Episode five closes the chapter with hereditary pancreatic cancer and the family-systems coordination that binds every syndrome together. The gating principle is absolute lifetime risk, not relative risk: surveillance begins above roughly five percent, so STK11, CDKN2A, PRSS1, and familial kindreds qualify on genotype alone while BRCA1, BRCA2, ATM, PALB2, and Lynch enter only with a family-history driver. The treatment side ties platinum and PARP inhibitors back to synthetic lethality in homologous-recombination-deficient tumors. The coordination side names the real failure mode, the carrier whose colonoscopy stays on schedule while gynecologic or urologic surveillance lapses, and the board traps around cascade testing, the GINA insurance gap, and the non-actionable variant of uncertain significance.

Topics covered

• Germline genes behind pancreatic cancer
• The absolute-risk surveillance threshold
• Which carriers qualify on gene alone
• Surveillance starting ages and modality
• PRSS1 hereditary pancreatitis
• Synthetic lethality, platinum, and PARP inhibitors
• Multi-organ coordination and cascade testing
• Risk-reducing surgery and reproductive counseling
• GINA limits and variants of uncertain significance

Key decisions

• Gate pancreatic surveillance on absolute lifetime risk above approximately five percent, above which cancer detection outweighs the false positives, procedural complications, and cyst-driven anxiety below it.
• Enroll STK11, CDKN2A, PRSS1, and familial pancreatic cancer kindreds on genotype or pedigree alone, but enroll BRCA1, BRCA2, ATM, PALB2, and Lynch carriers only with a first-degree or second-degree relative with pancreatic cancer.
• Start surveillance at thirty to thirty-five for STK11, forty for CDKN2A and PRSS1, and fifty for BRCA, ATM, PALB2, and Lynch, or ten years before the earliest family pancreatic cancer, whichever is younger.
• Alternate annual EUS and pancreatic-protocol MRI with MRCP because they are complementary, EUS for solid lesions and same-session sampling, MRI for cysts and ductal anatomy without procedural risk.
• Offer maintenance olaparib after at least sixteen weeks of platinum-based chemotherapy without progression in germline BRCA metastatic pancreatic cancer, because it roughly doubled progression-free survival and germline panel testing is now standard at diagnosis.
• Do not act on a variant of uncertain significance: it does not justify cascade testing or gene-specific surveillance, and the program stays anchored to personal and family history.
• Counsel carriers that GINA covers health insurance and employment but not life, disability, or long-term care insurance, and advise obtaining those policies before testing.

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• (00:00) - Germline genes behind pancreatic cancer
• (00:39) - Two mechanistic gene families
• (01:42) - The absolute-risk surveillance threshold
• (03:50) - Starting ages and surveillance modality
• (04:36) - Alternating EUS and MRI
• (05:51) - PRSS1 hereditary pancreatitis
• (07:03) - Synthetic lethality and PARP inhibitors
• (09:56) - Multi-organ coordination and cascade testing
• (12:53) - GINA limits and the VUS trap

Episode four moves from adenoma to hamartoma, where the dominant risk shifts away from colorectal cancer. STK11 drives Peutz-Jeghers, and the resection threshold is calibrated to intussusception rather than cancer, so any small bowel polyp over one centimeter comes out. PTEN drives Cowden, where the cancer burden tracks baseline PI3K signaling into breast and thyroid and the GI role is recognition through mixed-histology polyposis. CDH1 flips the algorithm hardest: multifocal submucosal signet-ring disease beneath intact mucosa makes endoscopy unreliable, so prophylactic total gastrectomy between twenty and thirty is the standard of care. The thread is constant, the gene dictates the histology, the histology dictates the natural history, and the natural history dictates whether the answer is surveillance, polyp-by-polyp resection, or removal of the organ.

Topics covered

• Peutz-Jeghers, STK11, and buccal pigmentation
• Arborizing hamartomas and intussusception risk
• Small bowel resection thresholds
• Peutz-Jeghers multi-organ cancer surveillance
• PTEN hamartoma spectrum and Cowden
• Hereditary diffuse gastric cancer and CDH1
• Prophylactic total gastrectomy
• The Cambridge surveillance protocol
• GAPPS as the HDGC differential

Key decisions

• Resect any Peutz-Jeghers small bowel polyp greater than one centimeter, any symptomatic polyp regardless of size, and any polyp showing rapid growth, because growth velocity predicts intussusception better than absolute size.
• Start Peutz-Jeghers surveillance young with baseline EGD and colonoscopy at age eight to ten plus small bowel capsule or MR enterography, avoiding CT enterography because of cumulative radiation across decades.
• Enroll STK11 carriers in pancreatic surveillance on the gene alone, unlike BRCA, ATM, PALB2, and Lynch, because STK11 lifetime pancreatic risk clears the absolute-risk threshold without a family-history modifier.
• Read Cowden as a breast and thyroid syndrome, with annual thyroid ultrasound from diagnosis, breast MRI and mammography from the early thirties, and no prophylactic thyroidectomy because the cancers are follicular and papillary rather than medullary.
• Recommend prophylactic total gastrectomy with Roux-en-Y reconstruction between ages twenty and thirty for confirmed CDH1 carriers, because random biopsy misses multifocal submucosal signet-ring foci that sit beneath grossly intact mucosa.
• Offer the Cambridge protocol of annual EGD with thirty to fifty random biopsies only as a fallback for CDH1 carriers awaiting or declining surgery, counseling explicitly that surveillance failure is documented despite rigorous adherence.
• Add annual breast MRI plus mammography from age thirty for female CDH1 carriers, because lobular breast cancer risk reaches forty to fifty-five percent and mammography detects it less reliably.

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• (00:00) - Peutz-Jeghers, STK11, and buccal pigmentation
• (02:05) - Arborizing hamartomas and intussusception
• (03:03) - The small bowel resection threshold
• (04:36) - Multi-organ cancer surveillance
• (05:33) - The recognition cancers to memorize
• (06:57) - The PTEN spectrum and Cowden
• (10:56) - CDH1 and hereditary diffuse gastric cancer
• (13:00) - The Cambridge surveillance fallback
• (14:56) - GAPPS as the differential

Episode three works the adenomatous polyposis syndromes by their governing logic: if you know the gene, you know the polyp count, the polyp type, and the surgery. APC drives classic FAP toward near-certain colorectal cancer by forty, the same gene at its ends produces the softer attenuated phenotype, and biallelic MUTYH mimics attenuated FAP through an autosomal recessive pattern of affected siblings and unaffected parents. The surgical pivot is not whether to take the colon but whether to take the rectum, which decides itself on polyp burden. After the colon is gone the duodenum becomes the surveillance organ, with Spigelman staging turning ampullary adenomas into an EGD interval and a pancreaticoduodenectomy conversation.

Topics covered

• Reasoning from gene to polyp count to surgery
• Classic FAP and APC on Wnt signaling
• Attenuated FAP and the Ashkenazi variant
• MUTYH-associated polyposis and recessive inheritance
• FAP extracolonic stigmata and desmoids
• Prophylactic colectomy and the rectal decision
• Spigelman-staged duodenal surveillance
• Chemoprevention as adjunct not substitute

Key decisions

• Start annual colonoscopy at puberty, age ten to twelve, in classic FAP, and delay attenuated FAP and MUTYH-associated polyposis to age twenty to twenty-five because the polyps and cancer arise later.
• Move to prophylactic colectomy for polyps larger than ten millimeters, high-grade dysplasia, rising polyp number, burden too high to clear endoscopically, or symptoms.
• Let the rectum decide the operation: total proctocolectomy with ileal pouch-anal anastomosis when the rectum carries burden, total colectomy with ileorectal anastomosis with annual rectal surveillance when it can be cleared.
• Test for biallelic MUTYH in a patient with multiple adenomas who is APC-negative, especially when a sibling is affected and the parents are not, because the pattern is autosomal recessive.
• Stage the duodenum by Spigelman and set the interval to the stage: EGD every four years at stage zero down to every year at stage three, with side-viewing ampulla inspection each time, because stage four carries a fourteen to thirty-six percent cancer risk and triggers surgical evaluation.
• Treat sulindac and celecoxib as adjuncts only, since they reduce polyp number but do not prevent colorectal cancer or remove the need for surgery.

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• (00:00) - Gene sets count, histology, and surgery
• (00:53) - Classic FAP and APC on Wnt signaling
• (01:39) - Attenuated FAP and the Ashkenazi variant
• (02:19) - MUTYH-associated polyposis and recessive inheritance
• (03:30) - Extracolonic stigmata and desmoids
• (04:52) - Colectomy and the rectal decision
• (06:00) - Spigelman-staged duodenal surveillance
• (07:20) - Chemoprevention as adjunct not substitute

Episode two takes Lynch syndrome, the syndrome the diagnostic framework most often surfaces, and anchors everything to one idea: lifetime cancer risk varies sharply by gene, and that gene-specific risk sets each surveillance interval to the dwell time of preinvasive disease in that organ. MLH1 and MSH2 carriers drive high colorectal and endometrial risk, while MSH6 flips uterine cancer above colorectal and MSH2 concentrates the upper urothelial risk. The reasoning extends to why the colonoscopy interval is short, why the cancer operation is extended, why endometrial surveillance is a bridge to hysterectomy, and why aspirin and pembrolizumab both trace back to the mutational burden the syndrome generates.

Topics covered

• Mismatch-repair genetics and the MSI phenotype
• Classic Lynch tumor histology and late-presenting carriers
• Amsterdam and Bethesda criteria
• Gene-specific lifetime cancer risk
• Colorectal surveillance and extended colectomy
• Endometrial surveillance as a bridge to hysterectomy
• Urothelial, gastric, and pancreatic programs
• Aspirin chemoprevention and checkpoint inhibition
• Lynch variants and Syndrome X

Key decisions

• Run colonoscopy every one to two years starting age twenty to twenty-five, or five years before the youngest affected relative, because Lynch adenomas progress faster than sporadic ones and a three-year interval is too long.
• When a Lynch carrier develops colorectal cancer, particularly an MLH1 or MSH2 carrier, perform extended colectomy with ileorectal anastomosis rather than segmental resection, because metachronous risk in the residual colon is high, then surveil the rectum annually.
• Treat MSH6 as the exception where uterine cancer outranks colorectal, discuss risk-reducing hysterectomy earlier, and offer total hysterectomy with bilateral salpingo-oophorectomy after childbearing as a bridge target rather than relying on surveillance permanently.
• Gate pancreatic surveillance on family history, enrolling only carriers with a first-degree or second-degree relative with pancreatic cancer in annual EUS or MRI at age fifty, because absolute Lynch pancreatic risk near six percent sits below the surveillance threshold.
• Offer daily aspirin for chemoprevention across a tolerable dose range, counseling that the colorectal benefit emerges only beyond five years and the per-protocol effect exceeds the intention-to-treat estimate.
• Give pembrolizumab first-line for advanced MSI-high or mismatch-repair-deficient Lynch cancers before chemotherapy, because the high mutational burden generates the neoantigens checkpoint inhibition needs.

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• (00:00) - Mismatch-repair genetics and the MSI phenotype
• (01:20) - Classic histology and late-presenting carriers
• (01:54) - Amsterdam and Bethesda criteria
• (02:28) - Gene-specific lifetime cancer risk
• (03:58) - Colorectal surveillance and extended colectomy
• (04:43) - Endometrial surveillance as a bridge to surgery
• (05:40) - Urothelial, gastric, and pancreatic programs
• (08:06) - Aspirin and checkpoint inhibition
• (09:38) - The Lynch variants and Syndrome X

Episode one of the Hereditary GI Cancer Syndromes chapter builds the diagnostic framework the rest of the series depends on. The organizing idea: universal tumor testing catches the carriers that pedigree gatekeeping misses, because family history alone overlooks thirty to fifty percent of them. The four-protein immunohistochemistry pattern then decides the next move, with combined MLH1 and PMS2 loss running a sporadic-cancer rule-out before germline sequencing and everything else reflexing straight to the blood test. The through-line is that protein-loss pattern drives testing, and once a proband is confirmed, cascade testing of relatives becomes the highest-yield step.

Topics covered

• Why tumor testing replaces pedigree gatekeeping
• Universal four-protein MMR immunohistochemistry
• Universal endometrial IHC and the sentinel cancer
• The reflex pathway and IHC patterns
• MLH1 and PMS2 loss with the BRAF and methylation gate
• EPCAM and the MSH2 and MSH6 pattern
• Multi-gene panels and phenotype overlap
• Cascade testing and multidisciplinary referral

Key decisions

• Run universal four-protein mismatch-repair immunohistochemistry, MLH1, MSH2, MSH6, and PMS2, on every newly diagnosed colorectal and endometrial cancer, because pedigree-based screening misses thirty to fifty percent of carriers.
• On combined MLH1 and PMS2 loss, test the tumor for BRAF V600E first and then MLH1 promoter methylation; only when both are absent does the patient reflex to germline sequencing, because roughly seventy percent of that pattern is sporadic.
• Isolated loss of MSH2, MSH6, or PMS2 has no sporadic counterpart and reflexes directly to germline sequencing without the BRAF and methylation gate.
• On the combined MSH2 and MSH6 pattern, the germline test must include EPCAM, because three-prime EPCAM deletions silence the MSH2 promoter and mimic a primary MSH2 mutation.
• Choose the multi-gene panel by dominant clinical phenotype, and require pre-test counseling before drawing blood because positive, negative, and uncertain results all carry consequences.
• Once a pathogenic variant is confirmed in the proband, prioritize cascade testing of first-degree relatives, each of whom is fifty-fifty at risk and carries the same surveillance program.

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• (00:00) - The framework runs on tumor biology
• (00:57) - Universal four-protein immunohistochemistry
• (01:30) - Endometrial IHC and the sentinel cancer
• (02:04) - The reflex pathway by IHC pattern
• (02:19) - MLH1 and PMS2 loss, the sporadic gate
• (04:19) - EPCAM in the MSH2 differential
• (05:33) - Multi-gene panels and phenotype overlap
• (06:59) - Referral and keeping surveillance from lapsing

Episode six closes the chapter on two luminal problems governed by anatomy and timing. Post-bariatric pregnancy reads every rule off what the surgery changed: bypassed duodenum drops iron and calcium, reduced parietal cell exposure drops B12, the bypassed pylorus invalidates the OGTT, and mesenteric defects plus a gravid uterus produce internal hernia, so right upper quadrant pain after gastric bypass is internal hernia until proven otherwise. Cholelithiasis is governed by the trimester window: conservative when mild, second-trimester laparoscopic cholecystectomy when complicated, and ERCP built around keeping fetal dose under one milligray.

Topics covered

• Anatomy and timing as the organizing logic
• Post-bypass malabsorption pattern
• Gestational diabetes screening after bypass
• Internal hernia emergency
• Marginal ulcers after RYGB
• Cholelithiasis and the trimester window
• ERCP and radiation minimization
• Antibiotic selection

Key decisions

• Conception is delayed twelve to twenty-four months after bariatric surgery because the rapid weight-loss phase and unrepleted micronutrient stores create a compromised environment for fetal growth.
• Micronutrient supplementation is mandatory through pregnancy after bypass and sleeve, with B12, iron, folate, calcium, vitamin D, and thiamine all followed and adjusted.
• The oral glucose tolerance test is avoided after Roux-en-Y because the bypassed pylorus produces dumping that makes the curve uninterpretable, and fasting glucose with home monitoring replaces it.
• Severe right upper quadrant pain in a post-Roux-en-Y patient in late pregnancy is internal hernia until ruled out, and CT with abdominal shielding is appropriate because missing it allows incarcerated bowel necrosis within hours.
• Mild biliary colic is managed conservatively, while recurrent colic, complicated cholelithiasis, or gallstone pancreatitis goes to laparoscopic cholecystectomy in the second trimester where all three windows align.
• ERCP is reserved for cholangitis, persistent obstruction, or a large stone with refractory symptoms, and keeps fetal dose under one milligray using limited pulsed fluoroscopy, lead shielding, and non-fluoroscopic cannulation when feasible.
• Fluoroquinolones and tetracyclines are avoided for their fetal tissue targets, and beta-lactam plus beta-lactamase inhibitor or cephalosporin plus metronidazole are the appropriate antibiotic choices.

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• (00:00) - Anatomy and timing as the logic
• (01:11) - Post-bypass malabsorption pattern
• (02:15) - Gestational diabetes screening after bypass
• (03:06) - Internal hernia emergency
• (04:41) - Marginal ulcers after RYGB
• (05:50) - Cholelithiasis and the trimester window
• (07:14) - ERCP and radiation minimization
• (08:56) - Antibiotic selection

Episode five flips a deeply intuitive instinct: pregnancy is not the time to back off immunosuppression, because the measured danger to the fetus is active maternal disease, not active maternal medicine. Once that principle is in place the medication rules become predictable, anything that maintained remission is continued and a small set of mechanism-toxic drugs is held. The molecular centerpiece is FcRn-mediated placental transfer, which loads IgG anti-TNF into cord blood by term but spares the Fab-fragment certolizumab, and that fact drives dose timing near term and infant vaccine decisions.

Topics covered

• Active disease as the fetal danger
• The central teaching against backing off
• The safe-to-continue drugs
• FcRn placental transfer and certolizumab
• Dose timing near term
• Infant live virus vaccination
• The contraindicated drugs
• Assessing disease activity in pregnancy

Key decisions

• Biologic therapy is continued through delivery rather than held in the third trimester, because active disease at conception, not the medication, is what predicts adverse pregnancy outcomes.
• Sulfasalazine requires folic acid supplementation bumped to two to three milligrams daily because the sulfa moiety antagonizes folate, and thiopurines are safe because the fetal liver cannot activate the prodrug.
• Infliximab, adalimumab, and golimumab are IgG antibodies that cross via FcRn so cord levels can exceed maternal by term, while certolizumab is a Fab fragment with no Fc region and minimal transfer in any trimester.
• For IgG anti-TNF agents the final dose is often spaced to roughly week thirty-two through thirty-eight so birth occurs at trough, and the biologic is resumed twenty-four hours after vaginal or forty-eight hours after cesarean delivery.
• Live virus vaccination such as rotavirus was conservatively delayed six to twelve months in IgG-biologic-exposed infants, though the 2025 consensus now permits rotavirus for anti-TNF, IL-23 inhibitor, and vedolizumab exposure.
• Methotrexate is absolutely contraindicated and stopped three to six months before conception, and tofacitinib, JAK inhibitors, ozanimod, thalidomide, and rifaximin are avoided.
• CRP is unreliable in pregnancy because it rises physiologically, so fecal calprotectin is used for activity assessment and a C. difficile stool test is sent whenever a flare presentation comes through the door.

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• (00:00) - Active disease as the fetal danger
• (00:27) - The central teaching against backing off
• (01:58) - The safe-to-continue drugs
• (02:59) - FcRn transfer and certolizumab
• (04:00) - Dose timing near term
• (04:48) - Infant live virus vaccination
• (05:54) - The contraindicated drugs
• (06:48) - Assessing disease activity in pregnancy

Episode four takes the hepatic disease that is not caused by pregnancy but is reshaped by it. Viral hepatitis turns on virus-specific decisions: the tenofovir-plus-HBIG-and-vaccine stack that decisively cuts HBV vertical transmission, universal HCV screening with treatment deferred, genotype-driven HEV severity, and the empiric acyclovir that any pregnant patient with high transaminases and low bilirubin earns before HSV PCR returns. The pre-existing diseases follow an immune and pharmacokinetic principle: continue what is working and swap out the teratogens, with the specifics being mycophenolate out, azathioprine acceptable, trientine over penicillamine, and propranolol not nadolol.

Topics covered

• Hepatitis A and vaccination safety
• Hepatitis B and the tenofovir decision
• Hepatitis C and universal screening
• Hepatitis E and genotype severity
• Disseminated HSV and empiric acyclovir
• Autoimmune hepatitis and PBC continuation
• Wilson disease and chelation
• Cirrhosis and portal hypertension

Key decisions

• Maternal antiviral therapy for hepatitis B is added when HBV DNA exceeds two hundred thousand international units per milliliter by week twenty-eight, using tenofovir disoproxil fumarate three hundred milligrams daily started at twenty-eight to thirty-two weeks.
• All infants of HBsAg-positive mothers receive HBIG plus the first vaccine dose within twelve hours of birth, taking transmission from over ninety percent down to under five percent, and cesarean delivery is not indicated for HBV alone.
• Ribavirin is essentially absolutely contraindicated as a teratogen requiring two forms of contraception for six months, and HCV is screened universally but treated before conception or after pregnancy, while hepatitis E genotypes one and two carry twenty to thirty-three percent third-trimester maternal mortality by geography.
• Disseminated HSV produces anicteric liver failure with transaminases twenty-five to forty times normal and bilirubin below three, and empiric IV acyclovir is started before PCR returns because it cuts mortality from thirty to fifty percent down to eight to twenty-five percent.
• Azathioprine is continued because the fetal liver cannot activate it, while mycophenolate is strictly contraindicated with a six-month pre-conception washout, and methotrexate-class exposure is avoided.
• In Wilson disease chelation must continue with trientine preferred over penicillamine, the dose reduced twenty-five to fifty percent in the third trimester, copper IUDs contraindicated, and levonorgestrel IUDs preferred.
• For variceal prophylaxis in cirrhotic pregnancy propranolol is preferred over nadolol, and vasopressin is avoided because it activates myometrial V1 receptors and induces contractions.

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• (00:00) - The incidental half and hepatitis A
• (00:34) - Virus-specific decisions begin
• (01:21) - Hepatitis B and the tenofovir decision
• (04:18) - Hepatitis C and universal screening
• (05:54) - Hepatitis E and genotype severity
• (07:23) - Disseminated HSV and empiric acyclovir
• (08:45) - Pre-existing liver disease principles
• (11:50) - Wilson disease and chelation
• (14:15) - Cirrhosis and portal hypertension