Doctors Perform Heart Surgery On Baby Still Inside Womb.


Children’s Hospital of Philadelphia is world-renowned for its fetal surgery in which an operation is performed on a baby still inside the womb.

Recently, in yet another historic procedure, CHOP doctors undertook a risky and delicate operation on a tiny fetal heart.

Health reporter Stephanie Stahl has the exclusive story of what it took to save an unborn baby named Juan.

After some setbacks, an excited family who learned they were finally going home to South America said goodbye to the team that saved their baby.

Baby Juan and his parents, Cecilia Cella and Pablo Paladino, are headed back to Uruguay where the infant has become a celebrity.

“We receive calls, messages from people we don’t know,” said Pablo Paladino.

Since October, the family has been camped out at CHOP where doctors saved little Juan’s life with an intervention that is largely unheard of in many places.

“It was a hard time, crazy time, but we are extremely happy how everything was solved,” said Paladino.

When Cella was five months pregnant, a routine ultrasound showed a mass on the baby’s heart.

Their doctor in Uruguay sent the images to his friend, Dr. Jack Rychik, who is the director of the Fetal Heart Program at CHOP.

“The minute I saw this I recognized there was a giant tumor sitting on the heart,” said Rychik.

It was a rare pericardial teratoma and the only hope was fetal surgery where doctors would operate on the baby Juan’s heart inside the womb.

“We never heard this before,” said Paladino.

“I started laughing, like what, they do that,” said Cella.

The family raced to Philadelphia because CHOP is the only place where the risky fetal heart operation has been done successfully on just one other occasion.

“We’re operating on two patients here with the single intent,” said Rychik. “Our goal is to get to the tumor and resect the tumor but we also have mother and baby.”

Juan is now the second baby to survive the fetal surgery.

The procedure was performed when his mother was 21 weeks pregnant with the baby.

“His heart at the time of surgery was the size of a peanut. The size of the tumor was three-times the size of the heart,” explained Rychik. “Had we waited an additional day, we probably would have been too late.”

After the fetal surgery, the pregnancy continued as the family waited in Philadelphia.

At 31 weeks, Juan was born on Dec. 11, but the tumor had grown back so there was a second heart surgery.

“There were a lot of chances the baby was going to die,” said Paladino.

And now, with a big scar on his chest, Juan is 3 months old and healthy.

 

However, his prognosis is unknown.

“There are no other human beings alive today who have had fetal surgery for this removal of this type of tumor that are 30, 40, 50, 60 years old. We could then say what the prognosis is going to be,” says Dr. Rychik.

But for Cella and Paladino, at least their son has a chance after the fetal surgery that still has their heads spinning.

“Crazy, unbelievable, I look at him, I can’t believe what they did here,” said Cella. “It’s awesome.”

“We are grateful that we came here,” added Paladino. “The doctors are amazing.”

The family is now back home in Uruguay where little Juan continues to thrive.

The tumor that was on his heart was benign.

It’s unknown as to what causes this type of tumor, but it is usually a fatal condition.

Source:http://philadelphia.cbslocal.com

Post-traumatic Stress Disorder Seen in Many Adults Living with Congenital Heart Disease


CHOP Study May Reveal Unmet Medical Needs in a Growing Patient Group

 

Adults living with congenital heart disease (CHD) may have a significantly higher risk of post-traumatic stress disorder (PTSD) than people in the general population.

A single-center study from The Children’s Hospital of Philadelphia (CHOP) found that as many as 1 in 5 adult patients had PTSD symptoms, with about 1 in 10 patients having symptoms directly related to their heart condition. The researchers suggest that clinicians and caregivers need to be aware of possible PTSD symptoms, such as anxiety and depression, in their patients.

“Although the life expectancy of adults living with CHD has improved, ongoing care may include multiple surgeries and procedures,” said the study’s senior author, Yuli Kim, MD, a cardiologist at CHOP. “These patients remain at risk for both cardiac and non-cardiac effects of their chronic condition, and face unique life stressors that may place them at elevated risk for psychological stress.”

Kim is the director of the Philadelphia Adult Congenital Heart Center, a joint project of CHOP and the Hospital of the University of Pennsylvania. Her research team’s study appeared in the March issue of the American Journal of Cardiology. It was the first analysis of PTSD in an adult CHD population.

Due to surgical and medical advances, there are now more American adults living with congenital heart defects than the annual number of children being born with them, even though heart defects are the most common birth defect in the U.S.

The researchers enrolled 134 patients with congenital heart defects and used two validated mental health scales with questions related to anxiety, depression and PTSD. Of 134 patients who completed one scale, 27 (21 percent) met criteria for global PTSD symptoms. Of the 127 patients who completed another scale, 14 patients (11 percent) had PTSD symptoms specifically related to their CHD or treatment.

The high prevalence of PTSD in this patient cohort — 11 to 21 percent — is several times higher than the 3.5 percent rate observed in the general population. The authors noted that the prevalence is comparable to that found in children with CHD and in adults with acquired heart disease.

The researchers also found two factors most strongly linked to PTSD in their patients: elevated depressive symptoms and the patient’s most recent cardiac surgery. Patients who had undergone cardiac surgery at an earlier year were more likely to have PTSD. This finding may reflect recent medical and surgical advances that lessen traumatic impacts, or alternatively, a “residual stress” explanation — that traumatic stress produces chronic, lasting effects.

The study team also noted that non-medical traumatic events may have contributed to PTSD in some patients. In addition, said the authors, the self-report measurements used in the study may not be as accurate as a clinical interview.

Overall, the new study may reveal important unmet needs in a growing population of patients. “The high prevalence of PTSD detected in these adult CHD patients has important clinical implications,” said corresponding author Lisa X. Deng, of CHOP’s Division of Cardiology. She noted that less than half of the study patients who showed PTSD symptoms were being treated for PTSD, and added that, “We need to conduct more research to identify measures along the lifespan to support our patients and ensure that they have a good quality of life.”

“Good” Protein Actually Promotes Liver Cancer.


  • Scientists at the University of Iowa say they have identified an unexpected molecular link between liver cancer, cellular stress, and these health problems that increase the risk of developing this cancer. Their study (“The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis”) is published in PLOS Genetics. It shows that a protein called CHOP, which had previously been thought to generally protect against cancer, actually promotes liver cancer in mice and may do the same in humans.

    “Good” Protein Actually Promotes Liver Cancer

    “Obesity, alcoholism, and viral hepatitis are all known independently to cause cellular stress and to induce expression of CHOP,” said Thomas Rutkowski, Ph.D., assistant professor of anatomy and cell biology in the UI Carver College of Medicine and senior study author. “So this finding suggests a biological pathway that links those ‘upstream’ health problems to liver cancer at the end.”

    CHOP is a transcription factor that is produced when cells experience certain kinds of stress. It is known to promote cell death. Usually, factors that promote cell death protect against cancer by causing damaged cells to die.

    The study shows that, despite its role in cell death, CHOP actually is elevated in liver tumor cells in mice. Furthermore, mice without CHOP are partially protected from liver cancer, developing fewer and smaller tumors than the normal mice in response to liver cancer-causing drugs. The mice without CHOP also had less liver scarring and inflammation than mice with the protein.

    “We show that CHOP expression is up-regulated in liver tumors in human HCC [hepatocellular carcinoma] and two mouse models thereof. CHOP-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation,” wrote the investigators. “CHOP-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation.”

    “We turned out to be completely wrong about CHOP. We found that it contributes to the development of liver cancer in mice and is associated with liver cancer in humans,” continued Dr. Rutkowski. “CHOP is indeed killing cells, just as we thought it would, but we think the consequence of this killing is not the prevention of tumors, but instead the stimulation of inflammatory signals in the liver that cause excessive proliferation of other cells.”

    Having implicated CHOP as a contributing factor in liver cancers associated with obesity, alcoholism, and hepatitis, Dr. Rutkowski next wants to learn whether CHOP acts early in the process of tumor formation or if it plays a role in helping established tumors to grow. He also is interested in identifying the other proteins that partner with CHOP to promote liver cancer.

    “This discovery opens up an avenue into a new pathway that promotes liver cancer,” explained Dr. Rutkowski. “Once we know what those other genes are that interact with CHOP, then maybe we can find a druggable target molecule. The hope is that down the line scientists will be able to convert that finding into something therapeutically useful for patients.”

Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.


Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.
METHODS: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.
FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved >/=3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).
INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.

Source: Lancet.

Radioimmunotherapy Consolidation for Mantle Cell Lymphoma.


A high response rate was achieved with limited cycles of R-CHOP followed by a single dose of 90Yibritumomab tiuxetan.

High overall and complete response rates can be achieved with six to eight cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with mantle cell lymphoma (MCL), but median response duration is only 18 to 24 months.

Given the high activity of radioimmunotherapy (RIT) in patients with relapsed MCL (J Clin Oncol 2009; 27:5213), investigators conducted a multicenter phase II trial to test the efficacy and safety of four cycles of R-CHOP plus yttrium-90 (90Y)–ibritumomab tiuxetan RIT consolidation in patients with previously untreated MCL.

Of 56 treatment-naive adults (median age, 60; 73% men; 91% with stage III–IV disease; 48% with extranodal involvement), 52 received four cycles of R-CHOP followed by a single dose of standard 90Y-RIT. The overall response rate was 82%, and response improved to complete or partial remission in 22 patients after 90Y-RIT. At a median follow-up of 72 months, the median time to treatment failure was 34.2 months; median overall survival (OS) had not been reached. The estimated 5-year OS rate trended higher for patients aged 65 versus those >65 (79% vs. 62%; P=0.08). Toxicities were as expected with R-CHOP and were primarily transient neutropenia and thrombocytopenia for 90Y-RIT.

Comment: Given the typically short duration of progression-free survival after immunochemotherapy in MCL patients, postinduction strategies are under study to improve outcomes. In younger patients, high-dose chemotherapy and autologous stem-cell transplantation are often utilized, whereas older or infirm patients might benefit from maintenance rituximab (JW Oncol Hematol Aug 21 2012). The present study confirms 90Y-RIT as an active agent that increases response rate and duration following abbreviated induction cycles, although without an established survival benefit as yet. Confirmatory studies will be important, as will optimizing patient selection for 90Y-RIT versus alternative postinduction regimens.

Source: Journal Watch Oncology and Hematology

Abdominal Pain and Altered Mental Status.


In the latest Case Record of the Massachusetts General Hospital, a 38-year-old man had weakness, abdominal pain, and confusion; he also had anemia, thrombocytopenia, hypercalcemia, circulating abnormal T cells, generalized lymphadenopathy, and hepatosplenomegaly. A diagnostic procedure was performed.

ATLL is geographically clustered, with prevalence in the Caribbean, southern Japan, western Africa, and parts of South America, Iran, and Central Asia, mirroring areas where infection with HTLV-I is endemic.

Clinical Pearls

What is the relationship between HTLV-I and ATLL and how is HTLV-I transmitted?

HTLV-I is a member of the deltaretrovirus family and was isolated in the early 1980s from a patient with ATLL; all malignant T cells contain integrated HTLV-I provirus. Although as many as 20 million people worldwide are infected with HTLV-I, ATLL ultimately develops in only a small minority (approximately 4% or 5%). Transmission of HTLV-I is thought to occur predominantly through breast-feeding, although the virus can also be transmitted by blood transfusion, sexual intercourse, and the sharing of hypodermic needles. There is typically a long latency period from initial infection to the onset of disease, and the majority of patients in whom ATLL develops are older than 40 years of age.

What is the clinical presentation of ATLL?

As the name of the disease implies, patients can present with peripheral-blood involvement (leukemia), lymphadenopathy without circulating tumor cells (lymphoma), or both. There are four variants of ATLL. The acute variant accounts for approximately 60% of cases, and is characterized by circulating malignant cells, lymphocytosis, tumor lysis syndrome, hypercalcemia, hepatosplenomegaly and lymphadenopathy. The chronic variant accounts for approximately 15% of cases, the lymphomatous variant approximately 20% of cases, and the smoldering variant approximately 5% of cases.

Q: What is the pathophysiology of hypercalcemia in ATLL?

A: The pathophysiology of hypercalcemia in patients with ATLL has been linked, in part, to increased osteoclast activity. The neoplastic cells express soluble factors linked to osteoclastic differentiation and bone loss, including parathyroid hormone-related protein, the level of which was mildly elevated in this patient. ATLL cells may have surface expression of the receptor activator of nuclear factor-(kappa)B ligand (known as RANKL) and may secrete the chemokine macrophage inflammatory protein 1(alpha), both of which induce osteoclast differentiation, suggesting that direct interactions between hematopoietic progenitors and malignant T cells in the bone marrow may play a role in this process.

Q: What is the treatment for acute ATLL?

A: The traditional treatment for acute ATLL is multiagent cytotoxic chemotherapy, typically with a regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). A Japanese trial showed that another regimen, referred to as VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, and prednisone; doxorubicin, ranimustine, and prednisone; and vindesine, etoposide, carboplatin, and prednisone), produced higher rates of complete remission than did CHOP but no significant improvement in overall survival. An alternative frontline approach, the combination of the antiviral agent zidovudine and interferon, has been explored; recent data has suggested that this regimen leads to longer overall survival than do traditional regimens, but the majority of patients did not achieve a complete remission. Since ATLL is a virally driven hematologic malignant condition, it is an ideal target for the therapeutic mechanisms of allogeneic hematopoietic stem-cell transplantation in selected patients.

Source: NEJM

Enhancement of photodynamic therapy by 2,5-dimethyl celecoxib, a non-cyclooxygenase-2 inhibitor analog of celecoxib


Photodynamic therapy (PDT) effectiveness can be improved by employing combined modality approaches involving pharmaceuticals targeting the tumor microenvironment and/or tumor cell death pathways. In one approach, combining PDT with celecoxib improves long-term tumoricidal activity without increasing normal tissue photosensitization. However, side effects arising from the use of coxib based cyclooxygenase-2 (COX-2) inhibitors, including cardiovascular injury, decreases the clinical applications of this class of compounds. A growing number of studies demonstrate that the tumoricidal actions of coxibs such as celecoxib involve non-COX-2 mediated mechanisms. The celecoxib analog, 2,5-dimethyl celecoxib (DMC), lacks COX-2 inhibitory activity but exhibits cytotoxic properties comparable to the COX-2 inhibitor celecoxib. We compared the effectiveness of DMC and celecoxib in modulating PDT response at both the in vitro and in vivo level using a C3H/BA murine mammary carcinoma model. Both DMC and celecoxib blocked PDT induced expression of the pro-survival protein survivin, enhanced the endoplasmic reticulum stress (ERS) response of PDT, and increased both apoptosis and cytotoxicity in BA cells exposed to combination protocols. DMC enhanced the in vivo tumoricidal responsiveness of PDT without altering PGE2 levels. Our data demonstrates that DMC improved PDT by increasing apoptosis and tumoricidal activity without modulating COX-2 catalytic activity. Our results also suggest that celecoxib mediated enhancement of PDT may involve both COX-2 dependent and independent mechanisms.

Enhancement of photodynamic therapy by 2,5-dimethyl celecoxib, a non-cyclooxygenase-2 inhibitor analog of celecoxib


Photodynamic therapy (PDT) effectiveness can be improved by employing combined modality approaches involving pharmaceuticals targeting the tumor microenvironment and/or tumor cell death pathways. In one approach, combining PDT with celecoxib improves long-term tumoricidal activity without increasing normal tissue photosensitization. However, side effects arising from the use of coxib based cyclooxygenase-2 (COX-2) inhibitors, including cardiovascular injury, decreases the clinical applications of this class of compounds. A growing number of studies demonstrate that the tumoricidal actions of coxibs such as celecoxib involve non-COX-2 mediated mechanisms. The celecoxib analog, 2,5-dimethyl celecoxib (DMC), lacks COX-2 inhibitory activity but exhibits cytotoxic properties comparable to the COX-2 inhibitor celecoxib. We compared the effectiveness of DMC and celecoxib in modulating PDT response at both the in vitro and in vivo level using a C3H/BA murine mammary carcinoma model. Both DMC and celecoxib blocked PDT induced expression of the pro-survival protein survivin, enhanced the endoplasmic reticulum stress (ERS) response of PDT, and increased both apoptosis and cytotoxicity in BA cells exposed to combination protocols. DMC enhanced the in vivo tumoricidal responsiveness of PDT without altering PGE2 levels. Our data demonstrates that DMC improved PDT by increasing apoptosis and tumoricidal activity without modulating COX-2 catalytic activity. Our results also suggest that celecoxib mediated enhancement of PDT may involve both COX-2 dependent and independent mechanisms.

source: cancer letter