0:00

Welcome. This is the

0:02

New England Journal of Medicine. I'm

0:04

Dr. Michael Bierer. This

0:06

week, November 2,

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2023, we feature articles on thalidomide

0:12

for recurrent bleeding due to small

0:14

intestinal angio-dysplasia,

0:17

pulsed field ablation for paroxysmal

0:20

atrial fibrillation, perioperative

0:23

chemoimmunotherapy in

0:25

lung cancer, and corrin

0:28

and cardiac phenotypes, a

0:30

review article on cystic fibrosis,

0:33

a clinical problem solving on

0:35

being encased in peril,

0:38

and perspective articles on minimum

0:41

staffing rules for U.S. nursing homes,

0:44

on reforming pharmacy benefit

0:46

managers, on scaling

0:48

up point-of-care fentanyl testing,

0:51

and on familiar shadows.

0:55

Thalidomide for Recurrent Bleeding

0:58

Due to Small Intestinal Angio-Dysplasia

1:01

by Hoimin Chen from the Shanghai

1:04

Jiao Tong University School of Medicine

1:06

Renji Hospital, China,

1:08

and colleagues. Recurrent

1:11

bleeding from the small intestine accounts

1:14

for 5 to 10 percent of cases of

1:16

gastrointestinal bleeding and remains

1:18

a therapeutic challenge. Thalidomide

1:21

has been evaluated for the treatment of recurrent

1:24

bleeding due to small intestinal

1:26

angio-dysplasia, SIA, but

1:28

confirmatory trials have been lacking.

1:31

In this trial, 150 eligible patients

1:35

with recurrent bleeding due to SIA

1:38

were randomly assigned to receive thalidomide

1:40

at an oral daily dose of 100 milligrams

1:43

or 50 milligrams or placebo

1:46

for four months.

1:48

Patients were followed for at least one year

1:50

after the end of the four-month treatment period.

1:53

The percentages of patients with

1:55

an effective response, which was

1:57

defined as a reduction of at

1:59

least

1:59

50% in the number of bleeding

2:02

episodes that occurred during the year after

2:04

the end of thalidomide treatment as compared

2:07

with the number that occurred during the year before

2:10

treatment was 68.6% in the 100 milligram

2:12

thalidomide group, 51% in the 50 milligram thalidomide

2:18

group, and 16% in

2:21

the placebo group. The results of

2:23

the analyses of the secondary endpoints

2:26

supported those of the primary endpoint.

2:29

Various events were more common in the thalidomide

2:31

groups than in the placebo group overall.

2:35

Specific events included constipation,

2:37

somnolence, limb numbness, peripheral

2:40

edema, dizziness, and elevated

2:42

liver enzyme levels. In

2:44

this placebo-controlled trial, treatment

2:47

with thalidomide resulted in a

2:49

reduction in bleeding in patients

2:51

with recurrent bleeding due to SIA.

2:56

Lauren Lane from Yale School of Medicine,

2:58

New Haven, Connecticut writes in an editorial

3:01

that guidelines suggest consideration

3:03

of medical therapy with somatostatin

3:06

analogues or thalidomide when

3:08

recurrent bleeding occurs despite the use

3:10

of endoscopic therapy, although supporting

3:13

evidence has been limited. In

3:15

addition to the well-known teratogenic

3:18

effect of thalidomide, which may limit

3:20

its use, this agent is associated

3:23

with a long list of side effects,

3:25

although lower doses, such as those

3:27

used in the current trial, are associated

3:30

with fewer unacceptable adverse

3:32

events. Given the possible dose

3:34

response with respect to efficacy

3:37

and adverse events, the appropriate

3:39

dose is uncertain. Clinicians

3:42

may administer 50 milligrams, 100 milligrams,

3:45

or 50 milligrams initially with

3:47

an increase to 100 milligrams on the

3:49

basis of clinical response and side

3:51

effects. Chen and colleagues

3:54

provide evidence supporting thalidomide

3:56

for persistent or recurrent bleeding due

3:58

to small intestinal angiosplasias

4:01

that is of higher quality than evidence

4:03

that is available for any other therapy

4:06

for this indication. In addition,

4:08

their results suggest that thalidomide

4:11

may be disease-modifying,

4:13

with efficacy persisting after

4:15

discontinuation. However, many

4:18

clinicians will still use somatostatin

4:20

analogs first, given the potential

4:23

for better adherence, once monthly

4:25

injections versus daily pills, and

4:28

safety, and will reserve thalidomide

4:30

for use in patients who have continued

4:32

bleeding or side effects with somatostatin

4:35

analogs. Pulsed

4:38

field or conventional thermal

4:40

ablation for paroxysmal atrial

4:42

fibrillation, by Vivek Reddy

4:45

from the Icahn School of Medicine at Mount

4:47

Sinai, New York, and colleagues.

4:51

Tissue-based pulmonary vein isolation

4:53

is an effective treatment for paroxysmal

4:56

atrial fibrillation. The procedure

4:58

is typically performed with the use of radiofrequency

5:02

or cryothermal energy that

5:04

heats or freezes tissue, respectively,

5:07

to electrically isolate the pulmonary

5:09

veins, which harbor triggers of

5:12

atrial fibrillation. However,

5:14

tissue indiscriminate effects

5:16

of thermal ablation may extend beyond

5:19

the myocardium to adjacent tissues.

5:22

Pulsed field ablation, which delivers

5:25

microsecond, high-voltage

5:27

electrical fields, may limit damage

5:29

to tissues outside the myocardium.

5:32

In this study, 305 patients

5:35

with drug refractory paroxysmal

5:37

atrial fibrillation were assigned to

5:40

undergo pulsed field ablation, and 302

5:43

patients were assigned to undergo thermal

5:46

ablation. The primary efficacy

5:48

endpoint was freedom from

5:50

a composite of initial procedural failure,

5:53

documented atrial tachyarrhythmia

5:55

after a three-month blanking period,

5:58

antiarrhythmic cardioversion,

6:01

or repeat ablation. At

6:04

one year, the primary efficacy

6:06

endpoint was met. That is, no

6:09

events occurred in 204 patients,

6:12

estimated probability 73.3% who underwent pulsed

6:17

field ablation, and 194 patients, estimated

6:19

probability 71.3%, who underwent thermal ablation. The

6:26

safety endpoint events of acute and

6:28

chronic device and procedure-related

6:31

serious adverse events occurred in six

6:33

patients, estimated incidence 2.1%, who

6:35

underwent pulsed field ablation,

6:39

and four patients, estimated incidence 1.5%,

6:42

who underwent thermal ablation. Among

6:45

patients with paroxysmal atrial fibrillation,

6:48

receiving a catheter-based therapy, pulsed

6:51

field ablation was noninferior

6:53

to conventional thermal ablation with

6:56

respect to a composite of procedural

6:58

and arrhythmia events, and with respect

7:01

to device and procedure-related serious

7:04

adverse events at one year. T.

7:08

Jared Bunch from the University

7:10

of Utah Health Sciences Center, Salt

7:12

Lake City, writes in an editorial

7:15

that there were several interesting findings

7:17

from the trial by Reddy and colleagues.

7:20

Future times were much shorter

7:23

with pulsed field ablation than with thermal

7:25

ablation, a clear advantage in

7:27

resource-constrained electrophysiology

7:30

laboratories. But the efficacy results

7:33

are disappointing for pulsed field ablation,

7:35

given the lack of incremental improvement

7:38

over currently available methods. Pulsed

7:40

field ablation reduced the time to

7:43

durable pulmonary vein isolation as

7:45

compared with thermal ablation, but did

7:47

not improve arrhythmia-free outcomes.

7:50

Regarding safety, pulsed field ablation

7:53

is probably more tissue-selective

7:56

than traditional thermal ablation tools.

7:58

However, there are unique risks and

8:01

the manifestation of complications

8:03

may be delayed or different. With

8:06

conventional thermal ablation, relatively

8:08

rare risks persist that can

8:10

result in substantial complications

8:13

and death. Of these, atrioesophageal

8:17

fistula is often moribund,

8:19

and avoidance efforts to prevent esophageal

8:22

heating during the ablation can

8:24

affect efficacy. It

8:26

remains that pulsed field ablation

8:29

may remove the risk of atrioesophageal

8:32

fistula. However, it is

8:34

too soon to know. If

8:36

the risk of esophageal injury is

8:38

mitigated or solved with pulsed

8:40

field ablation, it would be a big

8:43

step forward and a sign that

8:45

the technology may live up to the hype.

8:50

Perioperative dervallumab

8:52

for resectable non-small cell lung

8:54

cancer by John Haymack

8:57

from the University of Texas MD Anderson

8:59

Cancer Center, Houston, and

9:01

colleagues. Neoagivant

9:04

or adjuvant immunotherapy can improve

9:07

outcomes in patients with resectable

9:09

non-small cell lung cancer, NSCLC.

9:12

Perioperative regimens may combine benefits

9:15

of both to improve long-term outcomes.

9:18

In this study, 802 patients

9:21

with resectable NSCLC,

9:23

stage 2 to 3B, end

9:25

to node stage, were randomly

9:28

assigned to receive platinum-based chemotherapy

9:31

plus dervallumab or placebo

9:33

administered intravenously every three

9:35

weeks for four cycles before

9:38

surgery, followed by adjuvant

9:40

dervallumab or placebo intravenously

9:43

every four weeks for 12 cycles. Dervallumab

9:47

was stratified according to disease stage 2

9:50

or 3 and programmed death

9:52

ligand 1, PDL1, expression.

9:56

The duration of event-free survival

9:58

was significantly longer than the duration of the event-free with

10:00

Dervallumab than with placebo. The

10:02

stratified hazard ratio for disease

10:05

progression, recurrence, or death was 0.68

10:09

at the first interim analysis. At

10:11

the 12 month landmark analysis,

10:14

event-free survival was observed in 73.4%

10:16

of the patients

10:19

who received Dervallumab as compared

10:21

with 64.5% of the patients

10:24

who received placebo. The incidence

10:27

of pathological complete response

10:29

was significantly greater with Dervallumab

10:32

than with placebo, 17.2% versus 4.3%

10:36

at the final analysis.

10:39

Event-free survival and pathological

10:41

complete response benefit were observed

10:44

regardless of stage and PD-L1

10:47

expression. Adverse events of

10:50

maximum grade 3 or 4 occurred

10:52

in 42.4% of patients

10:55

with Dervallumab and 43.2% with placebo.

10:57

In patients with resectable

11:01

NSCLC, perioperative

11:03

Dervallumab plus neo-agivant

11:05

chemotherapy was associated

11:08

with significantly greater event-free

11:10

survival and pathological complete

11:13

response than neo-agivant chemotherapy

11:16

alone with a safety profile

11:18

that was consistent with the individual

11:21

agents. Corin

11:24

and left atrial cardiomyopathy,

11:27

hypertension, arrhythmia, and

11:29

fibrosis by Hageet Baris

11:32

Feldman from the Tel Aviv-Soraski

11:35

Medical Center, Israel and colleagues.

11:38

The cardiac natriuretic peptide

11:41

hormone system comprises two

11:44

main peptides, atrial

11:46

natriuretic peptide, ANP,

11:49

and B-type natriuretic peptide,

11:51

BNP, also known as brain

11:53

natriuretic peptide, that have overlapping

11:56

roles in maintaining blood pressure and volume

11:59

homeostasis.

13:54

decade,

14:00

and serves as an example of how an

14:02

understanding of the functional consequences

14:05

of a genetic disease can lead to

14:07

improved outcomes in affected persons.

14:11

Substantial progress had been made through

14:13

the implementation of therapies addressing

14:15

key downstream manifestations

14:18

of the disease, such as mucous

14:20

accumulation in the airways and persistent

14:22

airway infections. In addition,

14:25

the introduction of small molecule

14:27

drugs that address the underlying

14:30

molecular defects, cystic fibrosis

14:32

transmembrane conductance regulator,

14:35

CFTR modulators, has

14:37

resulted in unprecedented

14:39

improvements in the health of many persons

14:42

with cystic fibrosis. Only

14:44

half a century ago, most persons

14:47

with a diagnosis of cystic fibrosis

14:49

did not reach adulthood. But

14:52

the median age of survival now is

14:54

about 50 years in Canada, Australia,

14:57

New Zealand, European countries, and

14:59

the United States, and may further

15:01

increase with the broad use of CFTR

15:04

modulators. However, clinics

15:07

for adults with cystic fibrosis

15:09

are faced with growing numbers of patients

15:11

with complications that were previously

15:13

not encountered in cystic fibrosis care,

15:16

such as microvascular

15:18

and macrovascular complications

15:20

of diabetes, obesity, and

15:22

hypertension. Small molecule-based

15:25

CFTR pharmacotherapy has

15:27

been a huge success story,

15:29

but there is an unmet need to

15:32

also develop therapies for persons with

15:34

cystic fibrosis who are not eligible

15:36

to receive these medications, who do not

15:38

have a response to them, or who cannot

15:41

receive them without adverse effects. In

15:43

this review, the authors summarize

15:45

recent advancements, highlight how

15:48

they may affect clinical care in the future,

15:50

and describe unmet needs in the care

15:53

of persons with cystic fibrosis.

16:00

problem solving by Gerline Kauer

16:02

and colleagues from Brigham and Women's Hospital,

16:04

Boston. A

16:06

75-year-old man with a history of atrial

16:09

tachyarrhythmias, tricuspid

16:11

regurgitation, and pericarditis

16:13

presented with worsening dyspnea,

16:15

leg swelling, and abdominal bloating

16:18

after recent catheter ablation.

16:21

Paroxysmal atrial tachycardia was first diagnosed

16:24

in this patient in childhood. The patient

16:26

did well until three months before presentation

16:29

when symptomatic atrial fibrillation

16:32

developed. Worsening chest discomfort

16:34

and shortness of breath also developed.

16:37

Despite successful ablation, his shortness

16:39

of breath worsened, and new leg edema

16:42

and abdominal bloating developed in the two

16:44

weeks before the current presentation. Given

16:47

this patient's history of atrial tachyarrhythmias

16:50

and pericarditis, cardiac causes

16:52

of his symptoms were most likely. Dyspnea,

16:55

leg swelling, and abdominal bloating

16:58

were suggestive of symptoms of right heart

17:00

failure in the absence of symptoms of left

17:02

heart failure. In conjunction with

17:04

the clinical history, the examination

17:06

was highly suggestive of right congestive

17:09

heart failure with constrictive

17:11

physiological characteristics. He

17:14

was admitted for further evaluation.

17:17

CT of the chest showed

17:19

right heart enlargement, a moderate

17:21

pericardial effusion, and pleural

17:23

effusions in both lungs. Trans

17:26

thoracic echocardiography showed

17:29

mild left ventricular dysfunction,

17:32

severe right ventricular dysfunction

17:34

with moderate right ventricular dilatation,

17:37

severe right atrial dilatation,

17:39

severe tricuspid regurgitation,

17:42

and a small pericardial effusion.

17:45

Magnetic magnetic resonance imaging

17:48

showed extensive pericardial

17:50

inflammation with lockulated

17:53

pericardial effusions, a

17:55

structure posterior to

17:58

the left atrium and left ventricular dysfunction. was

18:00

visualized. Histologic examination

18:03

of the mass revealed markers

18:05

commonly expressed in mesothelioma.

18:10

Minimum staffing rules for U.S. nursing

18:13

homes, opportunities and

18:15

challenges, a perspective by

18:17

David Grabowski from Harvard

18:19

Medical School Boston and John

18:22

Bao Bliss from Miami University,

18:24

Oxford, Ohio. U.S.

18:27

nursing homes have faced staffing

18:29

challenges for decades. In

18:32

September of this year, the Centers for

18:34

Medicare and Medicaid Services released

18:36

a proposed rule mandating

18:39

a specific minimum staffing standard

18:41

for U.S. nursing homes. It calls

18:44

for 0.55 registered

18:46

nurse RN hours per resident

18:49

day and 2.45 certified nurse aid

18:53

CNA hours per resident

18:55

day, but it does not make any

18:58

stipulation about licensed practical

19:00

nurses LPN hours per

19:03

resident day. The rule also

19:05

calls for having an RN on site

19:07

at all times, which would replace

19:10

the current rule that an RN or

19:12

LPN always be on site. To

19:15

help nursing homes attract new workers,

19:17

the rule provides $75 million in funding for

19:21

staff training. In recognition

19:23

of labor shortages in certain markets,

19:26

nursing homes would be exempt from the

19:28

staffing requirements if they can meet certain

19:30

criteria and show good faith efforts

19:33

to hire and retain staff, which includes

19:35

demonstrating a financial commitment to

19:37

staffing by documenting expenditures

19:40

on nursing staff relative to revenue.

19:43

To give nursing homes time to adjust

19:45

to the new rule, CMS proposed

19:47

a delayed implementation. Certain

19:50

nursing homes would be required to always

19:52

have an RN on site two years

19:54

after the publication date of the final rule,

19:57

whereas rural nursing homes

19:59

would have to meet a

22:00

portion of the rebates they negotiate

22:03

or collect fees that are based on drugs

22:05

prices. These revenue streams

22:07

result in perverse incentives

22:10

for PBMs to favor

22:12

brand-name drugs with high prices

22:14

and large rebates offered by the drug's

22:17

manufacturer over lower-priced

22:20

options. At least six

22:22

congressional committees have introduced

22:24

bipartisan PBM reform

22:26

bills in 2023. Many

22:29

politicians expect that some of these

22:31

reforms will receive floor votes by

22:34

the end of the year. Although the bills

22:36

address several well-known problems

22:38

with the PBM industry, these authors

22:40

believe they are unlikely to

22:43

substantially reduce prescription

22:45

drug spending in the United States.

22:50

Scaling up point-of-care fentanyl

22:52

testing, a step forward, a

22:55

perspective by Brian Barnett from

22:57

the Cleveland Clinic, Cleveland, Ohio,

23:00

and colleagues. Although

23:02

fentanyl is now the dominant driver

23:05

of the opioid epidemic, our health

23:07

care system has struggled to adapt

23:09

toxicology screening practices

23:12

to this reality. Routine fentanyl

23:14

immunoassay screening has not been

23:16

fully adopted in clinical practice,

23:19

in part because of the costs of implementation

23:21

and maintenance of laboratory instrumentation,

23:24

as well as interpretation challenges

23:26

related to false positive results

23:28

from designer fentanyls and

23:30

cutting agents. Fortunately,

23:33

there is some recent progress on this

23:35

front. In December 2022, the FDA cleared

23:39

a qualitative point-of-care

23:42

POC instrument manufactured

23:44

by Shenzhen Super Biotechnology

23:47

for testing urine for fentanyl with

23:49

high sensitivity and specificity,

23:51

which may enable scaling up of POC

23:54

fentanyl testing in our health care system.

23:56

However, Shenzhen's POC

23:59

fentanyl test is instrument-based

24:01

and categorized under clinical

24:03

laboratory improvement amendments of 1988,

24:07

CLIA, as moderate complexity.

24:09

Sites using it must therefore be CLIA-certified,

24:13

submit to routine laboratory inspections,

24:15

and meet personnel training and other

24:18

requirements. These regulatory

24:20

demands, along with the cost of

24:22

the instrument, preclude implementation

24:25

in many healthcare settings, such as

24:27

community hospitals and syringe services

24:30

programs, as well as distribution

24:32

for home use. Though they have not

24:35

been FDA cleared, urine

24:37

fentanyl test strips that are read

24:39

visually are an attractive alternative

24:41

in settings where use of the POC test

24:44

is infeasible. The FDA

24:46

could expand access to POC

24:49

fentanyl testing for patients and less-resourced

24:52

healthcare settings by working with

24:54

manufacturers of urine test strips

24:57

and, where applicable, other POC

24:59

fentanyl tests to classify

25:01

these tests as CLIA-waivered.

25:06

Familiar Shadows, a perspective

25:08

by Susan Glass from the Children's

25:11

Hospital, Los Angeles. Dr.

25:14

Glass chose to specialize in

25:16

pediatric intensive care when

25:18

people find out that she works in the PICU,

25:21

they often respond, I don't know how

25:23

you do it. It's an understandable

25:25

reaction. Our minds reject

25:27

the idea of a child dying. It

25:30

shouldn't happen. Dr. Glass

25:32

doesn't really know how she does it, either.

25:35

The question makes her wonder why she

25:37

is able to. As a PICU

25:39

fellow, Dr. Glass often accompanies families

25:42

as their children are dying. Usually

25:45

these moments are surprisingly peaceful.

25:48

The child is being kept alive with a breathing

25:50

machine, but the family and medical

25:53

team have decided there is nothing more

25:55

to offer and they should stop life-prolonging

25:58

measures. In these moments, Dr.

26:00

Glass hears herself confidently

26:02

tell the respiratory therapist that

26:05

it's time to turn off the ventilator and

26:07

remove the endotracheal tube. She

26:10

watches as the child's heart

26:12

slows and the color drains

26:14

from the body. Depending on

26:16

the underlying disease, the process

26:18

can take seconds or minutes

26:21

or even days. The parents

26:23

cry or they yell. Sometimes

26:26

they do nothing at all. Dr.

26:28

Glass stands to the side trying

26:30

not to interfere in their pain. In

26:34

the pick you, the moments of suffering

26:36

and tragedy come interspersed

26:38

with the mundane operations of the hospital.

26:41

The medical team learns to pronounce

26:43

a child dead and goes straight into

26:46

morning sign-out. Dr. Glass

26:48

told a mother that her daughter's brain

26:50

bleed had progressed, touched her

26:52

arm and assured her that they were there for

26:54

her, and went right back to rounds.

26:58

Dr. Glass could not give in to the tears

27:00

that were welling up in her because the next

27:02

patient needed her attention. Medicine

27:05

has come so far in allowing

27:07

doctors to have emotional responses

27:09

and recognizing that we have to learn

27:11

to process them. But the realities

27:14

of the hospital mean that we must often

27:16

postpone our grieving until a more convenient

27:19

time. Sometimes that

27:21

convenient time never comes. Or

27:24

when it does come, the feelings have already

27:26

dissipated and are hard to find.

27:29

And so Dr. Glass carries these

27:31

memories, these bodies, these

27:34

patients. They visit her unannounced,

27:37

at a wedding or during a movie or

27:39

on a quiet Sunday morning. She

27:42

welcomes them like familiar

27:44

shadows. In

27:47

our images in Clinical Medicine,

27:49

a thirty-two-year-old woman presented

27:52

with a twenty-day history of vaginal

27:54

bleeding and a high serum HCG

27:57

level. intrauterine

28:00

mass with numerous cystic spaces

28:02

that created a so-called snowstorm

28:05

pattern. Owing to concern about

28:07

a hydrotylophore mole, dilation and

28:09

curatage was performed. Diffusely

28:12

hydropic chorionic villi without

28:14

any associated fetal parts were

28:17

removed from the uterus. Immunohistochemical

28:20

analysis of a histopathological specimen

28:22

showed expression of P57, a maternally expressed

28:26

gene product in uterine tissue

28:29

but not in the villi. This

28:31

finding confirmed the diagnosis of

28:33

a complete hydrotylophore mole, a

28:36

type of gestational trophoblastic

28:38

disease that results from an aberrant

28:41

fertilization in which all chromosomes

28:44

are paternal. In

28:47

another image, an 83-year-old

28:49

woman with type 2 diabetes

28:51

presented with a four-month history of

28:53

an itchy back rash. Examination

28:56

showed a linear array of crateriform

28:59

lesions on an erythematous base.

29:02

A skin biopsy from a small

29:05

lesion on the upper back revealed

29:07

a cup-shaped ulceration with

29:09

transepidermal elimination of basophilic

29:12

collagen and with cellular debris.

29:15

A diagnosis of acquired reactive

29:17

perforating collagenosis was made.

29:20

Unpowered reactive perforating collagenosis

29:23

is a perforating dermatosis, a

29:25

skin condition in which dermal

29:27

connective tissue perforates through

29:30

the epidermis. It is associated

29:32

with underlying systemic conditions

29:35

such as diabetes, as in this patient.

29:38

Treatment involves addressing the underlying condition

29:40

and reducing pruritus, which probably

29:43

triggers the development and perpetuation

29:45

of the skin disease. This

29:49

concludes our summary. Let us know

29:51

what you think about our podcast. Any

29:53

comments or suggestions may

29:55

be sent to audio at

29:58

nejm.org.

30:00

Thank you for listening.