How do Senna laxatives work?

My frustration with my inability to find a good reference that explains how Senna based laxatives work (before I prescribed it to one of my patients with HD and encopresis) was relieved by one of our fine Pedi GI folks.  She promptly sent me this paper from the deep archives of an appropriately name journal.

Here's the answer.

Senna, an anthraquinone laxative, is a glycoside that is metabolized in the GI tract into oxy-methyl anthraquinone.  OMA's (just made that up; not the official name) soften the stool by decreasing water absorption from the colon and promote colonic contraction by stimulating the Auerbach plexus of nerves.

There you go.

In the realm of surgical oncology, biology is King!

A gem from grand rounds today:

Law of the land in surgical oncology

Biology is King
Selection is Queen
Technical maneuvers are the Prince and Princess

Occasionally the prince and princess try to
overthrow the powerful forces of the King and
Queen, sometimes with temporary apparent
victories, but usually to no long term avail.


Blake Cady, MD

GIST tumors in kids

Looking down at the path report that read "Wild type gastrio-intestinal stormal tumor", I had to reach deep into my memories of adult general surgery training, and all I could come up with was Gleevec. Clearly not enough to formulate a management plan for my 12 year old patient.

Off to Pubmed...

Talk about children not being just small adults!  Pediatric GISTs, it turns out, are a whole different animal.

Adult GISTs are tumors of mesenchymal origin that carry a tyrosine kinase receptor activating mutation. 85% of tumors in adults will have a mutation in either oncogenic KIT, PDGRRA, or (less commonly) BRAF. The presence of a tyrosine kinase mutation is the basis for tumor response to tyrosine kinase inhibitors such as Imatinib (Gleevec).

The pediatric counterpart, a rare entity, differs in a critical way; namely the absence of a tyrosine kinase mutation in the majority (>90%) of cases. Gastrointestinal stromal tumors with no tyrosine kinase mutation are referred to as wild type GISTs.  The absence of these mutations translates to the lack of efficacy of tyrosine kinase inhibitors such as Imatinib. Essentially, no effective neo-adjuvant or adjuvant therapy is available for WT GISTs.

Because of the rare nature of GISTs in children, we do not have a clear idea about behavior. The general impression is that these are insidious lesions, that grow slowly and have a high recurrence rate, even in the setting of complete surgical resection.

What does this mean for us, the pediatric surgeons faced with the responsibility of primum non nocere?  this is a chronic disease that needs management and not cure; more like hypertension that appendicitis.  So avoid big morbid resections if possible, and plan for this disease coming back.

Reference:
Pediatric Gastrintestinal stromal tumor

Bilateral Wilm's Tumor

Now that the dust has settled on the move to the west coast... back to some reading.

A recent discussion about an infant with bilateral renal masses prompted a review of the COG recommendations and protocols for the management of patients with bilateral Wilm's tumor.

Obviously, the basic impetus behind the special consideration for this group of patients is the the need for preservation of functional renal tissue.  Kids with bilateral WT have several factors that contribute to potential renal failure.  These include  intrinsic disease in predisposed kidneys, loss of functional renal tissue after surgery, and injury from chemo and radiation therapy.

Historically, all pediatric patients with bilateral renal tumors have been found to have Wilm's tumor. This, along with the fact that biopsy upstages patients, increases the risk of local recurrence, and can not effectively rule out anaplasia, contributed to the current COG recommendation to proceed with chemotherapy without tissue biopsy.

Once chemotherapy is started, the pattern of tumor response after 6 and 12 weeks determines whether and how therapy is adjusted.

The COG protocol for bilateral renal masses calls for upfront three drug chemotherapy (no biopsy), with re-imaging in 6 weeks.  If, after 6 weeks, there is good response (>30% decrease in size), and the tumor is now resectable with partial renal preservation, then the surgeon proceeds with nephron sparing surgery.

For patients with partial response, but not enough for nephron sparing surgery after 6 weeks, three drug chemotherapy is continued.  At 12 weeks, all patients undergo operative resection; partial nephrectomy if made possible by further reduction in tumor size, or radical nephrectomy.

If there is no good response, then resection is needed to rule out an anaplastic component (chemotherapy needs to be adjusted) or to make sure this is not a benign lesion (further chemotherapy is unnecessary and surgical resection is curative)

Reference:
COG AREN 0534 Protocol: Treatment for Patients with Bilateral, Multicentric, or 
Bilaterally-Predisposed Unilateral Wilms Tumor

Neo-adjuvant chemotherapy for hepatoblastoma: Do tumors shrink away from major vascular structures?

No.

This was an eye-opening study by Murphy et al who looked at patterns of response of hepatoblastoma (both volume reduction and regression away from major vascular structures)  treated with neo-adjuvant chemotherapy.

It was eye opening for two reasons.

The first reason is that one would assume that substantial shrinkage of tumor would translate into substantial regression away from major vascular structures (and subsequently facilitate resection).  It turns out that although these tumors respond well to neo-adjuvant chemotherapy, they shrink towards major vascular structures (as if anchored to their main blood supply), and not centripetally.  In fact, the authors noted that the tumors, at most, regressed an average of 1 mm from major vascular structures.

The second, and more important eye opener, was the remark made by Dr Meyers in the discussion section of the paper.  The authors were addressing the recommendation by the COG protocol (AHEP0731) that patient with margins less than 1 cm from major vascular structures not undergo attempts at primary resection but receive neo-adjuvant chemotherapy.  The authors conculded that chemotherapy brought only a few patients closer to respectability  (because it brought only a few patients to this 1 cm level)

The misinterpretation of COG recommendations lies in the following:  The 1 cm recommended margin away from major vascular structures is intended to encourage neoadjuvant chemotherapy and avoid positive margins with attempts at primary resection.  So really, the < 1 cm margin is more an indication for neo-adjuvant chemotherapy than a contraindication for surgery.

Subsequently, once a patient has received neo-adjuvant chemotherapy, the entire < 1 cm business is out the window, and resection should be attempted if deemed possible and safe regardless of radiologic vascular margins.

Outcome of endorectal pull through with ileal-pouch vs straight ileo-anal anastomosis

The satisfaction gained from taking a child from a state of misery and malnutrition to "he is doing so wonderfully after his colon came out" is only tempered by the conversation that must follow. Asking a child and their parents to choose between too evils (multiple bowel movements/incontinence vs the risk of pouch complications/pouchitis) when discussing the next step can only be made more palatable when we have some outcome data to share.

A paper by Seetharamaiah et al in published in JPS in 2009 provided that data.

The authors retrospectively looked at 203 children (average age 15 years) who underwent either a straight ileo anal pull through vs a pouch anastomosis for UC or familial polyposis.  The authors compared several outcome variables, including the rate of complications (pouchitis/enteritis) and long term bowel functions as reflected by the modified Hoschneider scoring system (incorporates number/consistency of stool, risk of daytime/nighttime incontinence, severity of urgency, and need for therapy for stool control).

The authors noted that, as one would expect, the patients who underwent a straight pull through had more BM's per day than those who underwent a pouch anastomosis.  Interestingly, after 24 months, the number of bowel movements approached that of patients who underwent a pouch anastomosis (mean number of bowel movements for straight pull through vs. pouch anastomosis were 8 vs 6 per day, respectively).

As to the general quality of bowel function, both groups eventually scored similarly on the modified Holschneider coring system, and ultimately ~90% became totally continent after 24 months, regardless of type of operation.

As to pouchitis, the nagging complication of pouch creation, the authors noted that patients had a 49% risk of documented pouchitis, vs 24% risk of ileitis, the counterpart in a patient with a straight pull through.

Based on this data, it appears that both options area reasonable, with the benefit of a better outcome in terms of bowel function for the first two years, when a pouch is created, balanced against the increased risk of pouchitis and what is entails in terms of pain/discomfort, need for antibiotics, and potentially hospital admissions. 

Which kids with Wilm's tumor qualify for no post op adjuvant chemotherapy?

Adjuvant chemotherapy for favorable histology Wilm's tumor consists of either regimen EE-4A (vincristine and dactinomycin) or DD-4A (vincristine, dactinomycin, and doxorubicin) based on staging and the status of loss of heterozygosity (1p and 17q).

One special subset of patients with Wilm's tumor has been found to have a good outcome without chemotherapy.  Specifically, patients younger than 2 years of age, with stage I FH Wilm's tumor that weighs less than 550 g have an estimated 5-year EFS of 84% (compared to 97% for those receiving EE-4A).  Of the patients who receive no adjuvant therapy and relapse, the salvage rate (using DD-4A) exceeds that of those who are treated with EE-4A and relapse.

This protocol underlines importance of lymph node sampling (irrespective of gross appearance) as part of the surgical management of Wilm's tumor.  In this case, if nodes are not sampled, the patient would not qualify for the no-chemotherapy option.

Reference:
Coran, A.G (2012) Pediatric Surgery. Philadelphia, PA. Elsevier