My Nivo (Opdivo) trial - first dose - 4 years ago 12/29/2010 - thoughts...

 How very strange it is to look back!!!  4 years.  It seems like yesterday.  It seems like ages ago.  Anti-PD1 was an unknown.  Only a handful of patients had taken it in a couple of studies.  Neither ipi (yervoy) nor the BRAF inhibitors were FDA approved.  The Merck product, Keytruda, did not exist.  I am surprised to be here.  I can hardly believe I, and my fellow ratties, managed the every other week routine for 6 months:  Work 12 hours shifts Mon, Tue, Wed.  Drive to Atlanta on Thurs.  Fly to Tampa.  Get rental car and dinner.  Rest up at the good ol' La Quinta.  Friday am - Hop over to Moffitt at the butt crack of dawn for labs, office visit, injections, infusion.  Drive like mad back to the air port.  Fly to Atlanta.  Drive the two hours back to Chattanooga.  Back to work on Monday.  I've since discovered that many in my trial did not work during their treatment.  Though, some did and many continue their busy lives today while taking Keytruda as well as ipi combined with nivo!  For the remaining two years, Tampa visits and infusions were just every 12 weeks.  It seemed like a holiday!  I missed three work days over those 2 1/2 years.  There are those who said I was nuts and would have demonstrated better judgment by taking off more...but that's not how I roll.  And I was so lucky.  Lucky to be in the trial.  Lucky to be able to AFFORD to be in the trial.  Lucky to be NED going into it.  Lucky to have the support system I had while dealing with it.  Lucky for my battalion who marches with me...still.

It is hard to say what I thought would happen.  I really didn't expect much.  I certainly didn't look upon Nivo as my "cure" as so many seem to today on various boards, chat groups and forums.  Don't get me wrong.  I was thankful for the option.  Brain mets, lung mets, tonsilar mets, another brain met in rapid succession had made me well aware that something was desperately needed to break that cycle.  My only options were IL2 or interferon, since after every met, surgery rendered me NED....a boon and a reason to be refused from every other trial!  I still don't know what my future holds.  But, neither does anyone else.  I just worry about those who seem so certain that the anti-PD1 drugs will be their personal deliverance when the 30-40% response rate tells us that there are a large number of us who will be disappointed.

Having spent a lifetime reading research reports, case studies... it is surreal to read one that you know refers to your own experience.  It seems cold.  A little wrong somehow. "33 patients were enrolled.  10/33 patients relapsed. Of the 10 relapsed patients, five died due to metastatic melanoma; three were rendered free of disease surgically and remain disease-free at 2, 27 and 54 weeks after relapse.  One patient had spontaneous regression...and has been free of disease for over 3 years.  One additional relapsed patient is alive and on active therapy with dabrafenib plus trametinib."

My thoughts about the report and results:

SIDE EFFECTS:
"Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrated immunologic activity with promising survival in high-risk resected melanoma..."  Well tolerated?  Hmmm....  As compared to what?  A relaxing day of hikes along mountain trails, followed by a warm shower, good book by a cozy fire and delicious dinner?  Arsenic?  Dick Cheney's idea of simple Q & A?  There is no doubt that many have endured far more difficult treatments.  Still vaccine injection site reaction, fatigue, rash, itching, nausea, diarrhea and arthralgias were common.  Hypokalemia (low potassium...something that can be life threatening), enteritis, colitis, hypophysitis, and thyroiditis were certainly no fun for some of my fellow ratties.  There was one patient with grade 1 pneumonititis. Wonder who that was?  Maybe me, maybe not.  It is very strange to have those who do not have melanoma, have never been given those miserable vaccines or taken anti-PD1 even once, determine the quality of another's experience.

BRAIN METS:
"Ten patients had resected brain metastases."  Well...that's not entirely accurate.  Mine was not "resected" it was zapped via stereotactic radiation.  Not certain about anyone else.   Only 2 of these ten patients have relapsed.  One developed a lung met which was resected and she remains NED.  The other apparently had significant CNS disease at induction, though researchers were unaware at the time, "and expired 3 weeks from initiation."  Despite such a loss, this is a pretty remarkable outcome for folks post melanoma brain mets, given our shelf-life of just 6 months or so without treatment.

RADIATION:
"Radiation therapy was administered to 18 patients prior to or after surgery including nine with resected brain metastases." The study doesn't speculate and all I can do is that...but with more and more research looking at retrospective data and new studies specifically examining radiation combined with ipi, anti-PD1 and the BRAF inhibitors...I have to believe that this combo is working positively for those zapped ratties in my trial.  (Much more to come on this topic in 2015!!)

PD-L1
There have been hopes that testing tumors for various biomarkers would tell docs which patients would respond to which drug.  PD-L1 was one of those. 28 of us had our tumors tested.  I still don't know what mine showed.  But, in our study, "there was no significant association between PD-L1 and relapse free survival in this patient population, although there is a non-statistically significant trend towards better RFS in those whose tumors were PD-L1 positive..."  For whatever that is worth.  I suspect the test for PD-L1 is not quite good enough just yet and there is more to be learned on this subject.

MDSC  (myeloid derived suppressor cells)
"There was a trend towards lower baseline MDSC levels in non-relapsing patients compared to relapsing patients."  This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients.

RELAPSE FREE SURVIVAL:
"A retrospective study....showed a median overall survival of 12 months in stage IV melanoma patients undergoing metastasectomy."  Yet, my ratties and I have demonstrated an "impressive relapse-free survival...of 47.1 months and a median overall survival not yet reached with over 32 months of follow-up."  For me, I am now: 
136 months post melanoma diagnosis
56 months post Stage IV melanoma
50 months NED
48 months post start of nivo/Opdivo trial
18 months post my last infusion

It has been a strange, yet wonderful ride.  Here's to the ratties!  Here's to 2015! Much love - c

Merry Christmas! Today...and 4 years ago...as I began my Nivo (Opdivo) journey...

    Four years ago....  I can hardly believe it.  Believe that I am here.  Believe the support I have received from so many.  It has gone by in a blink!  Looking back:

Saturday, December 25, 2010   Merry Christmas! 

....awakened to 3 or so inches of snow, more falling, and 100's of flights being cancelled in Atlanta. After breakfast the kids are busy clearing the drive, Brent and our dear friend and neighbor, Les, are putting snow chains on the tires of Brent's car and I'm making a pot of soup for the kids in case of loss of power due to the icing that often follows snows up here. Fearing that our flight tomorrow will be cancelled anyway and the roads being worse in the am, Brent starts making plan number 9,010! Turns out Brent's work tonight (from 6p - 1am) gets cancelled since the manager doesn't think that nurses and front desk staff will be able to make it in, simplifying things some. In the end, he just cancels our flights himself, moves them to our next Tampa trip (for a one hundred dollar additional fee!), cancels our rental car, makes a hotel reservation in Macon and we will be on our way this evening. We plan to drive to Macon, spend the night, then on to Tampa tomorrow. Obviously, I am not happy. I felt that all this was too invasive, requiring way too much time, energy, and money in the first place....so this is NOT the way I wanted this to go! So much for what I want I suppose.... Oh, well...enough belly aching. Got to go do the elliptical and get a shower so I can go down the Signal Mountain Slip and Slide!!!

Hope all of you are having Christmases that are much less eventful and psychotic!!! Love to all - c 

Looking forward: 
Today the sky looks as though it may spit a few flakes or clear.  Yesterday B, Roo and I had a cook-a-thon, special surprises from Ruthie, laughs and spills (Yeah, that was me...upsetting the cans of milk B had just opened for me over the cookbook!!!), plans for dinners to come and maybe a book???? or at least long term plans for sharing food and fun.  (Second Saturdays people!  You heard it here first!)  Today we look forward to guests with whom to talk and play and share.  This Christmas may not be less eventful or psychotic...but it is certainly less frightening and traumatic.  Whatever yours may be....I wish at least some moments of peace, a few dreams for the future, and a day in which you KNOW...that you are loved.  Much love from me to all of you! - c

C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!

Wow!  When it rains it pours!!!  Nivoumab, now called Opdivo, was FDA approved today!  Unfortunately, with the same prerequisites (ipi/Yervoy and BRAFi, if BRAF positive, must be failed first) that Keytruda (Merck's Pembrolizumab/anti-PD1 product) has. Not what I was hoping for.  As far as the publication of my trial data.... No real surprises here....with the help of Ruthie and Bentie (for their good ears and memory during rapid fire, free floating discussions at my appointments and YEARS of tremendous support!!!) and all the other 32 ratties who signed up and put their lives on the line...I have been able to pretty accurately document our struggles and successes.  But...it is nice to see it in print somewhere other than my own ramblings.  Here is my synopsis of the article:

Safety, correlative markers and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.  Gibney, Kudchadkar, DeConti, Tetteh, Weber, et al.  clincancerres.aacrjournals.org December 20, 2014.

Nivo (at 1mg/kg in cohort 1, at 3mg/kg in cohort 2, or 10mg/kg in cohort 3...all IV) along with a multi-peptide vaccine was to be given every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses were given to 33 HLA-A *0201 positive melanoma patients {due to the vaccine} with completely surgically resected disease.  Two patients had stage IIIC disease and 31 had stage IV melanoma.  Prior systemic therapy (if given prior to surgery) and radiation were allowed except for anti-PD-1, anti-PD-L1/PD-L2, or anti-CTLA-4 agents.  Imaging studies (CT scan of the neck, chest, abd, and pelvis and MRI or CT of the brain) were performed at baseline and every 12 weeks during the trial, then every 6 months for 3 years.  Ten patients per cohort were selected based on sufficient samples for immune assessments.  Patients were replaced if not evaluable for safety and leukapheresis collection after the first induction phase. Patients were followed until relapse and/or death.  Correlative studies were performed on leukapheresis blood samples collected at baseline, week 12 and week 24.  Cells collected were assessed for...anti-CD3, CD8, CD25, CTLA-4 and PD-1 antibodies. Tregs and Myeloid-derived supproessor cells (MDSCs) were also assessed.  Tumors were tested for PD-L1 positivity.

Background:  Within the tumor microenvironment, the function of T-cells is thought to be impaired due in part to engagement of the programmed death 1 (PD-1) receptor found on T-cells with its ligand, programmed death receptor ligand (PD-L1), which is expressed by antigen presenting cells such as dendritic cells and macrophages as well as tumor and other cells.  Tumor cells can "hijack" this pathway by ectopically expressing PD-L1 on their surface, which often is associated with a poor outcome.  This interaction within the tumor microenvironment inhibits immune cell function leading to T-cell "exhaustion," thereby inhibiting T-cell function and promoting tumor growth.  A promising immunotherapy strategy being evaluated in multiple cancer centers is inhibition of this interaction between PD-1 and PD-L1 by the use of blocking antibodies, thereby overcoming a critical immune checkpoint to facilitate tumor cell destruction. 

Recent results from clinical trials of PD-1 and PD-L1 abrogating antibodies suggest that they can induce significant rates of tumor regression in melanoma, as well as renal cell, non-small cell lung and bladder cancer.  Objective response rated in ipi-naive and ipi-refractory metastatic melanoma patients treated with anti-PD-1 agents (nivo and pembro) range from 25-43%....

Adjuvant therapy for resected high-risk melanoma continues to be an area in need of more effective strategies.  Patients with resected stage IV melanoma have no FDA-approved adjuvant therapy option.  Median relapse free survival (RFS) has been reported to be as short as 5 months with overall survival (OS) ranging from 12 to 36 months.  Similarly, subset analysis of resected stage IV patients [in a] study comparing GM-CSF vs placebo demonstrated a median disease-free survival of 12 months and 6 months, respectively. ... Due to the high relapse rate (more than 80%), long-term survival of less than 30% and the need for evaluation of new adjuvant treatments for these resected melanoma populations we [engaged in this study].

Patients:  33 patients. 12 in cohort 1 {I was one of these}, 10 in cohort 2, and 11 in cohort 3.  Median age = 47.  2 patients had ocular melanoma and 2 had mucosal primaries.  10 had resected brain metastases. Radiation therapy was administered to 18 patients prior to or after surgery including 9 with resected brain mets.  16  received one or more systemic therapies prior to surgery and the study.  Chemo/biochem (6), adjuvant interferon (6), vaccine (3) and high-dose IL-2 (2).  All underwent surgery to be rendered free of disease (NED).

Dosing:  12 of 33 have received all 20 treatments of nivo and vaccines (36%).  Two additional patients completed the full course but skipped 1-2 doses due to transient grade 2 toxicities.  Of 13 who prematurely discontinued therapy, 8 were due to relapse and 5 were due to toxicity and/or withdrawal.  Two patients relapsed after finishing all planned therapy.

Toxicities:  481 grade 1-5 adverse events were reported with 286 attributed to treatment.  AE distribution was similar across cohorts (#1 = 81, #2 = 104, and #3 = 101).  Most common AE's were vaccine injection site reaction (discomfort, granuloma, and/or reactive lymphadenopathy - 94% of patients), fatigue (82%), rash (55%), pruritis (42%), nausea (42%), arthralgias (42%), diarrhea (36%), headache (36%). 5 drug related grade 3-5 AE's were noted:  hypokalemia (1 in cohort 2), rash (1 in cohort 1), enteritis (1 in cohort 3), and colitis (2 in cohorts 2 and 3).  The colitis patients responded to high-dose steroids and supportive care. The patient with the grade 3 rash was re-challenged with the study drug after recovery; there was no recurrence of serious rash. Other immune-related events = grade 2 hypophysitis (2) leading to adrenal insufficiency in both patients, grade 2 thyroiditis (7) leading to primary hypothyroidism, and grade 1 pneumonitis (1) without clinical sequelae.  Adrenal insufficiency and hypothyroidism were successfully managed with hormone replacement.

Results:  Median f/u from enrollment = 32.1 months.  Of 33 patients, 10 (30%) have had a relapse event.  6 patients relapsed during weeks 1-12, 1 during weeks 12-24, 1 during weeks 24-120, and 2 after completing all treatment (more than 2.3 years).  All other patients remain disease free, and 14 (42%) have finished all treatment.  Estimated relapse free survival was 47.1 months. Median overall survival has not yet been reached.  The estimated 12 and 24 month survival rates are 87% and 82% respectively. Of the 10 relapsed patients, 5 died due to metastatic disease, 3 were rendered free of disease surgically and remain disease-free at 2, 27, and 54 weeks after relapse.  One patient had spontaneous regression of disease after a biopsy-proven relapse and has been free of disease for over 3 years.  One additional relapsed patient is alive and on active therapy with dabrafenib plus trametinib.

Brain metastasis subgroup:  10 patients with resected CNS disease were enrolled.  3 in cohort 1, 2 in cohort 2, and 6 in cohort 3.  Only 2 of these 10 patients have relapsed after median follow up time of 22.5 months, both were in cohort 1.  The first patient completed all doses of study drugs and developed a new solitary lung met that was resected after 47 months on protocol; she again has no clinical evidence of disease.  The second was diagnosed with recurrent CNS disease after her first treatment with study drugs and expired 3 weeks from start of protocol from CNS hemorrhage.

Post relapse spontaneous regression {THAT GUY!!!}:  Cases of regression of melanoma after RECIST progression have been well documented for ipi and anti-PD1 antibodies, and have led to new criteria for anti-tumor response called immune related response criteria.  This may complicate evaluation of patients on adjuvant trial[s]... Patient noted in 'results' = with resected chest wall and pulmonary disease initiated treatment in the 3mg/kg cohort.  At week 12, CT scans showed new chest wall disease and a splenic nodule of 2.7cm, biopsy proven with fine needle aspirate to be melanoma.  While waiting to initiate treatment for metastatic disease, a repeat CT scan 4 weeks later showed shrinkage of both lesions.  Over the  next 24 weeks, repeat CT scabs showed further regression and eventual disappearance of both lesions, he remains free of disease 38.8 months since relapse.

Correlative Studies:  The identification of potential biomarkers to predict relapse was explored.  There were (in all cohorts together) a trend towards lower baseline CD25+Treg/CD4+ T-cell and MDSC levels in non relapsing patients compared to relapsing patients. Baseline PD-L1 tumor expression was assessed on archived tumor specimens from 28 of the 33 enrolled patients.  Using a 1% PD-L1 cutoff, 18 samples were positive and 10 were negative.  Relapse occurred in 5/18 (28%) PD-L1 positive patients and 4/10 (40%) PD-L1 negative patients.  At a threshold of 5% PD-L1 staining, 12 samples were positive and 16 were negative.  Relapse occurred in 3/12 (25%) PD-L1 positive patients and 6/16 (38%) negative patients. ....there was no statistically significant association between PD-L1 tumor staining and relapse free survival in this population, although there is a non-statistically significant trend towards better relapse free survival in those whose tumors were PD-L1 positive using either threshold...

Discussion:  Nivo and vaccine were well tolerated with only 4 of 33 patients discontinuing due to drug toxicities, and only 2 dose limiting toxicities (colitis) observed.  Grade 3 events occurred in 4 of 33 patients (12%) and were manageable.  Adverse events with adjuvant high-dose or pegylated interferon [show] 40-60% of patients experienced grade 3 events, 5-10% experience a grade 4 event, and as many as 31%...discontinued therapy due to toxicities.  Rate of grade 3 events for ipi at 10mg/kg for resected stage III melanoma patients [was reported as] 36.5% and 5.5% of patients experienced grade 4 AE's.
                    High dose and pegylated interferon have both been approved by the FDA as adjuvant therapy for resected stage III melanoma patients....but studies have failed to show a statistically significant improvement in overall survival [with these treatments].  Studies looking at bevacizumab (AVAST-M) and GM-CSF have each demonstrated improvement in disease free survival over placebo, but no statistical improvements in overall survival were seen.  Adjuvant ipi for resected melanoma is currently under investigation in two large randomized phase III trials.  Recent preliminary data presented in resected stage III patients demonstrated a median relapse free survival of 26.1 months with ipi compared to 17.1 months in the placebo group.
                    Our data suggest that nivo is clinically active in resected stage IIIC/IV melanoma, based on low rate of relapse (10 of 33), impressive relapse-free survival - estimated RFS of 47.1 months, and median overall survival not yet reached with over 32 months of follow up.  Median RFS for Canvaxin-IV trials was 7.2 months with median OS of 32 months.  Median OS for patients with metastasectomy {surgical removal of mets alone} has been found to be 12 months.  Overall, ...data suggests that a median RFS over 12 months would be a reasonable benchmark by which to judge the potential of an adjuvant treatment for stage IIIC/IV high risk resected melanoma.  By that criterion, our data with adjuvant anti-PD1 therapy surpasses RFS expectations and longer follow up will clarify whether superior median OS can be achieved.  Furthermore, the low event rate in resected brain metastases patients suggests a potential benefit in this very high risk population.
                    Enthusiasm for the use of PD-L1 as a predictive biomarker has diminished as other studies have shown that patients with PD-L1 negative melanomas can still respond to anti-PD-1, albeit at lower rates.  In our study, there were slightly fewer relapses in patients with PD-L1 positive tumors, but this was not statistically significant.  Other correlative studies showed that non-relapsing patients tended to have lower baseline levels of CD25+Treg/CD4+ and MDSC populations. This is supported by other data indicating the suppressive role of these immune cell populations, which may mitigate the effect of cytotoxic T-cells (and other immune cells) expected with anti-PD-1/PL-L1 therapy, resulting in dampened anti-tumor activity.

Wow. Very weird to read a scientific journal article that is talking about ME and my fellow ratties.... Lots to think about.  My thoughts will follow.  best - c

Survival graphs for my adjuvant resected Nivo trial

Pretty interesting, huh?  I think the line dropping down in the relapse graph on top is just a ditzle on the copy from printing, but not absolutely sure.  Hang on to your hats, ratties!! - c

SRS combined with anti-PD1 makes things better in ratties....this one's for you Artie!!!!

Stereotactic Radiation Therapy Augments Antigen-Specific PD-1 Mediated anti-Tumor 
Immune Responses via Cross-Presentation of Tumor Antigen.  Cancer Immunol Res.  Sharabi, Mirschl, Kochel, et al.  2014 Dec19.

"The immune modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. ....we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy.  [In] small animal radiation research...image guided sterotactic radiotherapy to...melanoma or...breast [cancer] tumors resulted in development of antigen-specific T-cell and B-cell mediated immune responses.  These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 or regulatory T cell (Treg) depletion, resulting in improved local tumor control.  ...radiotherapy increased the percentage of antigen-experienced T-cells and effector memory T-cells.  ...radiotherapy up-regulates tumor associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors.  These findings demonstrate the ability of radiotherapy to prime an endogenous antigen-specific immune response and provide additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic."

Prior post with two articles noting synergistic benefit when radiation was combined with ipi: http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/01/ipi-and-radiationa-good-combo-for.html

Individual patients, like dear Artie, seem to be experiencing this sort of effect when given radiation for pain control and other reasons, when already on or in rapid succession with immune therapy.  Way to go, ratties....the big and little ones!  Best wishes, Artie!  You rock!   - c

With immunotherapy tumors can grow or reappear...even though it is working. Will DNA analysis clarify response???

Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade.  Lipson, Velculescu, Pritchard, et al.  J Immunotherapy Cancer. 2014 December 16.

Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation.  We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.

Tumors from 12 patients with metastatic melanoma undergoing treatments with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT.  Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes.  In 5 of 10 patients studied, mutations were detected in BRAF (1), NRAS (2), TERT (1) and ALK (1).  Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens.  Plasma ctDNA levels ranged from undetectable to 5.5% of total circulating cell-free DNA.  In 3 patients, increasing ctDNA levels correlated with progressive disease assessed by radiography.  In one patient, ctDNA levels increased after undergoing a needle biopsy of a tumor deposit.  In another patient, ctDNA levels increased initially as lymphadenopathy progressed by examination, but then became undetectable 3 weeks prior to clinical improvement.

Levels of ctDNA correlated with clinical and radiologic outcomes, and, in one case, preceded eventual tumor regression.  Further prospective analysis is required to assess the utility of ctDNA as an early biomarker of clinical outcomes in patients receiving immune checkpoint blocking drugs.

How cool would this be if it works?!!!  Patients and their docs would be able to accurately assess tumor response earlier, allowing patients to proceed to a different therapy sooner rather than later when needed, thus saving time and money....and ultimately, lives!!!

Fingers crossed! - c

Songs that make movies worth watching...and romantic!!!

I've always loved and easily remembered tunes and lyrics. Once when I was a little girl I cried because I couldn't remember the multiplication tables.  However, I insisted that if only they were a song I would have no problem!!! Yes, I hear the Muzak...in the elevator, the grocery store.  But when I comment on the song, folks I'm with often say, "What song?"  Yep, that's me...the sound man's girl.  Whenever and wherever I hear these songs, I can see the scene in the movie...NOT necessarily the scenes shown in the videos below.  Check out all the songs...and maybe some of the movies.  You'll hear how perfectly placed within the story they are. Some of my fav's....

The reason to watch GI Jane

The reason to watch Playing by Heart

Step Mom

Good Morning Vietnam

A Man and A Woman

Love Story

Last of the Mohicans

Pretty Woman

Mrs. Doubtfire

Phenomenon

One more....from Phenomenon

Mr. and Mrs. Smith

Knotting Hill

Bridget Jones's Diary

And if the sound man's smart, here's what she'll be using next......

Joan Osborne....what if God was one of us?

Joan Osborn...Work on Me

Norah Jones...Turn Me On

Norah Jones...I've got to see you again


Sing out loud, sing out long!!!! - c