 75% reduction in the cross-sectional area of the vessel, leading to a 94% reduction in flow. Critical stenosis is when this reduction in cross-sectional area compromises blood flow leading to symptoms.

What are determinants of Resistance to flow?

By rearranging Poiseuille's Law, R = (8*viscosity*L)/(pi*r^4)
This means that a longer stenosis will increase vascular resistance linearly.
This also means that decreasing the vessel lumen radius will increase the resistance to the fourth power!

What is a pulse volume recording?

A segmental plethysmograph that records arterial pressure contours at various cuffs placed on an extremity. This allows for an indirect assessment of blood flow across the extremity. The distinct upstroke (anacrotic slope), pulse peak, downstroke (catacrotic slope), and wavelengths inform the interpreter, with flattening of the contour seen with severe stenosis.

What are segmental leg pressures?

Simply measuring thigh, calf, and ankle systolic pressures for assessment of extremity occlusion. All pressures are taken with reference to the dorsalis pedis doppler signal.

What is the gold-standard for evaluation of peripheral artery disease?

Angiography
Used if a surgical or endovascular intervention is planned. Alternatives to consider include MRA and CTA.

What are complications of angiography?

Contrast reactions (<4%)
Contrast nephropathy (<2%)
Bleeding (<2%)
Cholesterol embolization (<0.1%)

How do you treat peripheral vascular disease presenting as intermittent claudication?

You READ before you even think about operating!
1. Risk-factor modification
2. Exercise
3. Antiplatelet Therapy
4. Drugs

What are methods of risk-factor modification?

smoking cessation
regular exercise
dietary modification
control of hyperlipidemia (LDL <100, or <70 if high risk)
control of diabetes (HgA1c <7%)
control of blood pressure (<140/<90 or <130/<80 with DM)

What are the benefits of Exercise?

There is Level 1 evidence that exercise increases maximum walking distance by 150% over 3-12 months, with improvements greater than angioplasty and antiplatelet therapy (Cochrane Review).

The greatest benefit has been seen from continued walking until pain is maximal, at least 3 times per week, for at least 30min, for more than 6 months. Give the leg a chance to collateralize!

What are forms of antiplatelet therapy?

1. Aspirin - reduces cardiovascular death by 25%
2. Clopidogrel (Plavix) - use as an alternative to aspirin
3. Cilostazol (Pletal) - increases walking distance by 50% after 3-6mo

There is Class I, Level A evidence of benefit from cilostazol (Pletal) in patients with intermittent claudication.
There is Class IIb evidence (conflicting) of benefit from pentoxifylline (Trental).

What is the USPSTF recommendation for Aspirin use?

All patients at increased risk of coronary artery disease should consider aspirin chemoprevention. (Grade A)

How does Aspirin work?

It irreversible acetylates the enzyme cyclooxygenase. By blocking thromboxane A2 formation in platelets it decreases platelet aggregation and local vasoconstriction. Low-dose aspirin is thought to inhibit platelet thromboxane more than endothelial prostacyclin. Higher dose aspirins likely inhibit both.

What does thromboxane A2 do to blood vessels?

Causes vasoconstriction

What does prostacyclin (PGI2) do to blood vessels?

Causes vasodilation

How does clopidogrel (Plavix) work?

It blocks the ADP receptor on platelets, inhibiting platelet activation and the coupled activation of the glycoprotein IIb/IIIa complex (fibrinogen receptor).
This leads to inhibition of platelet aggregation and white clot (platelet/fibrinogen plug) formation.

How does cilostazol (Pletal) work?

It is a reversible PDE (phosphodiesterase) inhibitor that increases platelet cAMP, leading to vasodilatation and inhibition of platelet aggregation.

What is the mechanism of action of pentoxifylline (Trental)?

It is thought to improve the rheologic properties of blood by lowering blood viscosity and improving erythrocyte flexibility.

What are other drugs to consider?

Statins (HMG CoA Inhibitors)
Beta blockers
ACE Inhibitors
Nicotine replacement therapies

What is the most common vascular lesion associated with intermittent claudication?

Superficial femoral artery stenosis or occlusion

The region where the distal SFA enters Hunter's adductor canal is especially at risk.

What are indications for revascularization by angioplasty or surgery?

Claudication that limits lifestyle or ability to perform job
Claudication that is refractory to exercise and pharmacologic therapy
Claudication that progresses to rest pain

What are favorable lesion features for percutaneous transluminal angioplasty (PTA)?

Single stenosis less than 10cm long
Single occlusion less than 5cm long

What type of lesions is surgery preferred?

Occlusion greater than 20cm
Occlusion of the popliteal or tibial-peroneal vessels.

Surgery is also strongly considered for multiple lesions over 15cm and recurrent lesions after two endovascular interventions.

What are outcomes of femoropopliteal PTA?

Patency rates of 87% at 1y, 69% at 3y, and 55% at 5y.

We'll talk about surgical approaches to infrainguinal occlusive disease at a later time... SG

Sources:
White C. Intermittent Claudication. NEJM 2007; 356: 1241-1250.
Leng GC, Fowler B, Ernst E. Exercise for intermittent claudication. Cochrane Database of Systematic Reviews 2000; 2:CD000990.
Handbook of Patient Care in Vascular Diseases, 4th ed. Lippincott (2001).

Ultrasonography

Ultrasound is to the Surgeon as the Stethoscope is to the Internist!

Various technologies assist us in our ability to diagnose and create new therapeutic interventions. Today we'll talk about diagnostic ultrasound.

What are advantages of ultrasound compared to other imaging modalities?

Portable
Inexpensive
Quick
Dynamic - Spatially and Temporally
Easily Repeatable
Minimizes Risk to Patient

What are the disadvantages of ultrasound?

Learning curve
Operator dependence
Inability to assess through bowel gas or in obese patients
Inability to assess through bone or calcifications

What is the piezoelectric effect?

The process of converting electric energy into mechanical/acoustical energy, and vice versa. An ultrasonic transducer contains PZT (lead zirconate titanate) crystals that have piezoelectric properties allowing for signal conversion of a mechanical stress into a voltage.

What is the pulse-echo principle?

When a transmitted ultrasound wave (pulse) approaches tissue, part of the signal is reflected and part of the signal is transmitted into tissue. Waves that are reflected back (returning echoes) generate a signal that is interpreted by the transducer.

What is amplitude?

The height of a wave. This decreases (attenuates) as waves travel through tissue or are scattered.

What is frequency?

The amount of wave cycles per second. This is inversely proportional to wavelength.

Diagnostic ultrasound commonly uses frequencies of 2-20MHz.
The upper limit of detection by the human ear is 20kHz.

What is the "Frequency Trade-Off"?

Using high frequency transducers, there is greater spatial resolution.
Using low frequency transducers, there is less signal attenuation.

Because of this, abdominal transducers are generally low frequency (i.e. 3.5MHz curvilinear transducer), with greater depth visualization. A better transducer to visualize a superficial structure like a thyroid nodule might be a 10MHz linear probe.

What is the difference between linear-array and curvilinear-array transducers?

Linear transducers provide more near-field (superficial) information.
Curvilinear transducers have a sector-like field of view that becomes wider with increasing depth.

What is Acoustic Impedance?

A property of the tissue of interest related to its density and the speed of sound through it. Tissues with different acoustic impedance will be distinguishable using ultrasound (i.e. gallstone versus gallbladder). Sound waves reflect at the interface of different acoustic impedances.

Why do you use a coupling gel on the transducer probe at the interface with the patient's skin?

It removes air from the interface and matches the acoustic impedance of the crystal with the contact surface.

What is A-mode ultrasound?

Amplitude Modulation
This is the most basic, one-dimensional form of ultrasound, which records the amplitude of the echo in respect to time. It is now obsolete.

What is B-mode ultrasound?

Brightness Modulation
This is the most commonly used form of ultrasound, converting amplitude into pixel brightness/intensity. The more wave reflection, the greater echo amplitude, the greater the brightness or signal echogenicity.

What is echogenicity?

Characterizes the appearance of tissues based on relative brightness (echo amplitude).
Isoechoic = similar brightness
Hyperechoic = brighter/whiter
Hypoechoic = darker
Anechoic = black

What is M-mode ultrasound?

Movement Modulation
This allows assessment of a moving structure like heart valves, and was used prior to the development of 2D-real time B-mode displays.

How does 2D-real time B-mode ultrasound work?

The transducer contains an array of piezoelectric crystals, or contains a moving crystal. Sequential pulses of ultrasound beams are swept in a plane to create a field of echoes that is reconstructed as a 2D-image.

What is Tissue Harmonic Imaging?

An enhanced form of 2D-real time imaging using a complex form of signal processing that rejects artifacts from scatter.

What is Spatial Compound Imaging?

Another enhanced form of 2D-real time imaging that reduces speckle and graininess by averaging multiple signals.

What is the Doppler Effect?

A change in the received frequency of an observer due to a difference in relative motion between the source and observer. As a consequence, if the source is moving toward an observer it is received with a shift to a higher frequency. If the source is moving away it is received with a shift to a lower frequency. This is helpful to assess blood flow velocity.

What is a Duplex ultrasound?

Combines 2D real-time B-mode ultrasound imaging with color Doppler ultrasound. This allows you to simultaneously visualize the structure of blood vessels or heart valves and see a color correlate of flow velocity through them.

Does red flow mean it is an artery?

No! The red and blue colors with Duplex imaging are arbitrary and refer to positive or negative directionality of flow with reference to the transducer.

What are the basic components of an ultrasound machine?

Monitor
Keyboard
Signal-Processing Unit
Transducer
Image Recorder

What is Time Gain Compensation?

A form of signal processing that compensates for attenuation due to increasing level of depth.

What is the FAST exam?

Focused Abdominal Sonogram for Trauma
It is a rapid survey for assessment for truncal injuries as part of the secondary survey of trauma patients. It can be used to detect hemoperitoneum as an alternative to performance of diagnostic peritoneal lavage in hemodynamically unstable patients. It also surveys for pericardial blood. This may be repeated as necessary.

What are components of the FAST exam?

Using a 3.5MHz curvilinear-array transducer, and ensuring the patient has a full bladder, the following views can be imaged, assessing the heart and the three most dependent regions in the body:
1. Subxiphoid View (r/o pericardial effusion)
2. RUQ View (r/o blood in Morrison's Pouch, hepatorenal recess)
3. LUQ View (r/o blood in the splenorenal recess)
4. Pelvic View

Why do you image the heart first?

It allows a standard to set the gain for detection of blood.

What are common forms of ultrasound use in acute care and ICU settings?

-Localization of vessels for central venous access
-Screening for deep venous thrombosis
-Detection of pleural effusions and performance of thoracentesis
-Diagnosis of acute sinusitis
-Detection of foreign bodies in soft tissue
-Evaluation of patients with abdominal pain (i.e. cholelithiasis)
-Identification of abdominal aortic aneurysms
-Confirmation of reduction of incarcerated hernias
-Evaluation for fascial defect from suspected wound dehiscence
-Detection of abscesses
-Echocardiography

What does Echocardiography assess?

Cardiac Anatomy
Heart wall function
Heart valvular function
Ejection Fraction

What advantages does Transesophageal Echo (TEE) have over Transthoracic Echo (TTE)?

TEE has the transducer in the esophagus, which is closer to the heart, and avoids artifact from the ribs and lungs.
It has improved imaging of the valves and aorta.

What are the US Preventive Services Task Force Recommendations for Screening for Abdominal Aortic Aneurysms?

-Grade B: One-Time screening for AAA using ultrasound in men 65-75y who have smoked.
-Grade C: No recommendation for men 65-75y who have never smoked.
-Grade D: Against routine screening for AAA in women.

What are indications for breast ultrasound?

-Assessment of palpable or vaguely palpable breast mass
-Assessment of lesion detected on mammogram
-Evaluation of nipple discharge with assessment of ducts
-Assessment of dense breast
-Assessment of pregnant or lactating patients
-Follow-up of seromas, hematomas, prostheses
-Assessment of abscesses
-Guide intervention - FNA, Core-needle biopsy, or excisional biopsy

What probe is commonly used for breast ultrasound?

7.5MHz linear-array transducer

What are lesion characteristics to assess with breast ultrasound?

1. Margins
2. Retrotumoral acoustic phenomenon: shadowing, enhancement
3. Echogenicity
4. Compression effect on shape and internal echoes

What does a simple cyst look like on ultrasound?

Sharp, smooth-margined round mass
Homogeneous, anechoic interior
Some compression
Posterior enhancement

What are features of malignant breast lesions on ultrasound?

Indistinct, jagged margins
Few internal echoes
Posterior shadowing
Taller than wide

What are common uses of intraoperative ultrasound (IOUS)?

Hepatobiliary and pancreatic procedures
-detection of stones
-detection of mass lesions
-detection of vessels and ducts
-diagnosing splenic or portal vein thrombosis
-guide biopsy and ablative procedures

IOUS can be done with conventional or laparoscopic transducers.

What type of transducers are commonly used for endoscopic ultrasound?

7-20MHz radial or sector-scanning transducers

Radial transducers provide for a 360-degree visual field
Sector-scanning systems can be easier to perform Doppler and biopsy capabilities.

What type of transducer is used for endorectal ultrasound?

A 7-10MHz radial transducer covered by a water-filled latex balloon.

For TNM staging of a rectal cancer by endorectal ultrasound, what prefix is used?

uTNM = as assessed by EUS
cTNM = as assessed clinically
pTNM = as assessed by pathologist
yTNM = if neoadjuvant chemotherapy was used
mTNM = if multiple primaries were found at a single site
rTNM = for a tumor recurrence
aTNM = if detected at autopsy

Late... SG

Sources:
O'Leary's Physiologic Basis of Surgery, 3rd ed.
Hangiandreou NJ. AAPM/RSNA Physics Tutorial for Residents: Topics in US. B-Mode US: Basic Concepts and New Technology. RadioGraphics 2003; 23: 1019-1033.
Rozycki GS. Surgeon-Performed Ultrasound: Its Use in Clinical Practice. Ann Surg 1998; 228: 16-28.
US Preventive Services Task Force AAA Screening Recommendations (2005)

Society of Surgical Oncology, 2007

Just got back from a surprisingly cold meeting in one of my favorite towns, Washington, DC. While I was hoping to see a cherry blossom or two, it was obviously a few weeks too early, so I settled for the shelter of a dark conference hall.

A few highlights:

-SSO President, Raphael Pollock, announced an interest in opening SSO membership to all surgeons, rather than its primarily academic base of membership.
-Efforts have been initiated to make Surgical Oncology a board-certified specialty.

-Great talks overall on hepatobiliary surgery
-Eddie Abdalla (MD Anderson) gave a nice overview of portal vein embolization... Before this talk, I never really realized the rationale between PVE over hepatic artery embolization. From a physiological standpoint, PVE creates portal flow diversion that increases GI trophic factors that lead to hypertrophy of the contralateral liver lobe. Neat!
-Alan Koffron (Northwestern) had a cine-filled presentation on Laparoscopic Hepatic Resection. Here the technology seemed key, with use of a mix of the Laparoscopic Habib (RF bipolar; RITA Medical Systems), Saline-Enhanced Radiofrequency Ablation (SERF), and staplers.

-The Basic Science lecture by Leroy Hood was interesting, stressing the importance of viewing biology as an informational science - a product of digital and analog systems and signals (very engineering based concepts!)

-Among GI presentations, the peripheral opioid antagonist, methylnaltrexone, had been randomized in 65 patients with segmental colectomies receiving IV PCA narcotics. Methylnaltrexone led to significant improvements in 1st bowel movement (1 day) and discharge eligibility (1 day), but didn't effect time to PO tolerance, flatus, or actual discharge. The study seemed underpowered to detect differences in those factors.

-Amongst the Breast talks, extirpation of the primary in Stage IV breast cancer was revisited by a retrospective review of the SEER database by investigators at Wash U. Nearly half of the 9734 patients with Stage IV breast cancer had surgical excision of the breast tumor, with a survival advantage of about 35% after controlling for age, race, tumor size/grade, ER/PR status, and use of radiotherapy.

-Amongst the exhibitors, Incisive Surgical has developed a new skin stapler that creates an everted, interrupted subcuticular closure using absorbable polylactide-polyglicolide (INSORB). The device contains 20 absorbable staples and is packaged with disposable forceps. The closure can then be reinforced with adhesive strips.

-In conferences, my favorite talks are always the debates.
-The first was regarding excision alone versus excision+radiotherapy for DCIS, between Mel Silverstein and Terry Mamounas. I was surprised to learn that based on SEER data, a third of all DCIS in this country is being treated with excision alone. Mamounas discussed the differences in local recurrence seen in a few RCTs, including NSABP B-17, and the use of prospective rather than retrospective data. Silverstein focused on pathologic criteria (i.e. Van Nuys -margin, grade, necrosis) and age as important determinants of recurrence, and that margin status was not an issue of focus in the RCTs. He also stressed the fact that there is no survival benefit from radiation in DCIS, and that you would have to irradiate 250 people to save 1 life... a low absolute versus relative benefit. Plus there are issues with access, and later use of radiation in the same breast.
-The third debate was regarding local excision versus LAR/APR for Stage I cancer, between Julio Garcia-Aguilar and James Fleshman. Clearly the limitation of local excision is an inability to assess nodal status. Garcia-Aguilar focused on staging with EUS and MRI and proper preoperative selection, as well as avoiding the morbidities associated with abdominal approaches, including sexual and urinary function, as well as stoma formation. Fleshman saw as a limitation access to tumors (although this may be obviated with Transanal Endoscopic Microsurgery), as well as the high rates of local recurrence seen with local excision, especially for T2 tumors. I only wished they discussed more about the role of neoadjuvant therapies in their discussion.
-I think the consensus from the discussions of both DCIS and Stage 1 rectal cancer is that ideally with good preoperative selection criteria "doing less" may be appropriate in a subset of favorable patients (i.e. excision alone for DCIS with low VNPI score; local excision for small, low-grade uT1N0 rectal cancers without lymphovascular invasion), but the safer approach would continue to be "doing more" (excision + XRT; APR/LAR), primarily due to issues related to local recurrence. The problems are the decisions for favorable criteria depend on the quality of the pathologist, radiologist, and/or the EUS-operator and are probably highly variable between institutions.

But does one treatment fit all? It made me think about how new assays like Oncotype DX can help select for patients who can benefit from chemotherapy in addition to Tamoxifen with node-negative ER+ breast cancer. Rather than treating all patients aggressively with chemo, now only the subset of patients at high risk of recurrence need to be treated.

What if there were objective molecular marker(s) for severity of rectal cancer that could help select patients who might be amenable to local excision? What if there were biomarkers of invasion that could classify DCIS into low risk and high risk categories? DCIS is technically a pre-invasive stage of cancer, but what if we could know through a marker whether it confers risk of recurrence or harbors invasion without worrying about the ability of the human eye to detect it?

Late... SG

Mr. Gumby Needs a Brain Specialist...

My Brain Hurts! SG

Parenteral Nutrition

What are indications for parenteral nutrition?

-Inability to feed enterally
-Inability to maintain nutritional goals enterally
-Newborns with GI anomalies
-Short bowel syndrome
-Malabsorption syndromes
-High-output enterocutaneous fistulas (>500ml/day)
-Enteroenteric, enterocolic, enterovesical fistulas
-Postoperative ileus over 7-10days
-Hypermetabolic critically-ill patients
-Functional GI disorders (i.e. post-CVA)
-Malnutrition/cachexia from malignancy

What are lengths of intact remaining small bowel from massive resection that usually necessitate chronic TPN?

Less than 100cm without colon or ileocecal valve
Less than 50cm with the colon and an intact ileocecal valve

What are contraindications to hyperalimentation?

-Enteral nutrition is possible
-Good nutritional status
-Hemodynamic instability
-Severe metabolic derangements (i.e. hyperglycemia, hyperosmolarity, electrolytes)

What is PPN?

Peripheral parenteral nutrition
Administered through a peripheral catheter
Often used for short term, sometimes while waiting for central venous access
Dextrose: 5-10% (D5 or D10)
Protein: 3%

What is TPN?

Total parenteral nutrition
Requires central venous access due to high osmolarity
Dextrose: 15-25%
Crystalline amino acids: 3-5%
With or without Lipids: 10-15% of calories, limited to 1 g/kg/d

What are classic signs of fatty acid deficiency?

Dry, Scaly Dermatitis
Alopecia

What are recommended caloric requirements?

Normal to Mild Stress 25-30 kcal/kg/day
Moderate stress 30 kcal/kg/day
Severe stress 30-35 kcal/kg/day

What are recommended protein requirements?

Normal 1.0 g/kg/day
Mild stress 1.2 g/kg/day
Moderate stress 1.5 g/kg/day
Severe stress 2.0 g/kg/day

What are calorie equivalents for carbohydrate, protein, and lipid?

carbohydrate = 4 kcal/g
IV dextrose = 3.4 kcal/g
protein = 4 kcal/g
lipid = 9 kcal/g

What are common supplements and additives for TPN infusions?

Multivitamins
Vitamin K (not in multivitamin preparations)
Trace minerals (Zn, Cu, Mn, Cr, Se)
Insulin
Heparin
H2 Blockers

What are signs of Zinc deficiency?

Excematoid Dermatitis (intertriginous zones)
Impaired wound healing

What is a sign of Copper deficiency?

Microcytic anemia

What is a sign of Chromium deficiency?

Impaired glucose tolerance

What does Selenium deficiency cause?

Cardiomyopathy

What are recommendations for electrolytes in TPN?

Sodium 60-150 mEq/d
Potassium 70-150 mEq/d
Phosphorus 20-30 mmol/d
Magnesium 15-20 mEq/d
Calcium 10-20 mmol/d

What is the role of administering chloride or acetate salts in TPN?

Maintenance of acid-base status
Maintenance of electrolyte balance
Sodium and potassium can be administered in either form

What are issues with administering too much calcium and phosphorus in TPN?

They can precipitate in solution

Can glutamine be administered in TPN?

It is typically unstable in solution
Glutamine dipeptide is available in Europe and can be given parenterally.

What are considerations when starting TPN?

1. Electrolyte status
2. Volume status
3. Acid-Base status
4. Risk for Septic complications

What is often monitored when administering TPN?

Daily weights
Electrolytes, starting daily then every 2-3days when stable
CBC, BUN, LFTs, Phos, Mg at least weekly
Glucose every 6 hours

What are methods of short-term central venous access for TPN?

16G percutaneous catheters via subclavian vein or internal jugular vein

What are methods of long-term central venous access?

PICC line (via basilic or cephalic vein)
Port-a-Caths
Tunneled catheters (Hickman, Broviac, Groshong)
Hohn catheters

Where should the catheter tip be placed?

In the superior vena cava adjacent to the right atrium

What are catheter-related complications?

Cardiac arrhythmias
Septicemia
Pneumothorax
Hemothorax
Subclavian artery injury
Thoracic duct injury
Air embolism
Catheter or guidewire embolism
Cardiac perforation

What are metabolic complications of TPN?

1. Hyperglycemia - administer insulin and correct electrolytes
2. Overfeeding - can cause ventilator dependence and hepatic steatosis
3. Cholestasis - monitor transaminases, alkaline phosphatase, and bilirubin

What is the risk of catheter-related infection?

For catheters present over 7 days, infection risks of 5-10% have been reported.
Among catheter tips that reach microbiology labs, only 15-25% are culture positive.
Catheter-related septicemia carries mortality rates of 12-25%.

What clinical findings would make you suspicious of catheter-related infection?

Fever
Erythema or purulence at line site
Hyperglycemia

What are potential sources of catheter colonization and infection?

1. Skin insertion site
2. Catheter hub
3. Hematogenous seeding of catheter tip from distant site
4. Infusate contamination

50-70% of infections are estimated to originate from the catheter hub

How is suspicion for catheter-related septicemia conventionally addressed?

The catheter is removed and the tip is cultured after 2 paired blood cultures are drawn.
The catheter can be rethreaded over a guidewire while waiting for results, or one can be placed at a new site. If cultures are positive, a new catheter should be placed at a new site.

What are paired blood cultures?

One from the catheter hub and one from a peripheral site.
These may be evaluated quantitatively or semi-quantitatively

What defines catheter tip colonization?

>15 cfu grown from catheter tip
negative blood cultures

What defines catheter-related blood-stream infection?

>15 cfu grown from catheter tip
positive paired blood cultures with same organism (semi-quantitative)

What are three methods for diagnosing catheter-related blood stream infections that do not require catheter removal?

1. Paired quantitative blood cultures - compare bacterial growth of catheter blood with peripheral blood (catheter blood growth >5-10X peripheral)
2. Differential time to positivity of quantitative blood cultures - compare time to bacterial growth of catheter blood with peripheral blood (catheter blood growth >2hrs earlier than peripheral)
3. Semi-quantitative superficial cultures - swabs of skin and catheter hub (>15cfu) are compared with peripheral blood isolates.

In a prospective randomized controlled trial comparing the three methods in critically-ill patients without neutropenia, there were no significant differences between their diagnostic accuracy (94%, 91%, 90%). They recommended starting assessment with superficial swabbing and peripheral blood cultures as a potential way to avoid unnecessary catheter removal.

Late... SG

Sources:
Schwartz' Principles of Surgery, 8th ed.
O'Leary's Physiologic Basis of Surgery, 3rd ed.
Bouza E, Alvarado N, Alcala L, Perez MJ, Rincon C, Munoz P. A Randomized and Prospective Study of 3 Procedures for the Diagnosis of Catheter-Related Bloodstream Infection without Catheter Withdrawal. Clin Infect Dis 2007; 44: 820-826.
Linares J. Diagnosis of Catheter-Related Bloodstream Infection: Conservative Techniques. Clin Infect Dis 2007; 44: 827-829.

Oncotype DX and Gene Expression Profiling

No, that's not a Lite-Brite... It's a DNA microarray!

Over recent years, interest has blossomed in the development of biomarkers and assays to help predict cancer outcomes. Today, we'll talk about a few of these for breast cancer, focusing on Oncotype DX (Genomic Health).

What is a prognostic marker?

A pathologic or molecular marker that can predict disease-free survival, disease-specific survival, or overall survival.

What is a predictive marker?

A pathologic or molecular marker that is used to predict response to therapy.

What are some prognostic markers for breast cancer?

Tumor grade
Hormone receptor status
HER2/neu status
Ki-67 (a proliferation marker)
S-Phase Fraction (a proliferation marker)
Mitotic Index
Cathepsin-D (a protease)
Lymphovascular invasion

What are the primary prognostic determinants for breast cancer?

Tumor size
Nodal Metastasis
Distant Metastasis

What are some predictive markers for breast cancer?

Estrogen Receptor Status
HER2/neu Status

What is a therapeutic approach that can be used for node-positive patients with tumors that overexpress HER2/neu?

trastuzumab (Herceptin, Genentech)

What are some therapeutic approaches can be used for patients with tumors that are estrogen-receptor postive?

Selective estrogen-receptor modulators (SERMs): tamoxifen, fulvestrant (Faslodex, AstraZeneca)
Aromatase inhibitors

What did the clinical trial NSABP B-14 examine?

NSABP B-14 demonstrated the benefit of 5-years of tamoxifen as adjuvant therapy for node-negative, estrogen-receptor-postive breast cancer in both survival and recurrence.
Patients (N0,ER+) were randomized to placebo (n=1453) or tamoxifen (n=1439).
Tamoxifen benefited women over placebo with hazard ratios for overall survival of 0.80 (95% CI, 0.71-0.91) and for recurrence-free survival of 0.58 (95% CI, 0.50-0.67) when followed for 15 years.

What did the clinical trial NSABP B-20 examine?

NSABP B-20 demonstrated the benefit of tamoxifen and chemotherapy for node-negative, estrogen-receptor-positive breast cancer by decreasing recurrences, but only a borderline effect on survival.
Patients (N0,ER+) were randomized to tamoxifen (n=788) or chemotherapy (CMF) and tamoxifen (n=789).
Tamoxifen plus chemotherapy benefited women over tamoxifen alone with hazard ratios for overall survival of 0.78 (95% CI, 0.60-1.01) and recurrence-free survival of
0.52 (95% CI, 0.39-0.68) when followed for 12 years. This benefit was seen primarily in patients under 60 years.

In Fisher et al. Lancet 2004, they reanalyzed the data for B-20 by comparing it with the placebo group of B-14. They found that there was about a 20-25% absolute benefit in recurrence-free survival with tamoxifen and chemotherapy compared to placebo.

Adding chemotherapy to tamoxifen likely benefits some patients in reducing recurrences, but probably not all, with overtreatment of possibly 80% of patients based only on the criteria of node-negative, estrogen-receptor-positive...

At the moment, many oncologists recommend giving both tamoxifen and chemotherapy for all ER+, node-negative tumors greater than 1cm... This may be overtreating the majority.

What is Oncotype DX?

A gene expression assay developed for node-negative, estrogen-positive breast tumors that uses information derived from fixed, paraffin-embedded tissue specimens to develop a recurrence prediction score.

Why is it nice that they use paraffin-embedded tissue specimens for the assay?

You, the surgeon, do not need to think about sending fresh or frozen tissue samples at the time of surgery! The multidisciplinary team can decide at a later time after reviewing the pathology if the test will help with management.

How is the assay performed?

Quantitative RT-PCR (Reverse transcriptase polymerase chain reaction)
This quantifies RNA for 21 different genes to give an idea of their relative level of expression. These levels are then used in an algorithm to calculate a "recurrence score".

What categories of genes are studied by this assay?

5 controls and 16 cancer-related genes (derived from 250 candidates)
1. Proliferation: Ki67, STK15, Survivin, cyclin B1, MYBL2
2. Invasion: Stromolysin 3, Cathepsin L2
3. HER2: GRB7, HER2
4. Estrogen: ER, PR, Bcl-2, SCUBE2
5. Other: GSTM1, CD68, BAG1
6. Controls: beta-actin, GAPDH, RPLPO, GUS, TFRC

How was the recurrence score developed?

Based on analysis using blocks from patients in the Tamoxifen arm of NSABP B-20, they divided patients into three groups:
1. Low Risk
2. Intermediate Risk
3. High Risk

How did they validate the assay?

In Paik et al. NEJM, 2004, they examined available blocks from patients in the tamoxifen arm of NSABP B-14. Based on stratification of recurrence score risk categories, they were able to determine Kaplan-Meier estimates for recurrence rates.

What were their findings for rates of distant recurrence at 10 years?

Low Risk Category (51%) - 7% (95% CI, 4-10%)
Intermediate Risk (22%) - 14% (95% CI, 8-20%)
High Risk Category (27%) - 31% (95% CI, 24-37%)

The recurrence score also correlated with overall survival and relapse-free interval.

When performing multivariate analysis for independent predictors of recurrence in B-14, what variables were significant?

Before including the recurrence score, age less than 50 years and tumor size greater than 2cm were independent predictors of recurrence.
After including the recurrence score, both variables dropped out, and only recurrence score remained as an independent predictor of recurrence.

What treatment algorithm could be developed utilizing Oncotype DX for node-negative, ER-positive patients who will receive tamoxifen, without factoring cost and access into the issue?

For low risk patients, tamoxifen only
For high risk patients, tamoxifen plus chemotherapy
For intermediate patients, tamoxifen with or without chemotherapy (i.e. depending on age, size, grade)

What is the cost of Oncotype DX?

US $3460 (as of 06 Mar 2007)
Medicare covers this 100%
A few insurances are beginning to cover this.

What are some other prognostic assays creeping into the clinical mainstream?

The following utilize cDNA microarray technology to classify breast tumors based on molecular signatures.
1. 70-gene profile - categorizes tumors into good and poor prognostic groups
2. Intrinsic-Subtype Signatures - Categorizes breast tumors into 5 subtypes: basal-like (ER/PR-,HER2-), ER-negative/HER2-positive, luminal A, luminal B, and normal-like.
3. Wound-Response Signatures - categorizes tumors based on activated or quiescent responses

What is a cDNA Microarray?

Sometimes called a gene chip.
A test that examines the expression of numerous genes probed simultaneously. Analysis of the profile can allow categorization of tumors based on the characteristic signatures of overexpressed and underexpressed genes.

What is an IVDMIA?

In Vitro Diagnostic Multivariate Index Assay
It is the US FDA's new classification for algorithm-based gene profiling assays including Oncotype DX and Mammaprint.

What is Mammaprint?

Mammaprint (Agendia) is the 70-gene-profile microarray. It recently received FDA approval on February 6, 2007, but has been marketed in Europe since 2005.

How do Mammaprint and Oncotype DX differ?

Oncotype DX uses quantitative RT-PCR on fixed paraffin-embedded specimens.
Mammaprint uses DNA microarray technology on freshly-obtained core biopsy specimens.
Oncotype DX is marketed for node-negative, ER-positive patients who will be starting tamoxifen to decide on starting additional adjuvant chemotherapy.
Mammaprint is marketed for T1/T2N0M0 patients under 60 years old to decide on type of adjuvant therapy.
Mammaprint was developed in the Netherlands and has been a focus of study in Europe. Oncotype DX has been developed and studied primarily in North America.

In the future, the EORTC's MINDACT trial (Microarray in Node-Negative Disease May Avoid Chemotherapy), which uses the Mammaprint 70-gene profile, will give more to think about...

Phew! That's all for now... SG

Sources:
Schwartz' Principles of Surgery, 8th ed.
Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet 2004; 364: 858-868.
Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. NEJM 2004; 351: 2817-2826.
O'Shaugnessy JA. Molecular Signatures Predict Outcomes in Breast Cancer. NEJM 2006; 355: 615-617.
Mammaprint
Cost information obtained from a phone conversation with a representative from Genomic Health, 1-866-ONCOTYPE