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Welcome to NEGM this week. I'm Dr. Michael Bearer. This week we bring you advances in pancreatic and bladder cancer preventing gonorrhea, a promising new therapy for adolescent hypertrophic cardiomyopathy, and a review of antiretroviral treatment for hiv. We also follow a striking case of vision loss that led to an unexpected diagnosis and discuss perspectives on vaccine evidence, hepatitis C elimination, the endorsements of prescription drugs on social media, and the enduring intersection of love and loss in medicine. Daraxon Racib or chemotherapy in previously treated metastatic pancreatic cancer? By Eileen O'Reilly from the Memorial Sloan Kettering Cancer Center, New York and and Co authors Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with most patients presenting with advanced disease at the time of diagnosis. Among patients with metastatic pancreatic cancer, the median overall survival is less than one year. Current therapies offer limited benefit for patients with previously treated disease. Aberrant activation of the RAS pathway is the key driver of pancreatic ductal adenocarcinoma with oncogenic RAS mutations present in over 90% of cases. Daraxon Rasib is an oral panras inhibitor. In this phase 3 trial, 500 patients with previously treated metastatic pancreatic cancer, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxon rasib or chemotherapy of the investigator's choice. In both the RAS G12 patient population and and the overall patient population, treatment with daraxonrasib reduced the risk of death by 60%, with a median overall survival of 13.2 months among patients with previously treated disease. Treatment with daraxanrasib also led to significantly longer progression free survival than chemotherapy. The safety profiles of Daraxon rasib and chemotherapy showed no unexpected findings. Shivan Sivakumar from the University of Birmingham, United Kingdom, writes in an editorial that the findings by O'Reilly and co authors are among the most important therapeutic advances observed in pancreatic cancer in decades, with immediate implications for clinical practice. Historically, advances in metastatic pancreatic cancer have emerged only through incremental refinements in cytotoxic chemotherapy. After decades in which KRAS was viewed as an elusive and effectively undruggable target, direct inhibition of the dominant biologic driver of pancreatic cancer has now translated into substantial clinical benefit. The challenge ahead is no longer whether RAS can be targeted in pancreatic cancer, but rather how best to integrate RAS directed therapy across the continuum of disease. Enfortamab, vedotin and pembrolizumab in cisplatin eligible bladder cancer by Matthew Galski from the Icahn School of Medicine at Mount Sinai, NY Co Authors NeoAdjuvant cisplatin based chemotherapy is a standard therapy for muscle invasive bladder cancer. This phase three trial evaluated the efficacy and safety of both neoadjuvant and adjuvant and fortumab vedotin pembrolizumab, a combined antibody drug, conjugate and immune checkpoint inhibitor, as compared with neoadjuvant cisplatin gemcitabine. In 808 participants with muscle invasive bladder cancer who were eligible for cisplatin based therapy and cystectomy at 2 years, perioperative and fortumab vedotin pembrolizumab led to significantly better event free and overall survival outcomes and a significantly higher incidence of pathological complete response than neoadjuvant cisplatin gemcitabine but with more adverse events of grade three or higher. In an editorial, Srikala Sridhar from Princess Margaret Cancer Center, Toronto writes that the findings by Galsky and co authors strongly support enfortumab vedotin pembrolizumab as a new perioperative standard of care. The findings also bring several important clinical issues into focus, including the rationale for future prospective evaluation of bladder sparing strategies in light of the high incidence of pathological complete response, management of toxicity, predictive biomarkers to guide treatment escalation and de escalation, as well as major financial cost and equitable access. All patients with muscle invasive bladder cancer should be referred at diagnosis for consideration of perioperative and fortumab vedotin pembrolizumab clinicians should aim to deliver the full perioperative regimen when feasible. The era of perioperative platinum based chemotherapy appears to be ending. Meningococcal B vaccine to prevent Neisseria gonorrhea infection by Kate Seib from Griffith University, Gold Coast, Queensland, Australia and co authors no vaccines are currently licensed for the prevention of Neisseria gonorrhea infection. However, observational studies suggest that the four component meningococcal serogroup B vaccine 4C men B may reduce the risk of gonorrhea. In this trial, 587 men who have sex with men were randomly assigned to receive two doses of four semen B or or placebo. All the participants had recently received a diagnosis of N gonorrhea infection or infectious syphilis and either tested negative for HIV and were receiving HIV pre exposure prophylaxis or were living with HIV. Among these participants, 4C men B did not result in a lower incidence of N Gonorrhea infection than placebo among men who have sex with men who were at high risk for gonorrhea. Mavacamten in adolescents with obstructive hypertrophic cardiomyopathy By Joseph Rossano from Children's Hospital of Philadelphia and co authors Approved pharmacologic therapies for pediatric hypertrophic cardiomyopathy are lacking, and surgical intervention may be indicated in patients with left ventricular outflow tract obstruction. These investigators evaluated the efficacy and safety of mavacamten, a cardiac myosin inhibitor that is available for adults in in 44 adolescent patients. Among these patients, the primary endpoint of the decrease from baseline to week 28 in the left ventricular outflow tract pressure gradient provoked by the Valsalva maneuver was significantly greater with mavacamten than with placebo. Antiretroviral therapy A review article by Roy Gulick from Weill Cornell Medicine, New York. The development of effective treatment strategies for HIV infection is a major achievement. Antiretroviral drugs inhibit key steps in the viral replication cycle and consist of six mechanistic HIV entry inhibitors, reverse transcriptase inhibitors, both nucleosides and non nucleosides, capsid inhibitors, integrase inhibitors, and protease inhibitors. Antiretroviral therapy suppresses viral replication, thereby enhancing immune function, decreasing morbidity and mortality, and preventing viral transmission. Consequently, ART is recommended for all persons with HIV infection on the basis of randomized clinical trials. The Food and Drug administration has approved 36 antiretroviral drugs for the treatment of HIV infection since 1987. Of these, 27 are currently available in the United States, and combination ART regimens are used. Initial preferred ART regimens are potent, convenient, and unlikely to cause side effects and consist of an HIV integrase inhibitor with a high barrier to resistance combined with one or two nucleoside reverse transcriptase inhibitors. In the majority of patients using current ART regimens, both viral replication is durably suppressed below detectable levels. Patients receiving ART are monitored for virologic response over time, and if virologic failure occurs, the patient is given a next regimen selected on the basis of their treatment history and the results of drug resistance testing. Often, antiretroviral drugs from new classes are administered. Today, the life expectancy of someone with HIV infection who consistently takes ART approaches that of the general population. A 28 year old man with headache and vision loss in the right eye. A case record of the Massachusetts General Hospital by Aubrey Gilbert and colleagues. A 28 year old man was admitted with a severe headache and rapidly worsening vision loss in his right eye. His symptoms began a week after lifting a heavy object at work when he noticed flashes, floaters, neck pain and pain behind the right eye that worsened with eye movement. He had been treated for a recent streptococcal throat infection. Over several days his vision deteriorated. Examination revealed profound loss of visual acuity in the right eye, marked swelling of the right optic disc, and progressive retinal changes during hospitalization. Patient was found to have previously undiagnosed HIV infection along with enlarged lymph nodes and small liver lesions. Testing confirmed Bartonella Henselle neuroretinitis likely related to cat exposure. The patient was treated with doxycycline rifampin, antiretroviral therapy and a tapering course of prednisone. His vision steadily improved and follow up showed marked resolution of optic disc swelling, although retinal changes persisted during recovery. The best of both worlds Using clinical trial and observational data to evaluate vaccination Vaccine Protection A Perspective by Arnold Monto from the University of Michigan School of Public Health, Ann Arbor and Helen Chu from the University of Washington School of Medicine, Seattle Although randomized controlled trials are considered the standard for the initial assessment of efficacy of vaccines and other interventions, results from clinical trials don't necessarily translate to general use. Trial participants may be healthier than the general population, and trial settings may differ in important ways from real world settings. Well designed observational studies are therefore critical to advancing understanding of the effects of vaccines. Such studies can involve populations that are excluded from RCTs, assess rare outcomes, and evaluate population level benefits, but they are often dismissed as lacking the methodologic rigor necessary to inform policy making and regulatory decisions. RCTs and observational studies are both imperfect in their own ways. For vaccine policy making in the United States, the totality of evidence along with each study's gaps and limitations must be considered. Weighing evidence from both types of studies when making decisions and recommendations are could help maximize the public health benefits of vaccination. National elimination of Hepatitis C the case for starting in prisons and jails A Perspective by Josiah Rich from Brown University, Providence, Rhode Island. In 2020, an estimated 2.4 million to 4 million people in the United States had active hepatitis C virus HCV infection. Many people with HCV are unaware they have the virus. Meanwhile, calls for HCV elimination have multiplied. Modeling suggests that prison based treatment in Australia has substantially reduced HCV prevalence and incidence among incarcerated and community dwelling populations in the United States. If we focus on incarcerated populations and people on probation or parole, a large proportion of people with HCV in the United States could be diagnosed and cured, which could improve their health and prevent transmission. However, even if dedicated federal funding were secured with recently proposed legislation, approaches would have to be tailored to the needs and circumstances of each of the nearly 2,000 prisons and about 3,000 jails in the US with strong carceral community collaboration When Celebrities Prescribe Regulating Drug Promotion on the Internet A Perspective by Nils Kruger from Brigham and Women's Hospital, Boston and co authors in the past two decades, patient targeted promotion of prescription drugs has expanded beyond traditional print and television advertising to the Internet. With social media narratives shared by public figures becoming increasingly common, endorsements of prescription drugs on social media can be rapidly disseminated across platforms, complicating regulatory oversight. This challenge is compounded by the growing role of third party intermediaries such as telehealth companies in drug promotion. Today this shift is most visible in the promotion of GLP1 receptor agonists. Amid this prominent promotion, the US regulatory oversight system is showing its seams. New forms of marketing have evaded regulatory scrutiny, leaving patients exposed to potentially misleading information. The two recent high profile cases involving Oprah Winfrey and Serena Williams, have illustrated the shifting landscape of drug promotion and the limitations of current oversight. These authors believe stronger guardrails are needed to protect the public and to keep pace with the ways in which patients now encounter drug promotion. Social media platforms could more clearly label paid health content and more prominently feature disclosures about risks. Using their existing authority, the FDA and the Federal Trade Commission could update guidance to align oversight with the current promotional environment. Targeted guardrails could provide the necessary friction to discourage brazen violations of regulations governing drug promotion and protect patients from misleading medical narratives. Love and A Perspective by Tristan Jones from Virginia Commonwealth University Medical Center, Richmond It's December during Tristan Jones final year of residency, and he is ready to be done with intensive care units. He is tired of interpreting the blood gases. He is tired of performing procedures that he feels he is not good at. He's tired of the sunless days that melt into weeks. But mostly, Dr. Jones is tired of the death. He had recently completed a month each in the cardiac ICU and then the pediatric icu, and is now wrapping up a month in the medical ICU. Naturally, he thinks his holiday assignment is the medical ICU. Nights on Christmas Eve, one of the new patients is Cassie, a 29 year old woman admitted through the emergency department with skin yellow, bronze and lactate in the double digits. She was just diagnosed in October with metastatic lung cancer. It has taken a few weeks to get her into care and then a few more for staging. Her insurance has limited her ability to find doctors and she struggles to find child care. Now the beta HCG level is low in the teens and it has not budged in a month. Dr. Jones calls her emergency contact, her boyfriend, Dion. When Dion shows up right before shift change, they review Cassie's condition. He tells Dr. Jones of their life together, how they had met years ago, how she already had three small children, how he had become their stepfather. In all but the official sense, he has just one. Is there someone who can perform a wedding? Dr. Jones returns in the evening on Christmas Day. The couple has selected a chaplain. The unit secretary has arranged some simple paper decorations. Two friends of the couple are waiting in the room Just before midnight. After the other patients are tucked in, about a dozen staff wedge between the dialysis machine, IV poles and external warmer around Cassie's bed. Cassie, between dozes, is all smiles. Dion is positively levitating. During this brief ceremony, there is no mention of Cassie's condition. For a moment they suspend the reality written all over the room and simply witness two people's love. On Boxing Day, Dr. Jones comes in for sign out and learns that Cassie died that afternoon. She was a wife for all of 15 hours. Dr. Jones doesn't know what became of Dion or whether he was able to secure guardianship of his stepchildren. Dr. Jones just knows that Dion and Cassie loved one another. The writer Stephen Bergman, better known as Samuel Shem, describes the privilege of medicine as bearing witness to the two great themes of human love and death. When the death is so prominent, it can be easy to miss the love, yet no other career offers such proximity to both. How lucky we are, he writes. In our Images in clinical medicine, a 52 year old woman presented with a four month history of headache and visual hallucinations and a one month history of incoherent speech. MRI of the brain showed cystic lesions that contained bright eccentric nodules representing the scolices anterior end of the of tapeworms. A finding known as the.inhole sign that is pathogmonic for neurocysticercosis. In another image, a 35 year old man with a history of moderate to severe plaque psoriasis presented to the dermatology clinic with new skin lesions. The patient had recently undergone wet cupping for the first time to treat low back pain. During the treatment, clusters of small incisions had been made at different sites across the back, after which glass cups had been applied with negative pressure to draw out small amounts of blood. On physical examination, well demarcated, erythematous scaly papules and plaques were present at the sites of the incisions on his shoulders and middle and lower back. A diagnosis of Kebner phenomenon from wet cupping was made. Read more from our issue@nejm.org let us know what you think about our podcast. Send any comments or suggestions to audioyjm.org thank you for listening.